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mesagerulneamt · 7 years ago

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Manifestare anuală, Topul Firmelor Nemțene rămâne cel mai amplu eveniment prin care managerii de elită ai județului sunt recompensați, simbolic, pentru activitatea lor, prilej pentru schimburi de idei și experiență, pentru cunoaștere reciprocă și, nu în ultimul rând, pentru a se simți bine în cadrul unei festivități care le este, exclusiv, destinată și dedicată.

Odată trecut momentul festiv, se pot desprinde câteva concluzii din activitatea economică a județului aferentă anului trecut, iar, pentru a face asta, cea mai potrivită cale o reprezintă o discuție cu Mihai Apopii, președintele Camerei de Comerț și Industrie Neamț, gazda manifestării.

– Domnule președinte, o nouă ediție a Topului Firmelor Nemțene, într-o perioadă nu prea prietenoasă în general și cu mediul de afaceri în special. Este cea de-a XXIV-a ediție și poate ar fi bine, pentru început, să jalonăm evenimentul.

Topul reprezintă deja o manifestare de referință pentru comunitatea de afaceri din Neamț. Este, în egală măsură, un barometru al stării economice a județului și o modalitate care, printr-o metodologie unitară, realizează un clasament al firmelor, după domeniul de activitate, în funcție de niște parametri importanți din activitatea unei firme, după o formulă care a fost prezentată. Interesul oamenilor de afaceri este evident, participarea a fost pe măsură, iar prilejul ca, în același loc, să fie cele mai importante societăți comerciale, din toate domeniile de activitate, și să se poată interacționa este unic. Cred că ați observat, toată lumea s-a simțit bine, momentele artistice au fost gustate, dar cred că cel mai important lucru rămâne faptul că oamenii s-au văzut, s-au cunoscut, au putut interacționa și, în felul acesta, se naște sentimentul de apartenență la o comunitate. Este lucrul pe care Camera de Comerț și-l propune, ca una dintre priorități, pe lângă celelalte activități camerale.

În același context, trebuie să menționez că poate cea mai importantă sursă de informare pentru cei care doresc să facă afaceri în Neamț este catalogul ”Topul Firmelor Nemțene”, care reflectă o stare de lucruri reală și este ca un ”certificat de bonitate” pentru firmele clasate în top.

– Haideți să încercăm să-i caracterizăm, într-o frază, pe cei care au făcut posibilă organizarea unui asemenea eveniment.

Eu spun așa: printr-un management din ce în ce mai modern, firmele din Neamț reușesc, în condiții vitrege de multe ori, prin tenacitate, ambiție, flexibilitate, nu numai să reziste, dar să și sporească valoarea economică a județului. Este meritul celor care le conduc și care, mărturisesc cu bucurie, devin din ce în ce mai interesați să se instruiască în tehnicile de a conduce o firmă. Nu mai lasă lucrurile să meargă la întâmplare, încearcă să prevadă orice i-ar putea afecta ca activitate, se orientează spre noi piețe de desfacere și asta se vede în rezultatele obținute. Profit de moment pentru ca, în numele Colegiului de Conducere al Camerei de Comerț și Industrie Neamț, al întregului colectiv și al meu, personal, să-i felicit pe antreprenorii din Topul Firmelor 2016 și să le mulțumesc tuturor celor care ne-au sprijinit să realizăm acest eveniment de anvergură, al elitei mediului de afaceri nemțean.

* De 10 ani în Topul Firmelor Nemțene!

Kober SRL, Petrocart SA, Rifil SA, Tehnoprod SRL, Smirodava SA, Caremil SRL, Mecanica Ceahlău SA, Marsat SA, Moldocor SA, International Private Security SRL, Metex SA, Enzymes & Derivates SA, Centrul de cercetare și prelucrare a plantelor medicinale Plantavorel SA, Dinamic 92 Distribution SRL, Panauto SRL, Auto Moldova SA

– Camera de Comerț și Industrie Neamț este una dintre filialele cele mai active la nivel național, iar dezbaterile organizate pe diferite probleme de interes au generat, de multe ori, proiecte de legi, modificări legislative, după ce au scos la iveală probleme generale de sistem.

Da, dar trebuie să vă mărturisesc ceva. Inițiativa pentru asemenea dezbateri a venit, de cele mai multe ori, din partea oamenilor de afaceri, care au cerut să se întâlnească, să-și spună păsul, iar atunci când o problemă se dovedea a fi de importanță generală, noi, la Cameră, încercam să găsim o rezolvare, în sensul că identificam exact problema, vedeam ce se poate schimba și cum, după care trimiteam totul spre decidenții politici. Parlamentarii de Neamț, dar nu numai ei – pentru că, prin Camera Națională, propunerile ajungeau direct în comisiile de specialitate ale legislativului, la ministerele interesate și implicate – au primit aceste materiale, le-au primit și cei din conducerea județului și, trebuie să mărturisesc, în general răspunsul a fost pozitiv. Semnalul dinspre Consiliul Județean a fost unul pozitiv, actualul președinte, Ionel Arsene, având inițiative spre mediul de afaceri, fiind alături de noi în înființarea Biroului Unic, dar a și făcut pași spre a cunoaște și a promova nevoile stringente ale județului. De exemplu, colaborarea cu clusterul ASTRICO s-a materializat prin promovarea făcută la Bruxelles, se fac pași pentru materializarea ideii de parc industral, am discutat de multe ori despre un pavilion expozițional demn de județul Neamț și multe alte lucruri.

– Suntem într-un moment de sărbătoare, când trebuie să evidențiem aspectele pozitive. Ce anume credeți că ar trebui spus în acest moment?

Bucuria mea, ca președinte al Camerei, dar și ca om de afaceri, este că pot afirma că, în Neamț, avem firme extrem de puternice pe plan național, premiate an de an în Top și care confirmă constant acest statut. În același timp, avem și societăți care au intrat abia anul acesta în top, dar care demonstrează vitalitate și un ritm de creștere impresionant. Vă pot face o sinteză semnificativă: avem, în Neamț, 9.996 firme care au depus bilanț, din care 9.499 sunt angajatori activi, 50.367 salariați lucrează în firmele care au depus bilanț, iar la nivel județean au fost înregistrate 87.386 contracte de muncă, diferența fiind dată de contractele suspendate, de cele pe perioade detreminate sau de contractele multiple. La nivelul anului 2016, profitul brut a fost de 139,21 milioane de euro, în creștere cu 9,1% față de 2015, când suma era de 126,84 milioane de euro.

* Firme nou intrate în Topul Firmelor Nemțene

Cityshuttle Mobility Solutions SRL, Dinamic 92 Pro Logistics SRL, Nekos Security SRL, Vitamin Aqua SRL, Maria’s Ladybugs SRL, Serviciile Comerciale Române SA (reintrată în top cu altă activitate), Iosidoro SRL (berea Nemțeana), Super Pretzel SRL, Korona Construcții Lemn SRL, Almob Reia SRL, Larixplantsil SRL, Claudiu Demolări SRL-D, La Defense SRL-D, Laura Turism SRL

– Sunt semne foarte bune, dar asta nu înseamnă că nu trebuie ajutate toate societățile din Neamț, prin rezolvarea unor probleme care pun bețe-n roate afacerilor și care nu se datorează mediului de afaceri, ci unei legislații care se schimbă mult prea des, fără motivații economice, fără dezbateri reale și care duce, de cele mai multe ori, la blocaje.

Problemele sunt deja cunoscute, dar reamintirea lor este necesară cu fiecare prilej, pentru că, poate, în felul acesta, oamenii din legislativ vor deveni conștienți de importanța activității lor și de faptul că, fără firme potente, fără contribuțiile plătite de acestea și de angajații lor, nu vor fi bani la buget, indiferent ce taxe și impozite vor apărea, indiferent de mărimea accizelor. Trebuie să înțeleagă toată lumea că 10-15 bani pe litrul de combustibil nu înseamnă doar mai mulți bani pe care-i dă șoferul la pompă, înseamnă scumpiri pe orizontală și verticală, crește prețul transportului, al alimentelor de bază, etc. Oamenii de afaceri români nu doresc lucruri ieșite din comun. Doresc doar predictibilitate, așa cum se întâmplă în toate țările civilizate, doresc o infrastructură competitivă, care să permită cooperarea între toate zonele țării, să permită tranzitul internațional, care aduce venituri consistente bugetului național. Doresc un tratament egal cu marii jucători internaționali din economia românească și doresc să-și poată vinde produsele pe cât mai multe piețe din lume, iar toate acestea se pot face printr-o politică fermă a statului român.

Camera de Comerț și Industrie a României, prin echipa condusă de președintele Mihai Daraban, face eforturi considerabile de a promova produsele românești pe piețe noi, printr-o diplomație de ordin economic, care începe să dea roade. Au fost create baze de date, s-au stabilit relații, lucrurile se dezvoltă în continuare, mai rămâne ca toate acestea să fie valorificate atât de cei care conduc România, cât și de firmele care doresc să intre pe aceste piețe.

– Încercăm o concluzie?

Județul Neamț are potențial, are antreprenori bine pregătiți,. Mai are nevoie de infrastructură și de infuzie de capital, care este binevenit de oriunde ar veni – de la statul român, prin programele guvernamentale, prin proiecte europene sau din partea unor investitori privați. Camera de Comerț și Industrie Neamț încearcă să rămână același instrument care să faciliteze dialogul dintre autorități și mediul de afaceri, care să organizeze târguri și dezbateri specifice, să pună la dispoziție toate cele necesare pentru a porni o afacere, apoi pentru a o extinde. M-au bucurat mult aprecierile la adresa activității Camerei de Comerț venite din partea domnului Ștefan Vuza, un om de afaceri tânăr, dar care are un merit deosebit în salvarea unor mari unități industriale românești, care a pornit din Neamț și care, acum, dezvoltă acasă o activitate cu un potențial imens, valorificând o tradiție a zonei. Sper ca exemplul său să fie urmat și de alți jucători economici naționali, care au plecat cu afacerile din județ și acum reprezintă repere naționale.

* Partenerii Camerei de Comerț și Industrie Neamț în organizarea manifestării

Jora Service SRL, Grupul de firme TCE 3 Brazi SA, Comes SA, Rifil SA, Marsat SA, ADF Prod SRL, RTV Neamț SRL, Bico Industries SRL, Panauto SRL, Expo Carm SRL, Banca Transilvania, BRD Groupe Société Générale, Banca Comercială Română.

* Momentul Ștefan Vuza

Ștefan Vuza

Ca semnificație, un moment deosebit l-a reprezentat scurtul discurs ținut de Ștefan Vuza, președintele grupului de firme Societățile Comerciale Române, bucuros că a fost invitat la gală pentru a-i fi înmânat premiul, dar și un pic necăjit că se întâmplă asta după 20 de ani. Rămâne de reținut îndemnul spre curaj al unui om care a îndrăznit și a reușit:

”Buna seara și doresc să mulțumesc pentru premiu și pentru invitație! Grupul SCR își are sediul, într-adevăr, în județul Neamț. N-am mai fost invitat de 20 de ani de Camera de Comerț și Industrie Neamț. Este o firmă puțin mai mare, ca și cifră de afaceri a depășit 1 miliard de euro. Avem 19 fabrici. Într-adevăr, suntem în activi în industrie, dar, pentru prima dată, primim premiu în agricultură și, pentru că în judetul Neamț nu am mai dezvoltat anumite domenii, pentru că Grupul SCR are deja 25 de ani de activitate, ne-am gândit să reinvestim într-un domeniu nou. E vorba de piscicultură. Ne-am alocat 2 ani de zile să studiem ce fac ceilalți jucători din domeniu. Am descoperit că sunt 42 de jucători în țară. Afacerile lor erau mai mici, afaceri de familie. Am mers în alte țări și am văzut ce trebuie să facem în domeniul piscicol, cum ar trebui să ne dezvoltăm. Așa am creat această păstrăvărie pe lacul Bicaz. Este o păstravărie de 2.000 tone și speram cu toții să fructificăm cât mai bine resursele județului Neamț, care are cu ce se mândri. Aici avem și noi societatea-mamă, cu toate că eu locuiesc la Cluj și la București.

Cred că este bine să îndrăznim mai mult. Să îndrăzniți și voi mai mult, pentru că lucrurile nu sunt greu de făcut! Doar să te pui în poziția de a le face este mai greu.

Vă mulțumesc și vă doresc o seară frumoasă!”.

GALERIE FOTO:

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Mihai Apopii: ”Sunt mândru de firmele prezente în Topul Firmelor Nemțene” Manifestare anuală, Topul Firmelor Nemțene rămâne cel mai amplu eveniment prin care managerii de elită ai județului sunt recompensați, simbolic, pentru activitatea lor, prilej pentru schimburi de idei și experiență, pentru cunoaștere reciprocă și, nu în ultimul rând, pentru a se simți bine în cadrul unei festivități care le este, exclusiv, destinată și dedicată.

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ampk-progeria-hiv · 7 years ago

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Antibiotics produced by Bacteria activate Human Oocytes, creating Healthy Babies: AMPK links the Creation of Human Life with HIV, Progeria, & Cancer

CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0/)], via Wikimedia Commons;By De Wood, Pooley, USDA, ARS, EMU. [Public domain], via Wikimedia Commons

A recent study published online in the journal Fertility and Sterility in September of 2017 systematically reviewed for the first time evidence for the effect of two compounds, ionomycin and A23187 (also known as calcimycin), on fertilization rates and pregnancy outcomes in infertile couples undergoing an in vitro fertilization procedure known as intracytoplasmic sperm injection (ICSI) [1]. ICSI involves the direct deposition of sperm into the oocyte cytoplasm, which typically leads to high rates of fertilization. However, fertilization failure despite repeated ICSI is likely caused by a failure of the oocyte to activate [1]. Physiological oocyte activation is accomplished by the delivery of a sperm-borne oocyte activating factor called phospholipase C zeta (PLCζ). PLCζ activates human oocytes by inducing an intracellular signaling cascade that ultimately results in increased calcium (Ca2+) oscillations in the oocyte, which drives oocyte activation to completion [1]. As oocyte activation is an indispensable prerequisite for the creation of all human life, every human being alive today and any human being that has ever lived began their existence as an activated oocyte [2]. Ionomycin and A23187 increase the levels of intracellular Ca2+ and are thus commonly known as Ca2+ ionophores [1]. The authors of the Fertility and Sterility study showed that over a total of 1,521 ICSI cycles, calcium ionophores including ionomycin and A23187 led to a statistically significant improvement in fertilization, cleavage, blastulation, implantation rates, overall pregnancy, and live-birth rates [1]. Ionomycin and A23187 have also been shown in several independent studies to effectively induce human oocyte activation, leading to the birth of normal, healthy children [3,4].

Strikingly, as described further below, both ionomycin and A23187 are antibiotics that are naturally produced by certain species within the bacterial genus Streptomyces [5,6]. Other structurally distinct compounds and methods have also been shown to induce human oocyte activation, including ethanol, puromycin (an antibiotic and protein synthesis inhibitor produced by Streptomyces alboniger), as well as mechanical manipulation and electrical stimulation, both of with have been reported to result in the creation of normal children [7-11]. Interestingly, as mouse oocytes are considered models for human oocytes, ionomycin, A23187, anisomycin (an antibiotic and protein synthesis inhibitor produced by Streptomyces griseolus), mycophenolic acid (an immunosuppressant produced by the fungus Penicillium brevicompactum), cycloheximide (a protein synthesis inhibitor produced by Streptomyces griseus), carvacrol (a secondary plant metabolite produced by Origanum vulgare{oregano}), and phorbol 12-myristate 13-acetate (PMA, a secondary plant metabolite produced by Croton tiglium) each induce activation of mouse oocytes [12-22]. Ionomycin, A23187, PMA, and reactive oxygen species (ROS) also induce the acrosome reaction in human sperm, a process characterized by the release of hydrolytic enzymes from the head of sperm which is necessary for oocyte penetration and thus indispensable for the creation of all human life outside of a clinical setting (ICSI bypasses the need for oocyte penetration) [23,24]. Additionally, although an over-production of ROS, similar to Ca2+, may lead to deleterious effects including cell death/apoptosis, low levels of ROS have been shown to act as signaling molecules and ROS is significantly increased on or immediately following mouse oocyte activation [25,26].

Furthermore, the master metabolic regulator AMPK is critical for oocyte meiotic resumption and maturation (a process that precedes and is essential for oocyte activation), is found located across the entire acrosome in the head of human sperm, and is activated by increases in ROS and Ca2+ [27-29]. Ionomycin, A23187, ethanol, puromycin, mechanical force, electrical stimulation, anisomycin, mycophenolic acid, carvacrol, and PMA also induce AMPK activation, indicating that a common mechanism of action links chemically distinct compounds with the creation of human life [30-39]. This common mechanism of action likely centers on the induction of cellular stress, mediated by indirect increases in intracellular Ca2+, ROS, and/or the AMP(ADP)/ATP ratio, etc. as I originally proposed in 2016 [40]. Because the bacterial-derived antibiotics ionomycin and A23187 induce both the acrosome reaction in human sperm and human oocyte activation, producing normal, healthy children, it can be said that “non-human organisms have the power to create human life or the power to end life.” As explained below, the beneficial effects of cellular stress induction (i.e. a “shock”) crosses species boundaries and may indeed play a role in facilitating natural selection, a process that underlies and drives evolution.

A number of bacterial species residing within the genus Streptomyces have proven to be extremely important and medicinally valuable as approximately 70% of clinically useful antibiotics are derived from Streptomyces [41]. The antibiotics ionomycin and A23187 are naturally produced by Streptomyces conglobatus and Streptomyces chartreusensis, respectively [5,6]. Other important examples include the antibiotic tetracycline (produced by Streptomyces aureofaciens), the immunosuppressant rapamycin (produced by Streptomyces hygroscopicus), and the anti-helminthic avermectins (produced by Streptomyces avermitilis) [42]. Many soil and aquatic-dwelling species of Streptomyces can be found in harsh environments and are characterized by a unique life cycle, including spore germination followed by vegetative mycelium production, aerial hyphae formation, sporulation (i.e. spore formation), and antibiotic production [43,44]. Curiously, just as cellular stress induction leads to the creation of human life and other beneficial effects in human cells (see below), stress induction also promotes the induction of aerial hyphae formation, sporulation, and antibiotic production in many Streptomyces species (spp.). Indeed, a decrease in the levels of ATP and bacterial growth is associated with sporulation, aerial hyphae formation, and antibiotic production [42,45]. A reduction in glucose/nutritional deprivation, the preferred sugar/carbon source for many Streptomyces spp., also significantly increases antibiotic production [46]. An increase in intracellular ROS and Ca2+ is associated with spore germination, aerial hyphae formation, and antibiotic production [47-49]. Other cellular stressors, including heat shock and ethanol, also significantly increase antibiotic production, provocatively indicating that the effects of cellular stress crosses species boundaries, enhancing bacterial survival and facilitating the creation of human life [50,51].

The beneficial effects of low-level cellular stress induction also extends to plants, as many plants produce secondary metabolites partly for the purpose of self-defense, analogous to antibiotics. Similar to the harsh, stressful environments often inhabited by Streptomyces spp., the Great Basin Bristlecone Pine (Pinus Longaeva), considered the oldest living non-clonal organism on the planet ( >5000 years old), thrives in an exceptionally harsh environment, characterized by increased elevations and exposure to UV radiation, nutritionally-deprived soils, harsh temperatures, and mechanical stress due to wind variances, leading early researchers to conclude that it’s longevity is intimately associated with adversity [52-54]. Conversely, Pinus Longaeva species that are located in less stressful environments (i.e. lower elevations) are strongly associated with younger age classes (<875 years) [55]. Similarly, the Creosote bush (Larrea tridentate), considered one of the oldest living clonal organisms on the planet (>11,000 years old), also thrives in harsh environments including the Mohave Desert [56]. AMPK, which increases lifespan and healthspan in several model organisms, is the primary sensor of cellular stress in eukaryotic organisms (e.g. plants and humans) and the plant AMPK orthologue SnRK1 as well as Ca2+ and ROS are critical for seed germination, fertilization, root gravitropism, and secondary metabolite production [57-64]. The secondary plant metabolites PMA (which activates mouse oocytes and promotes the acrosome reaction in human sperm) and artemisinin (an anti-malarial drug) both activate AMPK and the antibiotic A23187 also increases production of the secondary metabolite resveratrol in grape cell cultures, again indicating that exposure to low-level stressors may promote extension of lifespan and initiate the creation of human life [17,23,39,65,66].

Organismal exposure to beneficial levels of stress may also play a critical role in evolution. As first noted by Charles Darwin, evolution is driven by natural selection, a process characterized by environmentally-induced phenotypic changes that may lead to inheritable survival and reproductive advantages [67]. From “On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life”, Darwin explained that “if there be, owing to the high geometrical powers of increase of each species, at some age, season, or year, a severe struggle for life, and this certainly cannot be disputed;��…But if variations useful to any organic being do occur, assuredly individuals thus characterised will have the best chance of being preserved in the struggle for life;” [67]. This “struggle for life” Darwin spoke of is embodied by selective pressures which may be abiotic (i.e. light, wind, temperature, etc.) or biotic (predation, disease, competition, etc.) [68,69]. As alluded to above, such selective pressures are indeed sources of cellular stress, sensed by both prokaryotes and eukaryotes, that induce beneficial responses (at appropriate levels), leading to the acquisition of phenotypes conducive for continued survival. Both biotic (e.g. infection) and abiotic (e.g. heat) stressors/selective pressures activate AMPK (which is evolutionarily conserved among eukaryotes) in human cells [70,71]. A phenomenon often cited as an example of natural selection on a readily observable timescale is the development of bacterial resistance to antibiotics, resulting in problematic mutant strains that may be life-threatening for some individuals (i.e. the elderly and immunocompromised) [72]. Intriguingly, lethal levels of bactericidal antibiotics have been shown to kill microorganisms via the induction of ROS, sub-lethal levels of bactericidal antibiotics however increase mutagenesis and bacterial resistance via induction of lower levels of ROS, and heat as well as nutritional stress increase bacterial resistance to antibiotics, providing compelling evidence that continuous exposure to low levels of stress likely plays a significant role in natural selection and evolution [73-75].

Moreover, gravity itself likely functions as a cellular stressor/selective pressure that has influenced the development of organisms on Earth since the emergence of the very first lifeform. Gravity exerts its effects on living organisms via the application of force, which is experienced by human cells in the form of mechanical loading or stress [76]. The application of force or a mechanical load has recently been shown to activate AMPK and simulated microgravity (i.e. hind limb unloading in mice) significantly decreases AMPK activation [77,78]. Spaceflight also inhibits the activation of T cells (immune cells essential for adaptive immunity), whereas the application of force and AMPK activation promote T cell activation [79-81]. Interestingly, spaceflight has recently been shown to decrease the levels of the master antioxidant transcription factor Nrf2 and the heat shock-inducible protein HSP90a but increase the levels of the growth-promoting kinase mTOR in mice [82]. AMPK however inhibits mTOR but increases the phosphorylation, nuclear retention, and transcriptional activity of Nrf2 [57,83,84]. Also, HSP90 interacts with and maintains AMPK activity and HSP90 is necessary for progesterone-induced human sperm acrosome reaction [85,86]. Interestingly, rapamycin, an immunosuppressant produced by Streptomyces hygroscopicus, extends lifespan in genetically heterogeneous mice, activates AMPK in vivo in normal aged mice, and increases human sperm motility [42,87,88]. Simulated microgravity via the use of NASA-designed rotating wall vessels (RWVs) however drastically reduces rapamycin production (~90%) whereas the antibiotic gentamycin increases rapamycin production by Streptomyces hygroscopicus, providing further evidence that cellular stress, in the form of mechanical loading induced by gravity, is essential for development, function, and survival of Earth-bound organisms [89,90].

The induction of cellular stress also links seemingly dissimilar physiological and pathological states with the activation of AMPK. As discussed above, both ionomycin and ROS activate AMPK and promote oocyte meiotic resumption, a process that is AMPK-dependent and is essential for efficient oocyte activation [27,30,91]. ROS is also critical for ovulation, PMA and ionomycin both activate mouse oocytes, and ionomycin is extensively used during ICSI procedures, creating normal healthy children, suggesting that cellular stress-induced AMPK activation is also essential for oocyte activation [3,4,12,17,92]. The activation of oocytes and T cells share strikingly similar intracellular signaling mechanisms (e.g. PLC-PIP2-DAG-PKC-IP3-Ca2+) and ionomycin combined with PMA are extremely effective in activating T cells and are often used as positive controls in HIV-1 latency reversal studies [93-95]. Reactivating latent/dormant HIV-1 in CD4+ T cells, potentially facilitating immune system detection and virus destruction, is currently being pursued as a method for the potential eradication of HIV-1 (called the “shock and kill” approach) [96]. Similar to oocyte activation, both Ca2+ and ROS are critical for T cell activation (and hence latent HIV-1 reactivation) and other cellular stress-inducing compounds, including NDGA derived from the Creosote bush, butyrate derived from bacteria, as well as ROS and HSP90 have been shown to reactivate latent HIV-1 [26,93,94,97-101]. Interestingly, AMPK inhibition leads to cell death on T cell activation, knockdown of AMPK significantly decreases HIV-1 replication, and metformin (a well-studied AMPK activator derived from the French Lilac plant) increases butyrate production in human diabetic patients [81,102,103]. Perhaps most convincingly, early preliminary data showed that metformin significantly reduced several markers preferentially associated with cells latently infected with HIV-1 (e.g. PD-1, TIGIT, TIM-3) and also destabilized the latent HIV-1 reservoir in chronically-infected HIV patients, indicating that cellular-stress induced AMPK activation likely links the creation of human life with the potential eradication of HIV-1, as I originally proposed in 2016 [40,104,105].

AMPK activation may also link the disparate disease states of HIV-1 latency and Hutchinson-Gilford progeria syndrome (HGPS). HGPS is a genetic disorder caused by aberrant alternative splicing of the LMNA gene, generating a toxic protein called progerin that induces an accelerated aging phenotype and premature death at approximately 14 years of age [106]. Excessive activity of the gene splicing factor SRSF1 has been shown to prevent reactivation of latent HIV-1 and contribute to aberrant splicing of the LMNA gene in HGPS [107-109]. Metformin however has recently been shown to ameliorate the accelerated aging phenotype in cells derived from children with HGPS by reducing the levels of both SRSF1 and progerin and activating AMPK, as I first proposed in 2014 [110-112]. Interestingly, both Ca2+ and ROS induce autophagy (a process of disposing of damaged/toxic proteins and organelles) and rapamycin, which activates AMPK in vivo and increases intracellular Ca2+ levels, improves accelerated aging in progeria cells by inducing autophagic degradation of progerin [87,113-116]. Temsirolimus, an analog of rapamycin, also alleviated accelerated aging defects in progeria cells but also increased the levels of ROS and superoxide within the first hour of treatment [117]. Such evidence strongly suggests that cellular stress-induced AMPK activation links the reversal of HIV-1 latency and alleviation of accelerated cellular aging defects in HGPS.

Cellular stress-induced AMPK activation also links the potential elimination of cancer stem cells (CSCs) with HIV-1 latency reversal and viral eradication. CSCs, which are largely resistant to chemoradiation therapy, are a subpopulation of cancer cells that exhibit characteristics similar to embryonic stem cells (ESCs), including self-renewal, multi-lineage differentiation, & the ability to initiate tumorigenesis [118,119]. Mechanisms that sustain quiescence & promote self-renewal in adult stem cells (ASCs) & CSCs likely also function to maintain latency of HIV-1 in CD4+ memory T cells. Indeed, HIV-1 has been found to establish long-lasting latency in a recently discovered subset of CD4+ T cells that exhibit stem cell-like properties known as T memory stem (TSCM) cells and increases in Ca2+, ROS, and AMPK activation have been shown to promote T cell activation and ESC, ASC, and CSC differentiation [119,120]. Additionally, A23187 and PMA have been shown to promote CSC differentiation (causing CSCs to become more susceptible to chemoradiation) and metformin induces CSC differentiation and/or apoptosis in an AMPK-dependent manner in the deadliest of cancers, including glioblastoma and pancreatic cancer, providing support for my publication in 2017 in which I first proposed that CSC differentiation and/or apoptosis and HIV-1 latency reversal/viral eradication may be linked by cellular stress-induced AMPK activation [119,121-124].

In conclusion, the ability of non-human organisms including certain Streptomyces spp. to initiate the creation of human life is predicated on the induction of cellular stress, mediated by increases in intracellular ROS, Ca2+, AMP(ADP)/ATP ratio increase, etc. The beneficial effects of transient cellular stress induction, which may be likened to selective pressures, crosses species boundaries and may indeed play a role in facilitating natural selection, a process that underlies and drives evolution, as evidenced by stress-induced increases in antibiotic production by Streptomyces spp. and stress-induced mutagenesis and antibiotic resistance in various bacterial strains. Because AMPK, a primary sensor of cellular stress in eukaryotic cells that increases lifespan and healthspan, plays a critical role in oocyte meiotic resumption/maturation, T cell activation, and stem cell differentiation, the creation of human life, the potential eradication of HIV-1, amelioration of accelerated aging in HGPS cells, and CSC differentiation/apoptosis are likely linked by a “Shock to Live”, or a “Shock to Kill”.

https://www.linkedin.com/pulse/antibiotics-produced-bacteria-activate-human-oocytes-creating-finley/

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#ampk #gut bacteria #metformin #oocyte #HIV/AIDS #progeria #cancer stem cell #evolution #charles darwin #sperm #acrosome reaction #fertilization #reproduction

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ampk-oocyte-hiv · 7 years ago

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Metformin & AMPK Link Nobel Prize-winning Telomeres & Jumping Genes with Learning, HIV, & the Creation of Human Life

Nobel Prize winners, from left to right: Elizabeth Blackburn (discovered telomerase), Barbara McClintock (discovered “jumping genes”), and Françoise Barré-Sinoussi (discovered HIV). By Science History Institute, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=30112731; By Smithsonian Institution/Science Service; Restored by Adam Cuerden - Flickr: Barbara McClintock (1902-1992), Public Domain, https://commons.wikimedia.org/w/index.php?curid=25629182; By Prolineserver (talk) - Own work, GFDL 1.2, https://commons.wikimedia.org/w/index.php?curid=5395403

This study substantiates and confirms several novel proposals in a recently published paper I authored in April of 2018 in which I first proposed that because telomerase is derived from a “jumping gene” (see below for discussion), metformin would activate telomerase via AMPK [6]. My paper also highlights a novel link between hippocampal long-term potentiation (essential for learning and memory), alleviation of accelerated cellular aging in Hutchinson-Gilford progeria syndrome, oocyte activation and the sperm acrosome reaction (prerequisites for human life creation), and transposable element (i.e. “jumping genes”)-mediated promotion of learning, memory, and the creation of human life [1-7]. Indeed, these novel proposals also link several Nobel Prize-winning discoveries, including the discovery of telomerase by Elizabeth Blackburn (photo-left), the discovery of “jumping genes” by Barbara McClintock (photo-middle), and the discovery of HIV by Françoise Barré-Sinoussi (photo-right).

The link between such disparate physiological and pathophysiological phenomena is cellular stress-induced modulation of energy metabolism, leading to the activation of the master metabolic regulator AMPK, a kinase that increases lifespan and healthspan in several model organisms [12]. I was the first to propose and publish (2014) that an increase in beneficial levels of cellular stress (e.g. increases in the levels reactive oxygen species [ROS], calcium [Ca2+], and/or an AMP(ADP)/ATP ratio increase, etc.) and activation of AMPK by compounds including metformin would alleviate accelerated cellular aging defects in children diagnosed with the genetic disorder Hutchinson-Gilford progeria syndrome (HGPS), a disease characterized by an accelerated aging phenotype and death at ~14.6 years of age [1]. This hypothesis was substantiated in 2016 and 2017, with metformin activating AMPK in cells taken from HGPS kids and ameliorating accelerated cellular aging defects (e.g. correcting nuclear morphology, decrease in senescence markers, etc.) [8,9]. Additionally, transfection of telomerase been shown to reverse senescence in HGPS cells [65]. As metformin activates telomerase and normal humans make the same toxic protein (called progerin) that leads to accelerated aging in HGPS kids (just at lower amounts that accumulate with age), AMPK activation may also play a significant role in ameliorating diseases associated with physiological aging [10,11].

AMPK also links HGPS with potential virus eradication. I first proposed in 2015 that AMPK activation links alleviation of accelerated aging in HGPS with the potential eradication of HIV-1 via the “shock and kill” approach, a method currently being pursued by HIV cure researchers to possibly eradicate HIV-1 [2,13]. The same gene splicing factor that promotes accelerated aging in HGPS (called SRSF1 or ASF/SF2) also inhibits reactivation of latent HIV-1 (i.e. “shock”), preventing immune system detection and virus destruction (i.e. “kill”) [8,14]. Metformin was shown to slow aging in HGPS cells by decreasing this splicing factor, as I originally predicted in 2014, and several compounds that potently induce latent HIV-1 reactivation in T cells from infected patients, including PMA (a phorbol ester) combined with ionomycin, each activate AMPK [1,8,15-17]. AMPKα1 deletion leads to a decrease in primary T cell responses to bacterial and viral infections in vivo, AMPK knockdown leads to cell death on T cell activation, and metformin has recently been shown to inhibit Zika and Dengue viruses, the malaria parasite, and Legionella pneumophila [18-23]. Intriguingly, early data presented at the International AIDS Conference in 2017 demonstrated that metformin destabilized the latent HIV-1 reservoir in chronically-infected HIV patients and decreased the percentage of CD4+ T cells expressing the immune checkpoint receptors PD-1, TIGIT, and TIM-3, each markers associated with T cells latently infected with HIV-1, indicating that AMPK activation may indeed contribute to a cure for HIV-1 [24,25].

As I first proposed in 2016 and 2017, the induction of cellular stress and AMPK activation also links HGPS and potential HIV-1 eradication with oocyte activation and the sperm acrosome reaction, prerequisites for the creation of human life [3,4]. Increases in both ROS and Ca2+ are critical for T cell activation (and hence latent HIV-1 reactivation) and ROS is transiently increased in HGPS cells when treated with a rapamycin analog to alleviate accelerated aging [26-28]. Stress-induced activation of AMPK by AICAR and other compounds promotes oocyte maturation, which precedes and is essential for efficient oocyte activation [29,30]. Oocyte activation is indispensable for the creation of all human life and PMA and ionomycin, which collectively reactivates latent HIV-1, activates mouse and human oocytes, respectively [31,32]. AMPK is also found in the acrosome of the human sperm head and ionomycin induces the acrosome reaction in human sperm, a process necessary for oocyte penetration and fertilization [33,34]. Ionomycin is also used extensively during fertility procedures to activate human oocytes (i.e. “shock”), creating normal, healthy children (i.e. “live”) [32]. Interestingly, ionomycin is a narrow spectrum antibiotic produced by certain species within the bacterial genus Streptomyces, from which ~70 percent of clinically useful antibiotics are derived [35,36]. Cellular stress, mediated by increases in ROS, Ca2+, and/or an AMP(ADP)/ATP ratio increase, etc. also enhances antibiotic production in many Streptomyces strains, reinforcing the notion that the beneficial effects of cellular stress induction crosses species boundaries [37,38].

Cellular stress induction and AMPK activation also link HGPS, potential HIV-1 eradication, and human life creation with learning and memory, a hypothesis I originally proposed in 2018 [6]. Hippocampal long-term potentiation (LTP) is considered the cellular correlate of learning and memory and AMPK has been found localized in hippocampal CA1 dendrites and is activated in neurons by metformin, AICAR, ionomycin, and glutamate, a neurotransmitter essential for hippocampal LTP induction [39-41]. The glutamate receptors AMPAR and NMDAR are found on and modulate T cell activation, AMPK activation increases synthesis and membrane insertion of AMPARs (critical for LTP expression), PMA enhances hippocampal CA1 LTP, and inhibition of ROS significantly impairs hippocampal CA1 LTP [42-46]. Also, neuronal depolarization decreases the recruitment efficiency of SRSF1 to nascent RNAs and promotes SRSF1 nuclear speckle accumulation [6]. SRSF1, a gene splicing factor that is inhibited by metformin, enhances progerin production in HGPS cells and prevents latent HIV-1 reactivation [2,8]. Metformin also significantly reduces pathology-associated reductions in LTP in animal models in vivo, indicating that learning and memory are linked to HGPS, potential HIV-1 eradication, and human life creation via the induction of beneficial levels of cellular stress [47].

Lastly, cellular stress and AMPK activation also links the activation and mobilization of transposable elements (i.e. “jumping genes”) with telomerase activation, potential HIV-1 eradication, learning and memory, and the creation of human life, a hypothesis I originally proposed in 2018 [6]. Transposable elements (TEs) are DNA sequences first described by Nobel laureate Barbara McClintock that comprise nearly half of the human genome, are able to transpose or move from one genomic location to another, and have played an extensive role in human genome evolution [48-50]. Strikingly, McClintock also described in her Nobel Prize speech that a genome “shock” seemed to promote TE activation and mobilization [50]. As first noted in my recently published paper, this “shock” is the same “shock” that HIV cure researchers are using during the “shock and kill” approach to reactivate latent HIV-1 to potentially effectuate a cure [6]. Indeed, several forms of cellular stress, including heat shock and radiation, have been convincingly shown to activate and enhance TE mobilization in several model organisms and in human cells [51-53]. This same “shock” McClintock referred to, mediated by increases in ROS, Ca2+, and/or an AMP(ADP)/ATP ratio, etc. is also what leads to the creation of human life, as the antibiotic ionomycin activates AMPK, promotes TE activation, and induces human oocyte activation [17,32,54]. LINE-1 (L1), a member of the retrotransposon class of TEs, is active and capable of mobilization in human oocytes, human sperm, and in human neural progenitor cells [55-57]. Inhibition of L1 impairs both oocyte maturation in vitro and long-term memory formation in vivo in mice [58,59]. L1 has also been detected in the human brain and is capable of mobilization in human neurons [57]. As noted above, AMPK is critical for oocyte maturation and metformin promotes hippocampal neurogenesis and spatial memory formation [29,60]. The landmark initial sequencing of the human genome also noted that both telomerase and RAG1 (promotes DNA cleavage and transposition in human cells) are derived from TEs [49]. Because metformin activates both telomerase and RAG1 via AMPK, it is likely that cellular stress-induced AMPK activation facilitates beneficial TE activation and mobilization (i.e. learning and memory associated with L1 mobilization), linking human genome evolution and the creation of human life with hippocampal LTP, HGPS, and potential HIV-1 eradication [61,62].

https://www.linkedin.com/pulse/metformin-ampk-link-nobel-prize-winning-telomeres-jumping-finley/

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#metformin #ampk #progeria #HIV/AIDS #telomere #Telomerase #fertilization #brain #learning #memory #evolution

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ampk-cancer-stem-cell-hiv · 7 years ago

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Metformin & AMPK Link Nobel Prize-winning Telomeres & Jumping Genes with Learning, HIV, & the Creation of Human Life

https://www.linkedin.com/pulse/metformin-ampk-link-nobel-prize-winning-telomeres-jumping-finley/