#anti-apoptotic pathways

[blueoaknx]

Mitochondria Combat Chronic Inflammation

Introduction

Chronic inflammation is a pathophysiological condition linked to numerous diseases, including obesity, diabetes, cardiovascular diseases, and neurodegenerative disorders. Mitochondria, the cellular powerhouses, are pivotal not only for ATP production but also for regulating cellular metabolism, redox balance, and apoptosis. Recent studies reveal that mitochondria play a crucial role in modulating inflammatory responses, and their dysfunction is often implicated in chronic inflammatory states. This article explores the intricate mechanisms by which mitochondria influence chronic inflammation and their potential as therapeutic targets.

Mitochondrial Structure and Function

Mitochondria possess a double-membrane structure that includes:

Outer Membrane: Contains porins that allow the passage of small molecules.

Inner Membrane: Rich in cardiolipin and contains the electron transport chain (ETC) complexes crucial for oxidative phosphorylation.

Matrix: Contains enzymes for the tricarboxylic acid (TCA) cycle, mitochondrial DNA (mtDNA), and ribosomes.

These structural features enable mitochondria to perform several essential functions, including ATP synthesis, calcium buffering, and reactive oxygen species (ROS) regulation.

Mitochondrial Dysfunction and Chronic Inflammation

Mitochondrial dysfunction is characterized by reduced ATP production, increased ROS generation, and impaired metabolic signaling. Key contributors to mitochondrial dysfunction include:

Oxidative Stress: Excessive ROS can damage mitochondrial components, leading to a vicious cycle of increased inflammation.

Aging: Aging is associated with mitochondrial dysfunction, contributing to the onset of chronic inflammatory diseases.

Environmental Toxins: Exposure to pollutants and toxins can induce mitochondrial damage.

Mitochondrial dysfunction is implicated in the activation of pro-inflammatory pathways, including:

NLRP3 Inflammasome Activation: Mitochondrial ROS and mtDNA release can activate the NLRP3 inflammasome, leading to the maturation and secretion of pro-inflammatory cytokines such as IL-1β and IL-18.

NF-κB Pathway: Mitochondrial stress can activate the NF-κB signaling pathway, promoting the expression of pro-inflammatory genes.

Mechanisms by Which Mitochondria Combat Chronic Inflammation

Energy Homeostasis and Immune Cell Function

Mitochondria are essential for the bioenergetic demands of immune cells, particularly during inflammatory responses. Immune cells like macrophages and T-cells switch from oxidative phosphorylation to glycolysis during activation, a process known as the Warburg effect. Mitochondria facilitate this metabolic flexibility by:

Providing substrates for glycolysis and subsequent oxidative phosphorylation.

Regulating ATP levels to support energy-intensive processes, such as cytokine production and phagocytosis.

Regulation of ROS and Redox Signaling

Mitochondria generate ROS as byproducts of the ETC. While excessive ROS can induce oxidative stress, physiological levels of ROS act as signaling molecules that modulate immune responses:

ROS can activate redox-sensitive transcription factors such as Nrf2, promoting the expression of antioxidant genes that mitigate oxidative stress.

Controlled ROS production aids in the differentiation of T-helper cells and enhances the immune response.

Apoptosis and Clearance of Damaged Cells

Mitochondria are central to the intrinsic apoptotic pathway, releasing cytochrome c and other pro-apoptotic factors that initiate caspase cascades. Effective apoptosis is crucial for:

Removing damaged or dysfunctional cells that could perpetuate inflammation.

Promoting an anti-inflammatory environment through the clearance of dead cells and debris, thereby preventing secondary necrosis and the associated inflammatory response.

Mitophagy: Mitochondrial Quality Control

Mitophagy is the selective autophagic degradation of damaged mitochondria, crucial for maintaining mitochondrial quality. Key mechanisms involved in mitophagy include:

PINK1/Parkin Pathway: PINK1 accumulates on damaged mitochondria, recruiting Parkin, which ubiquitinates mitochondrial proteins, signaling for degradation by the autophagy machinery.

Enhanced mitophagy reduces the release of pro-inflammatory factors and maintains cellular homeostasis.

Mitochondrial Biogenesis and Adaptation

Mitochondrial biogenesis is regulated by PGC-1α and other transcription factors. Increasing mitochondrial biogenesis can enhance cellular energy capacity and improve metabolic flexibility, which is particularly beneficial in inflammation. Strategies to promote mitochondrial biogenesis include:

Exercise: Physical activity enhances PGC-1α expression and mitochondrial function.

Nutritional Interventions: Certain bioactive compounds, like resveratrol and curcumin, have been shown to stimulate mitochondrial biogenesis.

Therapeutic Implications

Given their critical role in modulating inflammation, mitochondria represent promising therapeutic targets. Potential strategies include:

Nutraceuticals: Compounds like Coenzyme Q10 and α-lipoic acid may enhance mitochondrial function and reduce oxidative stress.

Exercise Interventions: Regular physical activity can improve mitochondrial health and reduce chronic inflammation.

Mitochondrial-targeted Therapies: Developing drugs that specifically target mitochondrial pathways could provide new treatment avenues for inflammatory diseases.

Conclusion

Mitochondria are integral to the regulation of chronic inflammation through their roles in energy metabolism, ROS management, apoptosis, mitophagy, and biogenesis. Understanding the complex interplay between mitochondrial function and inflammatory processes is essential for developing effective therapeutic strategies. By targeting mitochondrial health, we can potentially mitigate chronic inflammation and its associated diseases, paving the way for innovative approaches to improve public health outcomes. Continued research into mitochondrial biology will undoubtedly reveal further insights into their role in inflammation and disease.

[rnomics]

#cancers, Vol. 16, Pages 423: Mapping the Anti-#cancer Activity of α-Connexin Carboxyl-Terminal (aCT1) Peptide in Resistant HER2+ Breast #cancer

Connexin 43 (Cx43) is a protein encoded by the GJA1 gene and is a component of cell membrane structures called gap junctions, which facilitate intercellular communication. Prior evidence indicates that elevated GJA1 expression in the HER2-positive (HER2+) subtype of breast #cancer is associated with poor prognosis. Prior evidence also suggests that HER2+ breast #cancers that have become refractory to HER2-targeted agents have a loss of Cx43 gap junction intercellular communication (GJIC). In this study, a Cx43-targeted agent called alpha-connexin carboxyl-terminal peptide (aCT1) is examined to determine whether GJIC can be rescued in refractory HER2+ breast #cancer cells. A proposed mechanism of action for aCT1 is binding to the tight junction protein Zonal Occludens-1 (ZO-1). However, the true scope of activity for aCT1 has not been explored. In this study, mass spectrometry proteomic analysis is used to determine the breadth of aCT1-interacting proteins. The NanoString nCounter Breast #cancer 360 panel is also used to examine the effect of aCT1 on #cancer signaling in HER2+ breast #cancer cells. Findings from this study show a dynamic range of binding partners for aCT1, many of which regulate gene expression and #RNA biology. nCounter analysis shows that a number of pathways are significantly impacted by aCT1, including upregulation of apoptotic factors, leading to the prediction and demonstration that aCT1 can boost the cell death effects of cisplatin and lapatinib in HER2+ breast #cancer cells that have become resistant to HER2-targeted agents. https://www.mdpi.com/2072-6694/16/2/423?utm_source=dlvr.it&utm_medium=tumblr

[didanawisgi]

[CAUTION: This article is unusually complex. Life can be like that.]

There is growing interest in the nucleotide NAD+ (nicotinamide adenine dinucleotide) because of recent research revealing it’s regulation of diverse pathways controlling lifespan.1 A paper by Belensky et al2 in the same issue of Cell as a commentary on it1found that a precursor of NAD+ (nicotinamide riboside) extended yeast life span via activation of pathways that respond to increased NAD+, such as those that depend upon the SIR2 gene. Moreover, the beneficial effects of caloric restriction appear to be NAD+ dependent, as well as mediated by the NAD+-dependent SIRT1/Sir2 activity.3,4

The ratio of NAD+/NADH regulate many aspects of metabolism, including DNA repair, stress resistance, and cell death.4

“Changes in NAD+ metabolism have been associated with several pathologies, including neurodegenerative diseases, cancer, cardiovascular disease, and normal ageing.”4 In fact, the authors of paper #4 suggest that, “NAD+ synthesis through the kynurenine pathway [de novo synthesis of NAD+ from tryptophan] and/or salvage pathway [from nicotinamide] is an attractive target for therapeutic intervention in age-associated degenerative disorders.”

NAD+ is also reported to play a critical role as part of cellular respiration during the process of oxidative phosphorylation and ATP production.4 “Therefore, ATP synthesis and redox potential is directly proportional to intracellular NAD+ concentration.”4 The NAD+/NADH ratio is a measure of the metabolic state because of its importance in regulating intracellular redox state.4

Sirtuins are deacetylases that regulate large numbers of genes by removing acetyl groups from DNA. The function of the longevity gene SIRT1 has been shown to depend on the availability of NAD+. “Not surprisingly, the life-enhancing properties of sirtuins go hand in hand with those of NAD+ metabolism, suggesting a causal relationship where SIRT1 translates alterations of NAD+ levels into transcriptional events.”4 Interestingly, the DNA repair enzyme PARP (poly(ADP-ribose) polymerase) uses large amounts of intracellular NAD+ and is thereby in competition with sirtuins for the limited supply of NAD+. Under conditions of excessive expression of PARP, cellular NAD+ can be depleted, killing the cell. “Hyperactivation of PARP1 following DNA strand breaks can rapidly consume intracellular NAD+ pools, resulting in a loss of ability to synthesize ATP, and the cessation of all energy-dependent functions and consequent cell death.”4

The authors of paper #4 note that over-activation of PARP1 has been reported in the brains of Alzheimer’s disease patients, as well as in those with diabetes, MTPT-caused Parkinson’s disease, shock, and other conditions. It has been suggested that PARPs may play a role in aging by promoting NAD+ depletion. One study5 reported that PARP-1 activity in mononuclear blood cells increases with aging in at least thirteen mammalian species. In another study,5A researchers reported that “[o]ur results suggest that oxidative stress induced NAD+ depletion could play a significant role in the aging process, by compromising energy production, DNA repair and genomic surveillance.” The latter study5A examined the effect of aging on intracellular NAD+ metabolism in the whole heart, lung, liver and kidney of female Wistar rats, reporting that “[o]ur results are the first to show a significant decline in intracellular NAD+ levels and NAD/NADH ratio in all organs by middle age (i.e., 12 months) compared to young (i.e., 3 month old) rats … The strong positive correlation observed between DNA damage associated NAD+ depletion and Sirt1 activity suggests that adequate NAD+ concentrations may be an important longevity assurance factor.”

The authors of one paper5B write that “… when cells are subjected to oxidative stress by exposure to H2O2 [hydrogen peroxide], PARP-1 is activated and SIRT1 activity is robustly reduced, as PARP-1 activation limits NAD+ bioavailability. Treatment with PARP inhibitors in these circumstances allows the cell to maintain NAD+ levels and SIRT1 activity. … these observations indication that PARP-1 is a gatekeeper for SIRT1 activity by limiting NAD+ availability.”

The authors of paper #4 report that “[p]revious work from our group has shown for the first time that resveratrol induces a dose-dependent increase in activity of the NAD+ synthetic enzyme nicotinamide mononucleotide adenyl transferase (NMNAT1)” but that this is unpublished data.

Interestingly, a very recent paper found that “enhancement of the NAD+/NADH balance through treatment with NAD+ precursors inhibited metastasis in xenograft models [of breast cancer], increased animal survival, and strongly interfered with oncogene-driven breast cancer progression in the MMTV-PyMT mouse model.”6

Mitochondrial Biogenesis Induced by SirT1 Depends on Availability of NAD+

A very recent paper,6A in explaining how exercise or SirT1 activates PGC-1alpha, a master regulator of mitochondrial biogenesis, points out that the activity of SirT1 relies on NAD+ as a necessary coenzyme. The paper6A goes on to describe how, in its study of exercise in mice, chronic contractile activity (exercise) has a robust effect on mitochondrial biogenesis and that resveratrol acted synergistically with exercise to increase mitochondrial content when SirT1 was activated. “[T]he maximal effect of RSV [resveratrol] requires both SirT1 and a condition of energy demand in muscle that would be high in NAD+ and AMP, cofactors which activate SirT1 and AMPK, respectively.” 6A

Precursors That Can Be Taken As Supplements to Increase NAD+

There is (so far) remarkably little information on ways to increase NAD+ with natural products that are commercially available. There are three main physiological precursors: tryptophan, niacin, and niacinamide. It is reported that, “the administration of radiolabeled nicotinamide and nicotinic acid [niacin] has clearly shown that nicotinamide is a better precursor of NAD+ and that nicotinic acid is rapidly cleared by being converted to nicotinamide and excreted as nicotinuric acid.”6B Resveratrol was reported in paper #4 (but only as unpublished data) to dose-dependently increase the activity of the NAD+ synthetic enzyme nicotinamide mononucleotide adenyl transferase. In another paper,7 quercetin was reported to oxidize NADH to NAD+ in rat liver, thus increasing the availability of NAD+. However, as the researchers also explain, “direct measurements of NADH/NAD+ are very difficult to perform.”7 This was as of the paper’s publication in 2005. The researchers inferred the NADH/NAD+ ratio from the ratio of beta-hydroxybutyrate to acetoacetate. Quercetin has also been reported to be a PARP-1 inhibitor.7B Niacinamide is known to be an inhibitor of PARP, thus may prevent the decrease in NAD+ that results from PARP activity. There is a salvage pathway of specific enzymes that converts niacinamide to NAD+.

Niacinamide (NAM) As a PARP Inhibitor May Explain NAM’s Antiviral Effects

Interestingly, PARP is reported to be critical for the integration of foreign DNA, as absence of the PARP enzyme interrupts the HIV life cycle.7C An early study published in 1996 on the effects of niacin reported that a daily niacin (combining niacin and niacinamide) intake in AIDS patients that equaled only 3–4 times the U.S. recommended daily allowance (at that time) of 20 mg/day experienced slower progression and improved survival.7D That was, of course, well before the current multidrug cocktails were developed that enable HIV infected individuals to survive 20 years or more, but still demonstrates the anti-viral effects of the vitamin.

Other natural PARP inhibitors include the flavonoids fisetin and tricetin8 and flavone.9

More About PARP Inhibitors

Keep in mind that PARP is an important enzyme for DNA repair and transcription. Hence, PARP inhibition has to be limited so as to avoid excessive impairment of DNA repair. “Impaired SIRT1 activity due to PARP mediated NAD+ depletion allows increased activity of several apoptotic effectors such as p53, therefore sensitizing cells to apoptosis. Adequate NAD+ levels are therefore critical to maintaining Sirt1 activity which can delay apoptosis and provide vulnerable cells with additional time to repair even after repeated exposure to oxidative stress.”5A

PARP inhibitors are now being incorporated into therapy for diseases such as cancer and diabetes.10–12 This cripples the DNA repair ability of cancer cells, which generally have deficient DNA repair to start with, further limiting their ability to repair DNA and making the cancer cells more vulnerable to apoptosis. In diabetes, moderate PARP inhibition can help maintain cellular NAD+ availability for ATP synthesis. In fact, as mentioned above, overactivation of PARP1 has been reported in diabetes, Alzheimer’s disease, traumatic brain injury, shock, and other conditions.4 A recent paper5C reported that PARP is hyperactivated by oxidative stress induced by beta amyloid; this PARP overactivation (and depletion of NAD+) could be an important source of cell death in Alzheimer’s disease.

Another recent paper “provided quantitative evidence in support of the hypothesis that hyperactivation of PARP due to an accumulation of oxidative damage to DNA during aging may be responsible for increased NAD+ catabolism in human tissue. The resulting NAD+ depletion may play a major role in the aging process by limiting energy production, DNA repair and genomic signaling.”13 In this paper, the authors note that other investigators have linked PARP1 hyperactivity to diseases such as diabetes, MPTP-induced Parkinson’s disease and injury induced brain disorders. They further reported for the first time, in this study,13 that PARP activity increases with age in human skin, correlating with both age and NAD+ depletion (in males, but not in females). Consistent with the regulation of SIRT1 activity by NAD+ availability, they found a significant decline in SIRT1 activity with age in post-pubescent males but, again, not in females. The authors suggest that one possibility is that females have a greater capacity to recycle NAD+ from the PARP metabolite nicotinamide; however this remains to be determined.

References

1. Denu. Vitamins and aging: pathways to NAD+ synthesis. Cell. 1293):453-4 (May 4, 2007). 2. Belenky et al. Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell. 129:473-84 (2007). 3. Wolf. Calorie restriction increases life span: a molecular mechanism. Nutr Rev. 64(2):89-92 (2006). 4. Massudi et al. NAD+ metabolism and oxidative stress: the golden nucleotide on a crown of thorns. Redox Rep. 17(1):28-47 (2012). 5. Grube and Burkle. Poly(ADP-ribose) polynerase activity in mononuclear cell lines of 13 mammalian species correlates with species specific lifespan. Proc Natl Acad Sci USA. 89:11759-63 (1992). 5A. Braidy et al. Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in Wistar rats. PLoS One. 6(4):e19194 (Apr. 2011). 5B. Canto and Auwerx. Interference between PARPs and SIRT1: a novel approach to healthy ageing? Aging. 3(5):543-7 (2011). 5C. Abeti and Duchen. Activation of PARP by oxidative stress induced by beta amyloid: implications for Alzheimer’s disease. Neurochem Res. 37:2589-96 (2012). 6. Santidrian et al. Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest. 123(3):1068-81 (2013). 6A. Menzies et al. Sirtuin 1-mediated effects of exercise and resveratrol on mitochondrial biogenesis. J Biol Chem. 288(10):6968-79 (2013). 6B. Imai. The NAD world: a new systemic regulatory network for metabolism and aging — Sirt1, systemic NAD biosynthesis, and their importance. Cell Biochem Biophys. 53:65-74 (2009). 7. Buss et al. The action of quercetin on the mitochondrial NADH to NAD+ ratio in the isolated perfused rat liver. Planta Med. 71:1118-22 (2005). 7B. Milo et al. Inhibition of carcinogen-induced cellular transformation of human fibroblasts by drugs that interact with the poly(ADP-ribose) polymerase system. FEBS J. 179(2):332-6 (1985). 7C. Murray. Nicotinamide: an oral antimicrobial agent with activity against both Mycobacterium tuberculosis and human immunodeficiency virus. Clin Infect Dis. 36:453-60 (2003) 7D. Tang et al. Effects of micronutrient intake on survival in human immunodeficiency virus type 1 infection. [a study of the Multicenter AIDS Cohort Study] Am J Epidemiol.143:1244-56 (1996) 8. Weseler et al. Poly (ADP-ribose) polymerase-1-inhibiting flavonoids attenuate cytokine release in blood from male patients with chronic obstructive disease or type 2 diabetes. J Nutr. 139:952-7 (2009). 9. Geraets et al. Flavone as PARP-1 inhibitor: its effect on lipopolysaccharide induced gene-expression. Eur J Pharmacol. 573:241-8 (2007). 10. Peralta-Leal et al. PARP inhibitors: new partners in the therapy of cancer and inflammatory diseases. Free Radic Biol Med. 47:13-26 (2009). 11. Soriano et al. Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of poly(ADP-ribose) polymerase. Circ Res. 89:684-91 (2001). 12. Du et al. Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest. 112(7):1049-57 (2003). 13. Massudi et al. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One. 7(7):e42357 (July 2012).

[perfectlytinyworkspace]

eukaryotic cell cycle regulation

malignant metastatic cancers are often sourced back to mutations in genes encoding for cell cycle regulation machinery

to study these abnormal mutant phenotypes, grasp an understanding of WT phenotypes first

growth factors (GFs) 

molecule that regulates cell growth and division | either inhibition or activation

mitogen – GF that plays role in cell proliferation specifically [i.e., IGF, HgF]

growth inhibitor – cell cycle repressor that keeps targets from dividing [i.e., TGF-ß]

growth factors in extracellular environment bind growth factor receptors (GFRs) on cell surfaces to initiate signal transduction cascade pathway

signal transduction pathway’s end result is some mechanism of growth or its inhibition | generally, this mechanism is TF gene expression

types of growth factors:

extracellular GFs – secreted elsewhere in the system and bind independently to cell surface GFRs

cell-bound GFs – attached to the cell types that produce them and require direct cell-cell contact to activate relevant signal transduction pathway

regardless of type, GFs bind to GFRs that have a surface GF-binding domain, transmembrane domain, and intracellular domain that starts cascade inside cell once binding to surface domain changes GFR conformation

signaling transduction pathways

GF-bound GFR signals to / alters some intracellular signal transducer molecule that begins a chain activation of proteins in the pathway

EX: Ras-GDP is altered to Ras-GTP when GF binds to GFR (specifically a receptor tyrosine kinase, RTK, that dimerizes and autophosphorylates to become active recruiter / kinase enzyme)

GFR activates adaptor protein, which then activates Sos guanine exchange factor to hydrolyze GDP to GTP 

Ras-GTP binds some protein kinase that then phosphorylates another kinase, etc., etc.

Ras-GTP is returned to Ras-GDP when pathway needs to be halted

final step of most chain pathways is activation of some transnuclear membrane protein that bypasses from cytoplasm to nucleus and activates TF gene expression 

EX: Ras-GTP pathway’s last Mitogen Activated Protein Kinase (MAPK) crosses the nuclear membrane to influence gene expression of TFs that increase transcription of cell cycle genes

unregulated TFs are the proteins that then actually execute the mechanism that was signaled for by the entire transduction pathway

» the above signal transduction pathway is a generalized mechanism for paracrine signaling via any type of ligand, whether or not it is a GF

cyclins and cyclin-dependent kinases (CDKs)

cyclin-dependent kinase (CDK) binds different cyclin cytokines to form an actively phosphorylative cyclin-CDK complex

the substrate that cyclin-CDK phosphorylates depends on the type of cyclin cytokine that is bound to the CDK

each cyclin-CDK substrate stimulates a different downstream cascade pathway 

each pathway results in the manufacture of sets of proteins necessary for transitioning into a different stage of the cell cycle [G1, S, G2, M]

once one stage of the cell cycle is nearing its end, the relevant cyclin-CDK complex stimulates both gene expression of the next stage’s cyclin and its own degradation / decreased gene expression inside the cell

self-degradation + halted gene expression of previous stage’s cyclin ensures that the cell cycle only moves forward, G1 » S » G2 » M and so on

cyclin-CDK complexes are vital to the forward cell cycle in eukaryotic cells and is thus evolutionarily conserved

cell cycle checkpoints

mechanisms to pause cell cycle for gDNA repair, so that any potential mutations are not replicated into daughter cells

case focus: G1-S checkpoint for in-G1 DNA damage before in-S DNA replication

» normal G1 to S transition process:

cyclin D & E form cyclin-CDK complexes and phosphorylate the Rb-inhibitor of E2F transcription factor

uninhibited E2F then upregulates gene expression for proteins involved in DNA replication mechanisms

DNA replication initiation heralds the transition from G1 into replicative S phase

» when UV or ionizing radiation occurs / single strand nicks occur:

single strand nicks become double strand breaks after nicked DNA strand serves as template for newly synthesized sister strand during replication

UV / radiation or SSNs is sensed by Rad9 protein, which activates the p53 transcription factor

activated p53 TF then upregulates p21 inhibitor gene expression

p21 binds cyclinD-CDK4 complex to prevent it from phosphorylating Rb | thus, E2F remains inhibited by Rb and DNA replication genes are not upregulated for S phase until DNA is repaired

» in cases of massive, irreversible DNA damage

large-scale damage stimulates p53 to upregulate a different set of genes, for proteins involved in apoptosis (programmed cell death)

proteins degrade DNA and condense cell nucleus | signaling from dying cell to phagocytes in the organism for digestion

apoptotic pathway is an organismal anti-cancer mechanism, and thus conserved in multicellular eukaryotes

case focus: metaphase-anaphase M checkpoint

» normal metaphase to anaphase transition process:

at metaphase plate, sister chromatids are joined together by cohesin proteins

separase cleaves these cohesion proteins to separate chromatids and thus stimulate transition from metaphase to anaphase

separase is bound by securin inhibitor before anaphase transition

anaphase-promoting complex (APC) is activated when metaphase-specific cyclin-CDK complex decreases its inhibitory activity 

APC inhibits securin via ubiquitination | now, separase is not inhibited and cleaves cohesins for cell anaphase and onward

» when chromatids are not properly aligned at metaphase plate

aligned chromatids exhibit a specific degree of tension between metaphase, attached spindle fiber, and two centromeres’ kinetochores

MAD2 protein detects tension levels along centromeric kinetochores and inhibits APC even after metaphase-specific cyclin-CDK complex decreases

if MAD2 detects proper tension levels for aligned chromatids, it inactivates itself and APC is uninhibited | anaphase transition goes forward

otherwise, improper tension levels keep MAD2 active and APC remains inhibited until tension levels are corrected

checkpoints are not necessary for cell division but rather for prevention of cancerous mutations 

checkpoints halt cell cycle to repair DNA damage that would otherwise facilitate over-proliferation and invasive / metastatic behavior in daughter progeny

studies of Rad9- and MAD2- mutant cells reveal crucial checkpoint presence for resistance to cancerous and other phenotypically-dangerous mutations

yeast as a model organism for analysis of cell cycle mechanisms 

yeast cell cycle stages are phenotypically distinct and visible – easy to observe

cell division cycle (cdc) yeast mutants – generate mutations pertaining to cell cycle, so that mutants arrest at various stages of the cell cycle instead of proceeding forward all the way through division

screening for temperature-sensitive cdc mutants to use temperature as a regulator for expression or non-expression of arrest 

cdcs fall into two categories: cyclin-CDK mutants and DNA repair mechanism mutants

[ffrepos]

PATH3309 - UWA

Cancer Pathology (2017, Sem 2)

Unit coordinator: Dr Katie Meehan

L2-10:

pp. 1-3, 25 (Parenchymal/mesenchymal tissues, neoplasm, microscopic features of anaplasia, dysplasia/metaplasia/CINS)

4-5, 25 (Spread of malignancy, benign vs malignant)

6-7 (Cancer epidemiology, prevalence vs incidence)

11 (Case-control vs cohort studies)

13, 18 (Initator-promoter model)

19-22 (Regulation of gene expression at various stages: transcription, post-transcription, translation, post-translation & epigenetic)

24 (Know which are oncogenes & tumour suppressor genes)

26-31 (Invasion & metastasis)

35-36 (Melanoma & CML; know the mutations)

43-44 (Restriction point, cell cycle checkpoints, know which cyclin-CDK complexes are active at which stage of the cell cycle)

50 (Apoptotic pathways: extrinsic vs intrinsic)

51-54 (Apoptotic inducers, inhibitors & signalling pathway crosstalk)

I do not recall being specifically tested on the cancer statistics. My group did our project on the processes of invasion and metastasis so that may be why they stand out to me; but they are important concepts for cancer. For the various tiny molecules especially in the cell cycle regulation and apoptosis lectures, I know it's hard to memorise a bunch of letters but do have some inkling of them because they can appear as EMQ options to trip you up.

Please see here for my summary video on the cell cycle (L9) and cell death (L10) lectures by Ms Endersby. At the beginning of the video, I misspoke and stated that Venetoclax inhibits apoptosis (this is wrong); it is an anti-cancer drug that promotes apoptosis (I explain this near the end of the video).

[eannattoca-blog]

Ovarian Cancer - Latest Studies

Ovarian cancer is one of the deadliest cancer but with a lower incidence rate as compared to other cancers. It has been estimated that in 2019 itself, about 22,530 women in the United States of America will be diagnosed with ovarian cancer and about 13,980 women will die from ovarian cancer. At present, ovarian cancer ranks 5th in cancer deaths among women accounting for more deaths than any other cancer of the female reproductive system. The risk of a woman developing an ovarian cancer is about 1 in 108. Older women are very much prone to this cancer and about half the women who are diagnosed with ovarian cancer have been found to be 63 years of age or older. In the United States of America, the overall ovarian cancer incidence has declined by 29% from 1985 (16.6 women per 100,000) to 2014 (11.8 women per 100,000), while mortality rate has declined 33% from 1976 (10.0 per 100,000) to 2015 (6.7 per 100,000). Moreover, currently there is no recommended screening test for ovarian cancer thus very often it goes unnoticed in the earlier stages.

Although in the pursuit to fight ovarian cancer, several studies have been conducted on Annatto based Tocotrienol (Eannatto — DeltaGold) which has been observed to possess anti-cancer activities. One such study,“Delta tocotrienol in recurrent ovarian cancer. A phase II trial”showed that Delta — Tocotrienol(Eannatto — DeltaGold)possesses anti — neoplastic activity as demonstrated in several in vitro and in vivo investigations. The effect has been observed to rely on inhibition of different pathways. It also has anti — angiogenic activity, and an additive effect to bevacizumab can be expected. This study was a phase II trial of bevacizumab combined with Delta — Tocotrienol(Eannatto — DeltaGold) in chemotherapy refractory ovarian cancer. This study also included analysis of circulating ‘tumor specific HOXA9 methylated DNA (HOXA9 meth — ctDNA)’ during treatment. This study included 23 patients and the rate of disease stabilization was at 70% with very low toxicity. The median PFS was 6.9 months and the median OS 10.9 months, which is rather high as compared to the current literature. A division of the patients according to the level of HOXA9 meth-ctDNA after the first cycle of chemotherapy resulted in formation of two groups of patients with different prognoses. Patients with an increasing level of HOXA9 meth-ctDNA had a median PFS and OS of 1.4 and 4.3 months respectively as compared to 7.8 and 12 months in the group with stable or decreasing levels. The combination of bevacizumab andDelta — Tocotrienol(Eannatto — DeltaGold)was found to be quite potent in chemotherapy refractory ovarian cancer. The level of HOXA9 meth-ctDNA after one cycle of chemotherapy was observed to hold important prognostic information.

Most research in the past 50–60 years has been focused on Tocopherols and 50% of all the research in last 30 years has been done on Tocotrienols in last 5 years. Half of the Tocotrienol research ever published has been published in last 10 years as shown in Fig. 1. Each day it is becoming increasingly understood that Tocotienols (especially Eannatto — DeltaGold) are the right form of Vitamin E. Well in excess of 100 studies and clinical trials have shown the surprising benefits of Tocotrienols — without any known side effects.

Fig. 1: In the graph, as you can see, R & D on Tocotrienol has increased exponentially over the years in all fields while research on Tocopherols has decreased. Whether it is cancer, Cardiovascular diseases (CVD), Diabetes, Anti — Oxidant activities or others, in all fields research on Tocotrienol has not only gained pace but quant as well.

Study 1 — Delta tocotrienol in recurrent ovarian cancer. A phase II trial.

Even now, recurring ovarian cancer represents a therapeutic challenge. Most ovarian cancer patients will suffer from recurring ovarian cancer within a few years after the primary treatment like chemotherapies and radiation. Bevacizumab has been observed as an integrated part of both 1st and 2nd line treatment of ovarian cancer but still a majority of patients die from ovarian cancer. Tocotrienols are the part of Vitamin E family. Several in vitro and a few in vivo have showed a clear effect on malignant cells with respect to proliferation and invasion. Several mechanisms and effects on different pathways have been suggested among which inhibition of 2 important transcription factors NF — kB and STAT3 — rank high. Delta — Tocotrienol(Eannatto — DeltaGold)is especially active in relation to malignancies. Delta — Tocotrienol(Eannatto — DeltaGold)suppresses the vascular endothelial growth factor (VEGF) and inhibits proliferation of endothelial cells resulting in reduced tube formation. HOXA9 meth — ctDNA has been suggested as a prognostic marker in ovarian cancer. This study has been aimed to investigate the combination of bevacizumab and Delta — Tocotrienol(Eannatto — DeltaGold)in a phase 2 trial of multi — resistant ovarian cancer.

The patients were treated with bevacizumab 10 mg/kg i.v. every 3 weeks. Delta — Tocotrienol(Eannatto — DeltaGold)capsules were given in a continuous treatment in doses of 300 mg orally 3 times a day. Delta — Tocotrienol(Eannatto — DeltaGold)is a special formulation based on a patented method with 90% Delta — Tocotrienoland 10% Gamma –Tocotrienol.

The study included 23 patients from March 2015 to Jan 2018. It was observed that most patients were diagnosed with stage 3 disease, and serious histopathology was found to be the dominating type. The median number of prior chemotherapy regimens was 4.0. All patients were platinum resistant and more than half of them had previously received bevazicumb with progression on treatment. It was also observed that all patients but one were in good performance status. The median number of treatment cycles was 6 with 20% of the patients treated for more than 12 months.

Why Tocotrienol?

Antioxidants, especially Tocotrienol was observed to exhibit anti-cancer activity against ovarian cancer cells cells by lowering inflammation and oxidative stress as shown in Fig. 2.

Fig. 2: In the study conducted by Dr. Qureshi, he saw that at 250 mg of Tocotrienols, the endogenous anti-oxidant, TAS (represented with grey colour) increased, while the C-reactive protein (CRP) dropped by 40%, oxidized fat (MDA) dropped by 34% and Total Anti-oxidant increased by 22%. 

Angiogenesis which is the process of formation of blood vessels in cancer cells like in your ovarian cancer promotes cancer cell death to a very great extent. Studies have also demonstrated that Delta-Tocotrienol hindered hypoxia-induced VEGF and IL-8 overexpression and by lowering HIF-1 alpha, thus consequently inhibiting angiogenesis in cancer cells.

Fig. 3: In a study, it was observed in mice cells, that Delta — Tocotrienol inhibited the formation of blood vessels in cancer cells (Anti — Angiogenesis) while Tocopherol completely failed on such grounds. Delta-Tocotrienol was also observed to induce apoptosis in the mice cancer cells. 

Apoptosis is the programmed cell death which leads to the death of cancer cells. According to the study, Tocotrienol was found to induce apoptosis in ovarian cancer cells in vitro and in vivo by downregulating NF-kB and its regulated gene products.

Paraptosisis a type of programmed cell death distinct from apoptosis which features cytoplasmic vacuolation independent of Caspase activation and inhibition, and lack of apoptotic morphology. According to the research, it was observed that Delta-Tocotrienol induced paraptosis-like cell death in ovarian cancer cells.

Cell Proliferation is the process by which cancer cells copy their DNA and divide into two cancer cellsduring mitosis and rapidly multiply into more cancer cells. It was observed that Delta-Tocotrienol inhibited ovarian cancer cell proliferation, induce cancer cell death and prevented cell cancer invasion.

Cancer stem cell death has been observed by the action of Tocotrienols especially Delta — Tocotrienols (DeltaGold — Eannatto). Even after chemotherapies, radiation and surgeries, there are stem cells of those cancerous tissues left revolving in your body which can lead to your cancer coming back. Henceforth, their death is very necessary and Tocotrienols have been observed to kill cancer stem cells.

Fig. 4: About 1% of cancer cells are Cancer Stem Cells (CSC) which keep circulating in your body even after nailing the cancer through chemo. It has been observed that Gamma — Tocotrienol and Delta — Tocotrienol, both specifically target CSC. 

Tumor nutrition can also be obstructed by Tocotrienol as they may well work on dual antitumor mechanisms that include the removal of the vital nutrient to tumor lifeline.

Dosage

Under the study, 900 mg/day of Tocotrienols were used to treat ovarian cancer cells and no adverse effects were observed and the death of breast cancer cells was witnessed.

Substances that complement Tocotrienol for cancer include Vitamins C, D, Selenium, B complex.

Why Tocotrienol and Not Tocopherol?

Tocopherol, the enemy of Tocotrienol: Tocopherol has been observed to attenuate lung cancer inhibition, inhibits absorption, reduces adipose storage, and compromises cholesterol and triglyceride reduction. Tocopherol hinders the functioning of Tocotrienol and even when they are consumed simultaneously, Tocopherol obstructs all the functions of Tocotrienol.

Tocopherol, the antagonist in liver cancer treatment:It has been observed thatTocopherolnot only interferedwith the functioning of Tocotrienol but also showed harmful effects during the treatment.

Tocotrienol, the protector of State: Tocotrienol has more mobility than Tocopherol due to its small structure so it can cover a larger area targeting more number of ovarian cancer cells.

Small structure and less molecular weight: The higher anti-oxidant activity of Tocotrienols is due to their small structure and less molecular weight which assist in their integration of the cell, unlike Tocopherols.

Absorption: As compared to Tocopherols, Tocotrienols absorb better in the body and Tocopherols have been observed to prevent absorption of Tocotrienols.

Fig. 5: The 2nd pie chart represents Palm Tocotrienol rich fraction with 32% Alpha — Tocopherol which was given to people and when the Alpha — Tocopherol was removed then it was represented by the 1st pie chart with 0.3% Alpha — Tocopherol which was then given to people. In the graph, the hollow bar represents the Tocotrienol with Tocopherol which reduced the concentrations of Alpha, Gamma and Delta Tocotrienol in the body but when Tocopherol was removed from the dosage (Solid grey bars in graph), the concentrations of Alpha, Gamma and Delta — Tocotrienol significantly increased. 

References

Tocotrienols: Latest Cancer Research in Vitamin E by Barrie Tan, Ph.D., and Anne M.Trias, MS.

Tocotrienols: The Promising Analogues of Vitamin Efor Cancer Therapeutics https://doi.org/10.1016/j.phrs.2018.02.017

Delta tocotrienol in recurrent ovarian cancer. A phase II trial by Thomsen CB, Andersen RF, Steffensen KD, Adimi P, and Jakobsen A.

https://www.ncbi.nlm.nih.gov/pubmed/30639384

Note:

1. To read studies in detail, follow the references and links given.

2. The dosages given must not be taken as the advice of a medical practitioner. Consult your physician for the optimum dosage to be consumed.

[discoveringpmadupe]

The retrogene UTP14c, involved in human male infertility, ovarian cancer and the best way of studying it.

By; Palesa P. Madupe Literature survey So where does it all begin? Retrogenes, processed pseudogenes (PP) and pseudogenes are abundant in the human genome and most of their function was unknown up until recently (until the human genome project). They are mostly involved in disease development in humans, like in the case of myosin light chain kinase pseudogene which has been documented to be highly expressed in cancer cells (1). Pseudogenes are dysfunctional genomic loci with sequence similarity to functional genes but lacking coding potential due to the presence of disruptive mutations such as frame shifts and premature stop codons (2) . Pseudogenes are described into different categories; processed pseudogenes which are created via retrotranspositioning of mRNA from functional protein coding loci back into the genome, or duplicated unprocessed pseudogenes derived from duplication of functional genes or unitary pseudogenes, which arises through in situ mutations in previously functional protein coding genes (3) . Retrogenes are born via the reverse transcription of mature messenger RNA (mRNA) from parental genes and thus have no introns (mRNA sequence that can be converted into proteins) (4). They contain 3’ end poly A tail and are flanked by short directed repeats. They arise from transposable elements, defined as DNA sequences that have the ability to integrate into the genome at a new locus within the same cell. These elements contain DNA transposons and retrotransposons. Retrotransposons can be RNA that is reverse transcribed into DNA and then integrated into the genome at a new location (4). The original transposon is maintained in situ therefore it duplicates itself within the same cell; referred to as copy and paste method. Retrotransposons are devised into 2 classed based on the presence or absence of long terminal repeats (LTR). Those that contain LTRs are like retroviruses they contain them at both ends of the strand. The non-LTR have the 3’end poly A tails (5). The vast majority of retrotransposed copies of mRNA are inactivated into PP. It is only in a few cases that they evolve into new genes, ie. Retrogenes which can be transcribed and translated in to proteins. Like in the case of UTP14c gene; which is involved in 18S rRNA synthesis (the small subunit of the eukaryotic cytoplasmic ribosomes, which is essential in eukaryotic cells). The retrotransposed copy of the source gene is integrated into the 3’ un-translated region last exon of a glycerol transferase-containing gene (GT8). The 3’part of the exon 3 and the whole intron 3 and exon 4 of the GT8 gene are enlisted with unchanged exon-intron structure, to form a single intron containing UTP14c. This makes the exon segments of GT8 un translated (6). The source gene UTP14c is a ubiquitously expressed X-linked gene. In mouse; its retrogene UTP14b is expressed in the male germ cells and when its mutated it results in early spermatogenic arrest and male infertility (7). Humans have the strict ortholog of UTP14b in the synthetic region of chromosome 2, and it has degenerated and its no longer functional (it has become a PP). A second retrogene is found in chromosome 13 which is expressed in testis and ovaries the function has been documented to be equivalent to that of mouse UTP14b (6,8). The UTP14 protein has been predicted to be part of the small subunit processome complex that binds to U3 small nucleolar RNA involved in the synthesis of the 18S rRNA (9). The UTP14c gene has acquired specific promoter/enhancer elements, thus this restricts the activity of the gene in the ovaries and testis. The data machinery that is found in the germ cells is different from that is found in the somatic cells. Because the UTP14c gene is incorporated into the GT8 gene, this makes its production bypassed. The polyadenylation signal of the gene GT8 is lost (6). Mutations that occur within the UTP14c gene have shown to lead to early maturation arrest in the formation off sperm cells. The mutations lead to the protein of UTP14c gene not being able to form the protein complex of the synthesis of 18S rRNA. UTP14c is expressed in 50% of normal human ovaries and 80% of ovaries that have cancer (ovarian cancer). It was documented to down regulate tumour protein 53 (TP53) in both the nucleus and cytoplasm by targeting it for proteolytic degradation. This prevents the cancer cells expressing UTP14c from entering the apoptotic pathway. The loss of TP53 down regulates micro RNA-154 (miRNA-154) expression. This then activates factors that promote oncogenesis and cellular pluripotency which can develop ovarian cancer. How does expression of UTP14c actually disrupt the TP53 pathway? The TP53 regulates the expression of mi-RNA154, it binds to the promoter region of mi-RNA-154 and its up regulates the pre RNA synthesis of mi-RNA 154. It also bind to the muclear RNAse 3 drosha which stimulates the processing of the mi-RNA 154 pre- RNA into the mature version. The biological active form of mi-RNA 154 acts as an anti-tumorigenic factor blocking the expression of c-myc, cell reprogramming gene and the cells proliferation/invasion gene muc1 (6) . So how would we better study, UTP14c retrogene? A little bit of history Recombinant DNA technology (10) has changed how we understand the functioning of genes, proteins and nucleic acid. Recombinant DNA technology refers to making of new combinations of DNA fragments which are not found existing together in nature. The isolation of the desired DNA segments allows for exact DNA analysis, and practical application in medicine like drug discovery, in agriculture like the creation of bio-control agents and in industrial application production of food additives. Here is an oversimplified way of making recombinant DNA; isolate DNA from whatever source, cut with restriction enzymes, ligate (essentially paste) into cloning vector, then transform the recombinant DNA molecule into host cell, grow the host. Each cell from then onwards will carry the desired recombinant DNA molecule. Each of the steps mentioned here have intrinsic and extrinsic factors to them and their not as plain as mentioned. To further study the recombinant DNA molecule, depends on what the researcher is interested in. To determine the function of the recombinant DNA molecule one can conduct a site generated mutagenesis, the recombinant DNA fragment may be changed by changing a base in the primer sequence, for the polymerase chain reaction (PCR) of the cloned DNA molecule. During the PCR the amplicons generated will contain the mutation selected for by the researcher (11). Because of the generated site mutation the gene produce for that DNA fragment might not function like the wild type gene, thus one can then extrapolate that a mutation at position X leads to noticeable missing functions. More recently we have seen outbreaks of the combination of recombinant DNA technology and nanoscience. Nanoscience refers to the science; manipulation and the development of chemical and biological structure that are on the scale of single atoms. Like in the production of antibodies, this technology is been used to manufacture antibodies that have very high affinity to specific substrates. The problem has been a way of delivering these antibodies to that specific site. Ingestion would lead to the immune system attacking them. The attachment of these recombinant antibodies to carbon nanotubes with radio or fluorescent labelling, can directly deliver antibodies directly where their required (12). Recombinant DNA technology has also advanced the study of protein function and drug design. Knowing the three-dimensional (3-D) structure of a protein has enable the determination of the active site (where substrates bind) in vivo. Knowing the active sites of protein and enzyme has enabled drug design to be more effective (13). The 3-D structure of proteins can be determined via nuclear magnetic resonance (NMR) spectroscopy, which is able to reveal atomic structures of macromolecules in solution. NMR relies on the fact that atomic nuclei are magnetic. The purified protein in solution is then placed in a strong magnetic field and probed with radio waves. A distinct resonance is observed and that can be analysed to give a list of atomic nuclei that are close to one another, and to characterise the local conformation of atoms that are bonded together. All these specifications are used to a model a protein (14). Protein X-ray crystallography, it’s the determination of the 3-D structure of biological macromolecules using diffraction technology on a single crystal. This technique is much better than NMR because X-ray crystallography gives a better/ high resolution. The first protein crystal structure was of myoglobin in the year 1932 by Theorell A, the resolution of the protein was 6 Å (Angstron). Resolution measures the amount and level of details present in the protein. High resolution structure are those that have very low Angstron values

[letsansh123-blog]

DIET PLAN TO CURE CANCER NATURALLY WITH AYURVEDA

Any disease can be successfully treated or managed if its root cause is known and targeted effectively.

Ayurveda, one of the major traditional forms of medical practice in India, has produced many useful leads in developing medications for chronic diseases.

Ayurveda is an intricate system of healing that originated in India thousands of years ago. Historical evidence of Ayurveda can be found in the ancient books of wisdom known as the Vedas that were written over 6000 years ago. Ayurveda provides novel approaches to cancer prevention that are considered safe.

Classical Ayurvedic texts have several references to cancer. Some terms used to describe the condition are general while others are much more specific.

Charaka and Sushruta Samhita (700 BC) both described the equivalent of cancer as granthi (benign or minor neoplasm) and arbuda (malignant or major neoplasm). Both can be inflammatory or non-inflammatory, based on the doshas (Vata, Pitta and Kapha) involved. The term dosha describes the three principles that govern the psychophysiological response and pathological changes in the body. Ayurveda described health as the balanced coordination of these three systems in body, mind and consciousness. The fundamental theory of Ayurvedic treatment is based on restoration of the balance between these three major bodily systems.

Tridoshic tumours are usually malignant because all three major body humors lose mutual coordination, resulting in a morbid condition.

Arbuda is the most specific term for a cancerous malignancy. Gulma is one another reference used to describe any palpable hard mass in the abdomen. It is any hard, tumor like mass in the abdominal region, which could be benign or malignant.

Ayurvedic classification of neoplasms depends upon various clinical symptoms in relation to tridoshas.

Group I: Diseases that can be named as clear malignancies, including arbuda and granthi, such as mamsarbuda (sarcomas) and raktarbuda (leukaemia), mukharbuda (oral cancer), and asadhya vrana (incurable or malignant ulcers).

Group II: Diseases that can be considered as cancer or probable malignancies, such as ulcers and growths. Examples of these are mamsaja oshtharoga (growth of lips), asadhya galganda (incurable thyroid tumour), tridosaja gulmas, asadhya udara roga, (abdominal tumours like carcinomas of the stomach and liver or lymphomas).

Group III: Diseases with the possibility of malignancy, such as visarpa (erysipelas), asadhya kamala (incurable jaundice), asadhya pradara (intractable dysmenorrhea or leukorrhea) and tridosaja nadi vrana (intractable sinusitis).

At CHARAKA, we are providing effective treatment for cancer, focusing on the principle of detoxification, rejuvenation. Our treatment involves:

Shamana chikitsa (treatment using Ayurvedic medicines orally)

Shodhana chikitsa (detoxification through Panchakarma therapy)

Rasayana chikitsa (immunotherapy, rejuvenation or Kayakalpa)

Diet & life style management

Satvavajaya (couselling)

Daiva vyapashraya chikitsa (divine therapy), Yoga & Pranayama are also suggested as per the need and condition of the patient.

Our cancer therapies are based on the philosophy of Removal the cancerous cells when possible and destroy any cells that remain.

Our Ayurvedic treatments can be safely combined with chemotherapy and radiotherapy procedures to minimize the side effects. Even in surgical treatment, this treatment can be started immediately to prevent metastasis and further healing.

Early detection, early medical or surgical interventions are believed to be the key factors in combating cancer effectively. Similarly early stage Ayurvedic treatment as a co-therapy yields best possible results.

#How can Ayurveda treatment help to combat Cancer?

It is now established that "reverse" signalling from dysfunctional or abnormal Mitochondria play important role in the initiation and progress of Cancer cells and conversely it is also proven that Healthy Mitochondria can suppress the growth of cancer cells and make them more susceptible to the treatment. So any drug or treatment which can improve Mitochondrial function can modify the course of the disease and arrest its growth. In this article, we have seen that Mitochondria and Agni are the same organelles and in Ayurveda, for cancer following treatment is provided

1) To remove the free radicals, toxins, excess amount of dirty Pitta, Kafa and Vata which are known to impair the functions of Agni

2) To restore and strengthen the metabolic functioning of Agni due to which further chain of events are curtailed and disease process comes under control.

3) To change the cellular environment, which breaks down or absorb the Lactic acid which is produced by cancerous cells. By this, Cancer cells lose their ability to spread and metastasize

4) To improve the Immunity which then destroys Cancerous cells.

5) There are certain herbs, like Neem which stimulates tumour suppressor pathways and compel the body to produce more tumour's death promoting ( Apoptosis) chemicals and reduce anti-apoptotic chemicals; all of these modalities lead to the death of cancerous cells and are removed from the system.

6) There are certain herbs like Tinospora which are known to arrest abnormal cell cycle, without affecting the normal cell cycle. This mode of action further reduces the uncontrolled growth of abnormal cells.

7) Some herbs like Ashwagandha reduces budding of newer blood vessels in cancerous tissues, thereby cuts off the nourishment of cancerous tissues.

8) Some herbs like Turmeric acts blocks the effect of chemicals ( like TNF alfa) which are responsible for inflammation and Turmeric also blocks the effect of the growth factor called NF kappa -b, thereby uncontrolled multiplication is arrested.

9) Turmeric and Ashwagandha also stimulate p53 tumour suppressor pathway.

10) Some household herb like Fenugreek absorbs lactic acid and stops glucose supply to cancer cells hence they are deprived of their food and die.

What diet is recommended to a patient suffering from Cancer?

The best diet is to follow intermittent fasting or calorie restricted diet which is sufficient enough to provide all required nutrients to the body and immunity but at the same time, deprives cancer cells of their food and compel them to die. General guidelines are as follows

1) Strictly avoid all Maida and bakery products

2) No Sabudana, No vinegar, no Tobacco, No Liquor.

3) Avoid deep fried food

4) Avoid late night dinner ( dinner should be over by 7 pm)

5) No raw food or salad, especially when on chemotherapy

6) Minimum intake of Sugar with one or two days of " NO sugar" per week in any form (Which means no White/ brown sugar, No Jaggery, No honey, No fruit juices, no Carrot or beetroot juice)

7) Once a week fasting as per the advice of expert Vaidya.

Frequently asked queries?

1) Are there any steroids in the Herbal medicines - No, we do not do such kind of unscrupulous or non-ethical practice. My drugs can be tested and subjected to any kind of test for that matter.

2) Are these drugs safe during Chemotherapy- There are certain reports, published in good journals, which has proven the good effect of chemotherapy when combined with herbal treatment. ( Care to be taken that herbal treatment should be of standardized quality and should not be given on the day of injectable chemotherapy, rest it can be given. It also depends on stage and type of cancer, so final decision to be taken only after discussing every pros and cons). There are various clinical studies indicating that if standardized herbal preparations of Curcumin, Ashwagandha are given along with chemotherapy, results are better. Many chemoresistant cancers respond very well when supplemented with Curcumin, Ashwagandha and Tinospora cordifolia.

3) Can herbal therapy replace or avoid chemotherapy- No, one should follow complete modern protocol as it is. Herbal treatment is mainly given to as chemo adjuvant to improve the immunity and mitochondrial function as stated above.

4) Can Ayurveda treatment avoid surgery and radiation- All of you will be surprised to read the fact that, in Ayurveda, which was written 3000 years B.C., it is clearly mentioned that first line of treatment of Cancer is to surgically remove it and then to " Burn" the margins, this concept is similar to today's modern protocol of Surgery followed by Radiation. So any tumour, if operable, should be removed promptly by an expert Onco-Surgeon.

5) What is Chemoprevention? This term was coined by Dr Michel Sporm, in 1976. Chemopreventive are drugs, natural or Synthetic, which have potential to Reverse, Suppress and or Prevent the further growth of cancer. I advise various such Chemopreventive herbs and ways to many normal people and also to cancer patients.

AROGYAM PURE HERBS KIT FOR CANCER : http://www.ayurvedahimachal.com/pure-herbal-products/index.php?route=product/product&product_id=83&search=cancer#sthash.6JPSs9gC.dpbs

[biomedres]

Reviewing Leads That Promote Apoptosis-Cancer Treatment Strategies

Reviewing Leads That Promote Apoptosis-Cancer Treatment Strategies Biomedical Journal of Scientific & Technical Research

https://biomedres.us/fulltexts/BJSTR.MS.ID.005813.php

Apoptosis refers to a series of events which usher the cells into committing suicide in a coordinated manner. The intricate network of pathways works together to execute the cell’s demise. It has been established that cancer cells do not follow orthodox courses but instead, re-design the pathways to circumvent apoptosis. In this article, we review the various molecules which have been isolated for targeting major apoptotic pathways. Out of the many mechanisms that are disrupted, the pathways which mediate cell death are generally the most deranged. Considering the relevance of these apoptotic pathways, some molecules that act on these pathways were studied. The leads covered in this article were selected on the basis of their ability to either induce/ enhance proapoptotic signals or to inhibit anti- apoptotic signals. The actions of these leads have been demonstrated in various cancer cell lines. The array of compounds chosen include: some traditional medicines, RNA constructs and some which are chemically formulated. These compounds were characterized to target the TRAIL, caspase, Bax- Bak, p53, SIRT, STAT, Akt-p13- mTOR pathways which lead to increased auto- demise. Each of these leads have hallmark features that make them attractive as cancer treatment strategies. We propose the utilization of these leads as a part of routine treatment of cancer to enhance the survival of cancer patients.

For more articles in Journals on Biomedical Sciences click here

bjstr

Follow on Twitter : https://twitter.com/Biomedres01 Follow on Blogger :https://biomedres01.blogspot.com/ Like Our Pins On : https://www.pinterest.com/biomedres/

[healthveda]

BENEFITA OF GINKGO BILOBA AGE RELATED DISEASES

It is being tested in age-related diseases such as Alzheimer's, stroke, cancer, Parkinson's, and ageing antioxidative action, protective action on the cell's DNA, protection of the mitochondria, the cell's superpower, control of cholesterol breakdown, and apoptotic effect, which speeds the scheduled cell death.

Ginkgo Biloba's Brain Health Benefits:

The ability of a person to think, remember, learn, make decisions, speak languages, and so on is referred to as cognitive function of the brain. In age-related disorders like Alzheimer's dementia, these functions exhibit a deterioration. Alzheimer's disease causes dementia, which is the inability of a person to remember things.

In animal and cell culture experiments, the extract of Ginkgo biloba has shown neuroprotective effects via eliminating free radicals, boosting dopaminergic transmission, blood flow to the brain, and several other pathways, among others.

 When it comes to treating dementia that has already formed in a person, the plant has little effect. It is used as a supplement to help prevent dementia, but there isn't enough scientific evidence to back it up, and further research is needed. The extract is used to treat organic brain disorders, which include memory loss, tinnitus, headaches, dizziness, low mood, and poor focus.

Heart Health Benefits of Ginkgo Biloba:

Ginkgo biloba extract has blood vessel relaxing, platelet aggregation inhibiting, and anti-swelling properties, all of which contribute to heart health. However, due to a lack of strong evidence, the use of Ginkgo biloba extract for treatment or prevention of heart disease is not recommended at this time.

Ginkgo Biloba Eye Health Benefits:

Macular degeneration is a common eye illness that affects people over the age of 50, characterised by thinning of the macula, the region of the retina required for proper vision. Glaucoma is a condition in which vision is impaired due to an increase in eye pressure. Studies have demonstrated that increasing the blood flow to the retina and so protecting the retinal cells improves vision in macular degeneration and glaucoma.

[sunshineschem]

Aprocitentan/1103522-45-7

AR9281 inhibits soluble epoxide hydrolase (s-EH), an enzyme that plays a key role in the cytochrome P450 pathway of arachidonic acid metabolism. Nuclear factor alpha B (NF-alphaB) is a transcription factor implicated in cardiac hypertrophy, and can be anti or pro apoptotic under different conditions. Epoxyeicosatrienoic acids (EETs), a product of cytochrome P450 epoxygenase enzyme action, have a variety of anti-hypertensive and anti-inflammatory effects. EETs have a vasodilatory action similar to endothelium derived hyperpolarizing factor and may inhibit NF-alphaB through a currently unknown mechanism. The enzyme s-EH catalyzes the breakdown of EETs to dihydroxyeicosatrienoic acids. AR9281's inhibition of s-EH enhances EETs anti-hypertensive and anti-inflammatory activities by preventing their breakdown by s-EH, as well as inhibiting NF-alphaB.

[bostorbio]

STAT6 Antibody  - Boster Bio

Polyclonal antibodies are produced when mice are immunised with a synthetic peptide that mimics Stat6 (STAT6 Antibody) residues around amino acid 620. Research in immunology use protein A and peptide affinity chromatography to separate antibodies from antigens.

An interleukin 4 and an interleukin 13-induced signalling cascade include the Janus family of tyrosine kinases (Jak) and the STAT signal transduction pathway, which includes the inflammatory cytokine receptor 6 (STAT6) (1). There has been some evidence that STAT6 (predicted molecular weight 94kDa) may be responsible for the cytokine's anti-apoptotic properties. To activate transcription, the STAT family members gather in the nucleus once they have been phosphorylated by the receptor associated kinases.

This activation occurs when STAT6 is phosphorylated (Tyr641) in response to cellular interaction with IL-4.This gene has been located in the lymphocytes of the periphery as well as in the colon and the intestinal tract and in the ovaries as well as in the prostate as well as in the thymus and spleen. An crucial function for STAT6 in Th2 and Th9 responses is played by this transcription factor (2). When STAT6 (STAT6 Antibody) is deficient in mice, IL-4-mediated activities such as Th2 helper T cell generation, production of cell surface markers, T-cell proliferation, immunoglobulin class flipping to IgE, and a partial loss of IL-4-mediated proliferation are all affected. Allergies to nuts and malignant hemangiopericytomas have a link with the overexpression of STAT6.

[kathasanyal]

APOPTOSIS [PATHWAYS]

INTRODUCTION

Every normal living cell in animals, plants, and microorganisms is destined to die. Cell death is a highly tuned programme that is built into the genetic machinery of the cell. Apoptosis, or programmed cell death, is a type of normal cell death that occurs as part of the normal development and maintenance of homeostasis (PCD).

The fate of individual cells is carefully regulated such that the needs of the organism as a whole are met by programmed cell death. Adults rely on programmed cell death to balance cell proliferation and maintain stable cell counts in tissues undergoing cell turnover.

This process is closely regulated, and any flaw in the apoptotic machinery would cause cells to live longer, potentially leading to neoplastic cell proliferation, genetic instability, and mutation accumulation.

PATHWAYS 

Apoptosis could be initiated by signals from the intrinsic pathways, the extrinsic pathway and the perforin-granzyme pathway.

INTRINSIC PATHWAY

Various types of cellular stress may cause mitochondria to become leaky and spew forth proteins called cytochrome C, which triggers apoptosis. Anti-apoptotic proteins named Bcl-2 and Bcl-x are found in the cytoplasm and mitochondrial membrane, and they keep the mitochondrial membrane intact by preventing apoptotic proteins like cytochrome c from leaking into the cytoplasm. [NOTE: I will be writing about all the proteins involved in Apoptosis on my next blog.] However, in the absence of a growth signal or due to radiation of protein mis-folding stress protein called BH3 only protein are stimulated. Bcl 2 and x only protein consisting of Bim, Bid, Bad, PUMA and NOXA proteins blocks the function of Bcl 2 and Bcl-x.

These proteins also activate bax and bak, two pro-apoptotic effectors that build channels in the mitochondrial membrane, allowing intra-mc proteins like cytochrome c to seep into the cytoplasm. Apoptosomes are formed when cytochrome c in the cytoplasm interacts to the protein Apaf-1 (apoptosis activating factors 1). This complex attaches to caspase 9 and starts cleaving and activating caspase 9 molecules nearby.  Caspase 9 is an initiator caspase, and activated Cas-9 molecules trigger executioner caspases such as 3 and 6, causing the cell to die.

EXTRINSIC PATHWAY

Cytotoxic T lymphocytes or CD8 t-cells cause apoptosis of infected cells of tumor cells by FasL and Fas/death receptor interaction. Many cell types express a receptor call Fas receptor and cytotoxic T cells express FasL. These cytotoxic T cells bind to the fas receptor on tumor cells or infected cells through their FasL and this interaction may produce apoptotic signals through 2 pathways – the TNF or granzyme /perforin pathways.

The extrinsic pathways involves binding of an adapter protein called fas-associated death domain FADD to the cytoplasmic end of at least 3-4 fasL. This then binds with caspase 8 an initiator caspase which gets cleaved to become active. The active cas8 further activates other cas8 molecules. These in turn activate executioner cas-3 and 6 leading to apoptosis of the cell.

PERFORIN-GRANZYME PATHWAY

At times the granzyme/perforin pathway is initiated on FasL/Fas receptor interaction T cells release perforins which form trans-membrane pores on cells. Through which granzymes another protein secreted by t-cells enters. Granzyme could either directly activate executioner cas molecules or cause DNA cleaving leading to apoptosis. Executioner cas 3 and 6 cause degradation of chromosomal DNA also degradation of cytoskeletal protein which cause morphological changes cause nucleus fragmentation and cellular shrinkage respectively. However, it is not yet known what cause changes like cellular blebs and apoptotic bodies. Apoptotic bodies are coated with a phospholipid called phosphatidylserine which is recognized by phagocytic receptors. Also, apoptotic bodies may be coated with opsonins like antibody IgG or complement protein like C3b which are recognised by phagocytes thus facilitating rapid phagocytosis of apoptotic bodies.

CHECK APOPTOSIS PPT HERE INSTAGRAM POST

NEXT BLOG : PROTEINS INVOLVED IN APOPTOSIS

[healthcare-market]

BCL-2 (B-cell lymphoma 2) Inhibitors Market Trends and Forecast up to 2027

BCL-2 (B-cell lymphoma 2) Inhibitors Market: Introduction

· BCL-2, also known as B Cell Lymphoma 2, is a protein encoding gene belonging to the B cell lymphoma family. This protein is considered to be an outer mitochondrial protein membrane, which functions as a signaling pathway to further control the mitochondrial permeability against the apoptotic stimuli response. Aberrant expression and translocation of chromosomes are considered to be cancer symptoms in various tissues. The BCL-2 family comprise the 25-apoptotic and anti-apoptotic members that maintain a balance between new forming cells and old dying cells.

· Venetoclax is the only and fist approved FDA BCL-2 inhibitor drug for chronic lymphocytic lymphoma (CLL) patients. Although various clinical trials are being carried out for the development of new BCL-2 inhibitors.

Read Report Overview: https://www.transparencymarketresearch.com/bcl-2-b-cell-lymphoma-2-inhibitors-market.html

Get an Idea about the Offerings of Our BCL-2 (B-cell lymphoma 2) Inhibitors Market Report from this Brochure

Key Drivers and Restraints of Global BCL-2 (B-cell lymphoma 2) Inhibitors Market

· There is a rise in the prevalence of Diffuse B cell Lymphoma (DLBCL), a common type of non-Hodgkin lymphoma. As per Lymphoma Research Foundation article, in 2019, in the U.S., DLBCL accounted for 22% of new diagnosed B cell lymphoma cases. Each year, 18,000 people are diagnosed with DLBCL globally. This B cell lymphoma affects people over 60 years of age. As per the American Cancer Society's, in the year 2019, 20,720 people are estimated to be diagnosed with CLL. Moreover, 90% of the people diagnosed with CLL are estimated to affecting people above 50 years of age. In the U.S., 2,220 men and 1,710 women are expected to be suffering from CLL every year. Moreover, as per the American Cancer Society, about 3,930 death are expected to take place in 2019.

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· Governments of developed and developing countries are initiating awareness campaigns to reduce mortality and morbidity rates. This is expected to boost the demand in the effective cancer treatment. For instance, Public Health England, an executive agency of the Department of Health in the U.K., started “Be Clear on Cancer” campaign aimed at improving early diagnosis of cancer by holding the public awareness program. In April 2016, the U.S. Government allocated US$ 5.2 Bn for the National Cancer Institute (NCI), a Federal Government agency, for cancer research and training. The budget increased by 5.3% as compared to the previous year. NCI conducts clinical trials on cancer patients who require repetitive diagnosis to check the prognosis of cancer.

· Availability of BCl-2 inhibitors is limited, the first and only approved drug for the BCL 2 inhibitor is Venetoclax. The FDA approved this drug as a second line treatment for CLL. This limits the availability of treatment to physicians and patients globally.

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Combination Therapy a Preferred Treatment for CLL

· Venetoclax is the only selective inhibitor of the BCL-2 for the relapsed /refractory CLL with 17p deletion depending on the high response rate and safety profile. The inhibitor belongs to the BH3-mimetics class, which is an emerging and novel compound class for the treatment of the BCL-2 indication.

· Various clinical settings have proved the combination of Venetoclax with other compounds successful in treating the BCL-2 indication. Venetoclax is expected to be used in combination with other agents. As compared to monotherapy, the usage of Venetoclax in combination with other drugs reduces adverse events in patients of nausea, diarrhea, thrombocytopenia, and others.

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North America to Lead Global BCL-2 (B-cell lymphoma 2) Inhibitors Market

· In terms of region, the global BCL-2 (B-cell lymphoma 2) inhibitors market can be divided into: North America, Europe, Asia Pacific, Latin America, and Middle East & Africa

· North America is expected to lead the global BCL-2 Inhibitors market, owing to rising cases of CLL and hematology malignancies patient pool. Moreover, approval for Venetoclax in the region, along with combination with other drugs is likely to the drive the market in the region. Ongoing strategic collaborations are also anticipated to fuel the development of the North America BCL-2 inhibitors market. Technological advancement and investments in research & development will propel the market in the region.

· Campaigns for creating awareness about CLL and treatments are likely to boost the demand for BCL-2 inhibitors

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Biomed Grid | Mesenchymal Stem Cells: A New Approach for Treating Bronchopulmonary Dysplasia

Introduction

Worldwide approximately 15 million babies are born prematurely before 37 weeks gestational age, of which an estimated 1 million of these babies die due to complications directly associated with preterm delivery [1]. Premature babies are highly susceptible to several neonatal related-morbidities, namely respiratory, neurological, and gastrointestinal [2]. Several of these illnesses can persist past infancy and childhood and ultimately become a considerable financial burden to both families and healthcare systems [3]. A type of chronic lung disease, bronchopulmonary dysplasia (BPD), particularly prevalent in preterm babies that had received supplemental oxygen and supported by mechanical ventilation for alleviating respiratory failure was first communicated in 1967 [4]. At that time, BPD manifested itself as lung injury with marked inflammation and fibrosis [4]. Since then, significant progress in perinatal and neonatal medicine, together with innovative practices, and procedures have greatly improved survival of extremely premature babies born as early as 22-24 weeks gestational age [5]. At the same time, the incidence of BPD has increased; 45% of preterm babies that are delivered between 22-27 weeks gestational age will go on to develop BPD; in the United States there are up to 10,000 reported incidents of preterm babies with BPD each year [5].

Concurrent with these changes, the pathophysiology of BPD has altered and is now characterized by reduced alveolarization, impaired development of blood vessels and the microvasculature, enlarged airspaces, and poor lung function [6]. The etiology of BPD in the preterm baby is multifactorial; the extent of prematurity, several antenatal insults, and anomalies followed by postnatal influences and other co-morbidities which occur as a consequence of preterm birth all contribute to the onset and progression of BPD, summarized in Figure 1 [6-8]. Anomalies in lung function that began at birth owing to prematurity, subsequent extrauterine adaptations, and the manifestation of BPD persist throughout life [9,10]. Studies have reported that children formerly born premature with BPD were more likely to exhibit poor lung function by the time they reached school-age [10]. Long-term follow-up studies have also reported sub-optimal lung function and increased incidence of emphysema in young adults who were former BPD patients [11,12].

Figure 1: Left, The multifactorial risk factors of bronchopulmonary dysplasia. Right, Present therapeutic options and clinical strategies with the aim to reduce the severity of bronchopulmonary dysplasia

Existing Therapeutic Options for BPD

Despite considerable advances in neonatal clinical management BPD persistently presents itself as a significant illness for premature babies. As the etiology of BPD is multifactorial this presents a confounding therapeutic conundrum. In the ideal setting prevention of premature birth is the sole solution to avoiding the onset of BPD; a feat that has yet to be achieved. Current therapies are mainly supportive and directed towards minimizing lung injury (summarized in Figure 1), but neither significantly diminish the incidence of BPD nor do they alter the pathophysiological course of the disease process [13-18]. In follow-up studies, certain treatment regimens such as postnatal dexamethasone has been associated with adverse neurological outcomes [19]. Clearly, there is a pressing requirement to identify alternative therapies that are both effective and safe for alleviation of this debilitating, multifactorial lung disease.

An Untapped Therapeutic Option: Mesenchymal Stromal/Stem Cells

Bone marrow-derived mesenchymal stromal/stem cells (MSCs) were first described by Friedenstein and colleagues and their intrinsically diverse properties, attributes (e.g. self-renewal, differentiation, pro- angiogenic, anti-inflammatory, anti-fibrotic, and antioxidant), and classifications have been previously reviewed [20-22]. MSCs have been identified in almost all fetal and adult tissues and play crucial roles in promoting tissue development and the reparative responses to the injured host tissues/cells [21,23,24]. In the fetal lung resident or endogenous MSCs coordinate and foster alveolar development, tissue reparative processes, and growth of the pulmonary vasculature [23,25]. Recently Collins and colleagues reported that the repair potential of resident fetal lung MSCs isolated from an oxygen-induced rat BPD model was altered [26]. In addition, studies by Popova and colleagues showed that cultured MSCs isolated from tracheal aspirates of preterm babies that subsequently developed BPD exhibited a myofibroblast phenotype suggesting these cells exhibit a dual mode of action that is dependent upon their environment; Specifically, under normal circumstances resident lung MSCs promote lung growth, repair and development, whereas under constant injury these cells very likely switch to a pathogenic pathway [27].

Owing to the diverse properties and attributes of MSCs coupled with experimental evidence describing their dysfunction in BPD, sound judgement prevails that exogenous MSCs will be a suitable alternative treatment option for BPD. To further support the utility of MSCs as a therapeutic contender for BPD, several logistical aspects have to be considered:

a) MSCs can be easily isolated from adipose and bone marrow tissue in sufficient amounts [28]. MSCs can also be isolated devoid of ethical constraints from placental and umbilical cord tissue (Wharton’s jelly) and blood, and amniotic fluid which provides an autologous source of cells [29,30]. Regardless of the source, MSCs can be easily cultured and rapidly expand in carefully controlled environments, essentially following good manufacturing practices;

b) MSCs do not express human leukocyte antigen class II which affords allogenic treatment [31]; and

c) MSCs can move towards injured tissues and selectively adapt their reparative actions [32].

At first, it was postulated that MSCs exerted their beneficial effects by migrating to the site of injury, followed by engraftment, and then differentiating in to the compromised/damaged cells [34]. Subsequent studies in rodent models of BPD reported poor rates of engraftment of exogenous MSCs coupled with the finding that MSCs only lasted for a few days in the lung [34-36]. The accepted means by which MSCs exert their beneficial effects is via paracrine mechanisms. This includes secretion of bioactive substances with anti- apoptotic, anti-inflammatory, and pro-angiogenic properties (collectively referred to as the secretome or conditioned media) within the microenvironment and exosomes, containing proteins, microRNAs, and mRNA fragments [37,38]. Exosomes are then taken up by the damaged cells by means of vesicle fusion [40]. Also, MSCs can transfer mitochondria to target cells through nanotubes or microvesicles [37]. This is particularly beneficial to minimize apoptosis in target cells [37].

Therapeutic Effects of MSCs: Proving a Concept

The conviction that exogenous MSCs and or the secretome will be beneficial in ameliorating BPD-like lung damage in experimental animal models was validated by Augustine and colleagues, who completed a systematic review and meta-analysis study [41]. In this study the authors categorized 25 independent research reports which utilized newborn rodents (mice and rats) who were exposed to hyperoxia and displayed BPD-like lung injury. Animals received either human umbilical cord or cord blood or rat bone marrow derived MSCs which were administered either via intraperitoneal, intravenous, or intratracheal routes [41]. Variables in these studies included source and route of administration of MSCs, the number of administered cells, and long-term outcomes. In the MSCs-treated rodents, significant improvements in lung function and alveolarization, and vascular growth coupled with decreased inflammation and oxidative stress was observed [7,41-43].

Clinical Trials: Taking the Concept to the Bedside

The outcomes of the initial, groundbreaking phase I clinical trial was recently reported [44]. In this study, nine preterm babies (23-29 weeks gestational age) requiring mechanical ventilation between 5-14 days following birth were treated once with either 107 or 2X107 umbilical cord blood derived MSCs (intratracheal delivery). It is extremely important to note that these babies did not exhibit any undesirable consequences thus strongly supporting the safety and practicality of this novel therapeutic modality [44]. The same investigators went on to report that there were no indications of neurological, respiratory, or growth deficits in these babies after 2 years [45]. These pioneering studies have set the precedence for several other independent investigators to initiate their own phase I-II trials, summarized in Table 1.

Table 1:Clinical Trials of Mesenchymal Stromal Cells Therapy for Bronchopulmonary Dysplasia.

Conclusion

Identifying the most effective treatment for BPD has indeed proven an onerous task. However, owing to advancements in MSCbiology has now afforded us with a potentially very promising therapeutic option. Preclinical studies using MSCs for the treatment of BPD have essentially paved the way for the initiation of several clinical trials. Of note, given the multifactorial nature of BPD, one has to consider that MSCs combined with other drugs may yet prove to be an additional useful therapeutic option. Concurrent with the clinical trials, we must still continue to investigate the long-term efficacy and safety of this particular therapy. Also, of importance is to 1) further understand the mechanistic pathways of MSCs mode of action using both in vivo and in vitro models; and 2) investigate the effects of the microenvironment on the biological properties of lung tissue resident/endogenous MSCs. It is unknown as to whether endogenous fetal lung-MSCs recover and regain their biological properties after cessation or lessening of BPD or how for long they remain in a quiescent/altered state. In a similar context, although recent studies have clearly demonstrated the therapeutic efficacy of exogenously applied MSC or their secretome via a paracrinemediated effect in animal models of neonatal lung disease, the interaction between exogenous MSCs and compromised resident fetal lung-MSCs is unclear.

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