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⇩ 2022.12.27.tue 25日でwad collection room でのpopupが終了となりました。 会期中はご来場いただきました皆様、誠にありがとうございました。 また、wadの小林さん、スタッフのみなさんにも大変お世話になり感謝いたします。 今年も残りわずかですがオンラインは明後日29日までのご対応となりますのでよろしくお願いいたします。 @wad.collectionroom wad collection room @wadcafe wad+ #minimalistic #miniwallet #smallwallet #minimal #minimalism #革 #財布 #革財布 #小さい財布 #ミニ財布 #二つ折り財布 #三つ折り財布 #薄い財布 #軽い財布 #leather #wallet #clutch #leatherbag #小さい財布 #ミニ財布 #chamoto #wad #wadcollectionroom #pottery #ceramics #器 #うつわ #古物 https://www.instagram.com/p/CmqvfJXvLf2/?igshid=NGJjMDIxMWI=
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獄中紙『すがも新聞』戦後史の証言 茶本繁正
晩聲社
装幀＝杉浦康平＋鈴木一誌
#獄中紙『すがも新聞』戦後史の証言#shigemasa chamoto#茶本繁正#kohei sugiura#杉浦康平#hitoshi suzuki#鈴木一誌#anamon#古本屋あなもん#あなもん#book cover
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SMALL STAND GRILL Hii ni nzuri sana unakula chakuala kikiwa chamoto, Unaweza kuiweka mezani ukachoma vipande vya samaki, kuku, nyama, mboga mboga nk. Non stick 6 rectangle Brand may bum Germany Bei-80,000 Tupo mikocheni b mwaikibaki road karibu na nakiete pharmacy #0757252557 #0686979377 #afroboel #afrotalia #afrotalia_international #afrotaliatz #stockTanzania https://www.instagram.com/p/COemzT8nw7y/?igshid=1mjchxuv45vgs
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#UmbeaHeist New BANGER 🔥🌍 KAN DANCE Video Out Now Kioo Chamoto kabisa kutoka kwa @mauasama link on her Bio. #KANDANCE 🎶 Produced by @davymachords 📺 Movie Director @director_elvis 💃🏻 💜 @macridajoseph https://www.instagram.com/p/CFgw23pBjW6/?igshid=19vu0elo4gtjl
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Psychiatric man arrested for killing wife
Police in Mchinji have arrested a 39 year old man, Tifanji Raphael believed to be a psychiatric for allegedly hitting to death his wife with an axe.
The deceased has been identified as Sofilet Banda aged 36.
Mchinji Police Station Public Relations Officer, Kondwani Kandiado told Malawi News Agency (Mana) on Tuesday that the suspect who was at large was arrested on Sunday and is expected to answer murder charges.
“Facts are that during the morning of March 19, 2020 a neighbour went to the deceased’s house to borrow a mat. The neighbour had found a four year old child who told her that the deceased was sleeping,” he said.
Kandiado said when the deceased did not respond to the call, it prompted the neighbours to get into the house and were baffled to see the deceased lying in a pool of blood unconscious, with a deep wound on her head.
The PRO said during interrogation by Mchinji Police detectives, the suspect had revealed that he had committed the offence because the deceased was involved in extra marital affair with another man from the same village.
He added “The deceased was then referred to Mchinji District Hospital where she was pronounced dead upon arrival”.
Post-mortem report conducted at the hospital revealed that death was due to severe head injuries.
The deceased hailed from Chadzanga Village, while the suspect comes from Chamoto Village both in the area of Traditional Authority (TA) Nyoka in Mchinji
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Waziri wa Kilimo Maliasili mifugo na uvuvi zanzibar, Mh. Mmanga Mjengo Mjawiri, amesema hataweza kumnyamazia mtumishi yoyote wa wizara ...
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POPO (BAT)⠀ ⠀ Popo ni wanyama warukao na ndio wanyama pekee wenye uwezo huu (yaani ananyonyesha na uwezo wa kuruka),⠀ kuna species zipatazo 1300 za popo⠀ ⠀ Popo ni kiumbe kisichoweza kusimama na kutembea hivyo hulazimika kulala huku akiwa kichwa chini na miguu juu⠀ ⠀ Popo pia huruka na kuongozwa na mwangwi maalumu uitwao echolocation ambao humsaidia kujua aina ya kitu kilichopo mbele yake⠀ hali hii hutumiwa pia na kundi la nyangumi na dolphin, nao hutoa sauti ambao huwajuza mbele kunani?⠀ ⠀ Popo wanakula wadudu kama chakula japo kuna popo wapo marekani wanaitwa vampire bats hao hunywa damu tu na Popo wanakula mbu zaidi ya 1000 kwa muda wa saa moja wakari wa usiku (hivyo ukifuga popo utasahau kuhusu mbu😀 japo chamoto utakiona)⠀ ⠀ Baada ya kupiga menyu digestion hufanyika kwa dakika 20 tu tumboni (sisi masaa mawili )⠀ ⠀ Popo ni nocturnal animals yaani mchana hawaoni na hupumzika ila usiku ndo huwa active, na wanauwezo wa kuona mbali sana wakati huo wa usiku⠀ ⠀ Wanaishi miaka 40 na wanashika mimba kuanzia siku 40-mpaka miezi 6⠀ japo inategemea na jamii,⠀ huzaa mtoto mmoja kwa mwaka⠀ Wanaishi kijamii sana wanaweza wakawa kumi mpaka 50 eneo moja⠀ ⠀ Video⠀ kama inavyosemekana kwamba mwana ndio chanzo kikuu cha huu ugonjwa unaotusumbua hapa duniani wa corona⠀ ⠀ Sasa popo kitaalam ni mnyama anayeweza kukaa na ugonjwa bila yeye kudhuruka ila unapotoka kwenda kwa wanyama wengine ndipo balaa huanza, na hawa wanyama huitwa "carrier" ⠀ Huu mchezo pia unaweza kuukuta kwa nyani na sokwe, wanaweza kuwa na ugonjwa na usiwape tabu ila sasa ukijisogeza wakakupa collabo basi jiandae kwenda kumlaki izraili 😀⠀ ⠀ #baraka_gerald255 https://www.instagram.com/p/CQJdqWqn-NE/?utm_medium=tumblr
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Suspected Oil Keeps Coming Out From Three Hill Tops In Gwembe - Councillor
Gwembe’s Chisanga Ward Councillor, Teddy Chamoto has disclosed that there are three spots with a liquid substance in his area that could possibly be crude oil.
In an exclusive interview with Byta FM News, Chamoto explains that the liquid has always been there for as long as he can remember and reveals that soils at the three points are wet throughout the year.
Chamoto explains that the liquid…
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Daily updates: STORI KALI TANO ZA SIKU /STORI KUBWA LEO/WANAOPOST HABARIFEKI MITANDAONI KUKIONA CHAMOTO
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⇩ 2022.12.25.sun wad collection room popup 本日最終日となります。 18時までとなりますがお待ちしております。 当日お持ち帰りいただけます展示販売となっておりますので最終日までよろしくお願いいたします。 (※カラー等で欠品の物は受注となります。) 2022.12.17 sat - 25 sun 12:00 - 19:00 ※最終日のみ18:00まで 会場 wad collection room @wad.collectionroom wad collection room 〒542-0081 大阪市中央区南船場4-9-2桜ビル3F tel 06-4708-3616 http://wad-cafe.com @wadcafe wad + 〒542-0081 大阪市中央区南船場4-9-3東新ビル3F tel 06-4708-3616 http://wad-cafe.com 通常ラインナップに加えて今回のpop up に際し準備させていただいた新作商品、1点ものなどの展示販売もさせていただきますのでお気軽にお越しください。 ⇩ ▫︎ roll wallet ▫︎ replica wallet ▫︎ mini wallet / léger ▫︎ bifold wallet ▫︎ bellows foldwallet ▫︎ card holder ▫︎ meno / miniwallet ▫︎ flat wallet ▫︎ trifold wallet ▫︎ coin wallet ▫︎ box handle clutch ▫︎ ◻︎ ring belt ▫︎ vintage money clip ▫︎ iremono #minimalistic #miniwallet #smallwallet #minimal #minimalism #革 #財布 #革財布 #小さい財布 #ミニ財布 #二つ折り財布 #三つ折り財布 #薄い財布 #軽い財布 #leather #wallet #clutch #leatherbag #小さい財布 #ミニ財布 #chamoto #wad #wadcollectionroom #pottery #ceramics #器 #うつわ #古物 https://www.instagram.com/p/Cmk03knvkJg/?igshid=NGJjMDIxMWI=
#minimalistic#miniwallet#smallwallet#minimal#minimalism#革#財布#革財布#小さい財布#ミニ財布#二つ折り財布#三つ折り財布#薄い財布#軽い財布#leather#wallet#clutch#leatherbag#chamoto#wad#wadcollectionroom#pottery#ceramics#器#うつわ#古物
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原理運動の実態－ファッシズムへの道 茶本繁正
三一書房
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Analytical performance of a new automated chemiluminescent magnetic immunoassays for soluble PD-1, PD-L1, and CTLA-4 in human plasma.
Analytical performance of a new automated chemiluminescent magnetic immunoassays for soluble PD-1, PD-L1, and CTLA-4 in human plasma.
Sci Rep. 2019 Jul 12;9(1):10144
Authors: Goto M, Chamoto K, Higuchi K, Yamashita S, Noda K, Iino T, Miura M, Yamasaki T, Ogawa O, Sonobe M, Date H, Hamanishi J, Mandai M, Tanaka Y, Chikuma S, Hatae R, Muto M, Minamiguchi S, Minato N, Honjo T
Abstract
Current clinically approved biomarkers for the PD-1 blockade cancer immunotherapy are based entirely on the properties of tumour cells. With increasing awareness of clinical responses, more precise biomarkers for the efficacy are required based on immune properties. In particular, expression levels of immune checkpoint-associated molecules such as PD-1, PD-L1, and CTLA-4 would be critical to evaluate the immune state of individuals. Although quantification of their soluble form leased from the membrane will provide quick evaluation of patients' immune status, available methods such as enzyme-linked immunosorbent assays to measure these soluble factors have limitations in sensitivity and reproducibility for clinical use. To overcome these problems, we developed a rapid and sensitive immunoassay system based on chemiluminescent magnetic technology. The system is fully automated, providing high reproducibility. Application of this system to plasma of patients with several types of tumours demonstrated that soluble PD-1, PD-L1, and CTLA-4 levels were increased compared to those of healthy controls and varied among tumour types. The sensitivity and detection range were sufficient for evaluating plasma concentrations before and after the surgical ablation of cancers. Therefore, our newly developed system shows potential for accurate detection of soluble PD-1, PD-L1, and CTLA-4 levels in the clinical practice.
PMID: 31300681 [PubMed - in process] http://dlvr.it/R8Pbmz
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HAND BLENDER . Hii ni kwajili yakusaga juice,smoother au chakula cha mtoto.Ni nzuri sana inauwezo wa kusaga kwa muda mrefu ni imara sana,inasaga mpaka chakula chamoto mtori,soup,veggie nk Brand JOYTECH GERMANY Watts 300 Bei-50,000 Tupo MBEZI MAKONDE NSSF road& Faraja st Block H Plot 1 Dareslaam Tanzania #0757252557 #0686979377 #afroboel #afrotalia #afrotalia_international #afrotaliatz #stockTanzania https://www.instagram.com/p/CLqWP4bHZHn/?igshid=a2aeaal67e5c
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*WATAKAOKULA PESA ZA MICHANGO YA WANANCHI WATAKIONA CHAMOTO,KOROGWE.* Mkuu wa wilaya ya korogwe Mh Kissa Kasongwa amesema hatamvumilia mtu yeyote ataekula pesa za michango ya wananchi ambazo zimechangwa kwa ajili ya kusaidia ujenzi wa miradi mbali mbali ya maendeleo. Dc Kissa ameyasema hayo wakati alipokuwa kwenye msalambo wa ujenzi wa nyumba ya walimu wa shule ya msingi mlalo ikiwa ni muendelezo wa ziara yake katika Tarafa ya bungu. Aidha Dc Kissa amewapongeza wananchi kwa jinsi walivyojitolea katika ujenzi wa jengo hilo la walimu, pia ameahidi kutoa mifuko 20 ya saruji ili kufanikisha ujenzi huo. Nae diwani wa kata ya Vugiri ambae pia ni mwenyekiti wa halmashauri ya wilaya ya Korogwe amempongeza mkuu wa wilaya kwa jitihada zake za kufanikisha miradi mbalimbali katika halmashauri ya wilaya Korogwe huku baadhi ya wananchi wakishukuru kwa ziara ya hiyo ya mkuu wa wilaya. @korogwempya #TANGAHABARI Comment Like Share #BABADUDATES (at Tanga, Tanzania) https://www.instagram.com/p/BvQ7v4NHito/?utm_source=ig_tumblr_share&igshid=linum1ckaod2
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AMPK activator metformin shown for the first time to destabilize latent HIV-1 reservoir in chronic HIV-1 patients & lower immune checkpoint PD-1
Goldsmith Content Providers: CDC/ C. Goldsmith, P. Feorino, E. L. Palmer, W. R. McManus [Public domain], via Wikimedia Commons; CC BY 2.5 (http://creativecommons.org/licenses/by/2.5)], via Wikimedia Commons; By NASA [Public domain], via Wikimedia
At the International AIDS Society’s (IAS) HIV Cure and Cancer Forum held in Paris, France in July of 2017, researchers from the University of Hawaii demonstrated for the first time that the anti-diabetic drug and AMPK activator metformin not only decreased the percentage of CD4+ T cells expressing the immune checkpoint receptors PD-1, TIGIT, and TIM-3 but also destabilized the viral reservoir in chronically-infected HIV-1 patients, indicating that metformin may indeed contribute to HIV-1 eradication by reactivating CD4+ T cells latently-infected with HIV-1 [1-3]. Current antiretroviral drugs selectively targets only replicating viruses capable of inducing viral gene expression in activated CD4+ T cells [4]. However, a method known as the “shock and kill” approach in HIV-1 cure research involves the reactivation of a small subset of primarily CD4+ memory T cells latently infected with HIV-1 (dormant) with various agents/drugs (i.e. “shock”) and is thought to facilitate virus-induced cell death or immune recognition and destruction of the virus (i.e. “kill”) [4]. Immune checkpoint receptors including PD-1 are considered markers of T cell exhaustion and have also previously been found to be positively associated with T cells that harbor latent HIV-1 [5,6].
As the inhibition of PD-1/PD-L1 significantly enhances CD8+ T cell-mediated immunological responses to both viruses and cancer cells, the finding that metformin decreases PD-1 and destabilizes the latent viral reservoir in chronically-infected HIV-1 patients provides additional evidence and supports several recent publications in which I proposed for the first time that AMPK, which is critical for T cell activation, links the reactivation of latent HIV-1 with the differentiation and/or apoptosis of cancer stem cells and the amelioration of accelerated cellular aging defects in Hutchinson-Gilford progeria syndrome (HGPS) [4,7-10]. Because metformin has recently been shown to improve accelerated aging defects in cells derived from HGPS patients, decrease PD-1 expression on T cells, and potently induce cancer stem cell differentiation and/or apoptosis (e.g. glioblastoma), AMPK activation may indeed lead to the inhibition of tumorigenesis, viral eradication, and mitigation of accelerated aging [1,11-13].
At the IAS HIV Cure and Cancer Forum, Chew et al. presented data from an open label, 24 week clinical trial in which metformin (500 mg increasing to 1000 mg at week 4) was administered to 12 HIV-1 positive patients who were on antiretroviral therapy for greater than a year with plasma HIV RNA less than 50 copies/ml [1]. A non-metformin treated observational arm was also included. Compared to the observational arm, metformin-treated patients exhibited a significant 24 week decease in the change of single positive PD-1+, dual expressing TIGIT+PD-1+, and triple expressing TIGIT+PD-1+TIM-3+ CD4 T cells [1]. Strikingly, although integrated HIV DNA (an indicator of HIV-1 latency) in T cells remained remarkably stable in the 3 subjects in the observation arm, a variance in integrated HIV DNA was observed in metformin-treated patients, indicating that the viral reservoir had been destabilized. Interestingly, the authors also noted a statistically significant decrease in CD32a in metformin-treated patients [1]. CD32a is a surface receptor protein in immune cells that has recently been demonstrated as a reliable marker of CD4+ T cell reservoirs in HIV-1 infected patients harboring replication-competent proviruses, providing compelling evidence that metformin-induced AMPK activation may promote viral eradication by inducing reactivation of latent HIV-1, as evidenced by reductions in PD-1, TIGIT, TIM-3, and CD32a, all markers of CD4+ T cell latent HIV-1 reservoirs [1,14].
In addition to inducing latent HIV-1 reactivation, metformin-induced AMPK activation may also mitigate T cell exhaustion and enhance the immunological response of cytotoxic CD8+ T cells to viruses and cancer cells. Indeed, PD-L1, a ligand that binds to the PD-1 receptor on T cells, has been found on breast and colon cancer stem cells and metformin, AICAR (an AMPK activator), and rapamycin (a macrolide that activates AMPK in vivo) have each been shown to decrease PD-L1 expression on human lung cancer cells [15-18]. Intriguingly, metformin has also been shown to improve intratumoral T cell function and tumor clearance in mice by potentiating PD-1 blockade and significantly increasing the number of activated CD8+ T cells [19].
Moreover, as AMPK is critical for T cell activation and AMPK inhibition during T cell activation leads to T cell death, recent studies indicating that AMPK activators decrease PD-1 expression on T cells and enhance CD8+ T cell-mediated immunological responses strongly suggests that AMPK represents a central node linking latent HIV-1 reactivation with T cell-mediated virus and cancer cell elimination (i.e. immunotherapy) [20]. Eikawa et al. for example showed that metformin enabled normal mice (but not T cell-deficient mice) to reject solid tumors by increasing the number of CD8+ tumor-infiltrating lymphocytes (TILs) and protecting them from exhaustion in an AMPK-dependent manner [21]. Perhaps most convincingly, Chamoto et al. demonstrated in a model using mouse colon cancer MC38 cells that PD-1 blockade (using a PD-L1 inhibitor) led to activation of mitochondria in tumor-reactive cytotoxic CD8+ T lymphocytes, evidenced by increased mitochondrial ROS (i.e. superoxide), larger mitochondrial mass, and higher mitochondrial membrane potential [22].
As mitochondria-derived ROS have previously been shown to be critical, if not indispensable for T cell activation, the combination of a PD-L1 inhibitor/mAb with Luperox (a ROS precursor) greatly enhanced the antitumor activity and survival of tumor-bearing mice [22,23]. Interestingly, the mitochondrial uncouplers FCCP and DNP also extended the survival time of PD-L1 mAb-treated animals, which was mitigated by the ROS scavenger MnTBAP [22]. As ROS have been independently shown to induce AMPK activation and AMPK is essential for T cell activation, the PD-L1 mAb alone induced AMPK activation and the combination of mitochondrial uncouplers with the PD-L1 mAb also further enhanced AMPK activation in CD8+ T cells, indicating that AMPK is essential for enhanced CD8+ T cell activation by PD-1 blockade, ROS generators, and mitochondrial uncouplers [4,22]. Indeed, the authors also showed that the AMPK activator A769662 further enhanced the antitumor activity by PD-L1 mAb treatment and improved animal survival. Additionally, oltipraz and bezafibrate, two compounds that also activate AMPK, strongly enhanced tumor-growth suppression and animal-survival by anti–PD-L1 treatment [22,24,25].
Such data, combined with the recent findings from the IAS HIV Cure and Cancer forum showing that metformin decreases the percentage of CD4+ T cells expressing PD-1, TIGIT, and TIM-3 and destabilizes the viral reservoir in chronically-infected HIV-1 patients, indicates that AMPK activation likely links the reactivation of latent HIV-1 with the facilitation of CD8+ T cell-mediated virus and cancer cell killing, potentially leading to HIV-1 eradication and cancer stem cell elimination, a hypothesis I initially proposed in May of 2017 [4].
Furthermore, AMPK activation also promotes oocyte meiotic induction and maturation (processes that are critical for efficient oocyte activation) and AMPK has recently been found localized across the entire acrosome in human spermatozoa [10,26,27]. The induction of cellular stress (e.g. increases in ROS, intracellular Ca2+, and/or AMP(ADP)/ATP ratio increase), which activates AMPK, also promotes oocyte meiotic induction/maturation, oocyte activation, and the acrosome reaction in human sperm, processes critical for the creation of all human life [26,28,29]. Indeed, the calcium ionophore ionomycin, which activates AMPK, is commonly used to promote latent HIV-1 reactivation and is extensively used to activate human oocytes, creating normal healthy children [29-31]. Such evidence further substantiates the novel and provocative assertion that AMPK activation links the amelioration of pathological cellular defects in Hutchinson-Gilford progeria syndrome with HIV-1 latency, adult and cancer stem cells, learning and memory, and the creation of all human life [4,8-10,32].
https://www.linkedin.com/pulse/ampk-activator-metformin-shown-first-time-destabilize-finley
References
G.M. Chew, D.C. Chow, S.A. Souza, et al. Impact of adjunctive metformin therapy on T cell exhaustion and viral persistence in a clinical trial of HIV-infected adults on suppressive ART. Journal of Virus Eradication 2017; 3 (Supplement 1): 6–19.
http://viruseradication.com/supplement-details/Abstracts_of_the_IAS_HIV_Cure_and_Cancer_Forum_2017/
http://www.iasociety.org/HIV-Programmes/Towards-an-HIV-Cure/Events/HIV-Cure-Cancer-Forum
Finley J. Elimination of cancer stem cells and reactivation of latent HIV-1 via AMPK activation: Common mechanism of action linking inhibition of tumorigenesis and the potential eradication of HIV-1. Med Hypotheses. 2017 Jul;104:133-146.
Fromentin R, Bakeman W, Lawani MB, et al. CD4+ T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence during ART. PLoS Pathog. 2016 Jul 14;12(7):e1005761.
Chew GM, Fujita T, Webb GM, et al. TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection. PLoS Pathog. 2016 Jan 7;12(1):e1005349.
Sakthivel P, Gereke M, Bruder D. Therapeutic intervention in cancer and chronic viral infections: antibody mediated manipulation of PD-1/PD-L1 interaction. Rev Recent Clin Trials. 2012 Feb;7(1):10-23.
Finley J. Alteration of splice site selection in the LMNA gene and inhibition of progerin production via AMPK activation. Med Hypotheses. 2014 Nov;83(5):580-7.
Finley J. Reactivation of latently infected HIV-1 viral reservoirs and correction of aberrant alternative splicing in the LMNA gene via AMPK activation: Common mechanism of action linking HIV-1 latency and Hutchinson-Gilford progeria syndrome. Med Hypotheses. 2015 Sep;85(3):320-32.
Finley J. Oocyte activation and latent HIV-1 reactivation: AMPK as a common mechanism of action linking the beginnings of life and the potential eradication of HIV-1. Med Hypotheses. 2016 Aug;93:34-47.
Park SK, Shin OS. Metformin alleviates ageing cellular phenotypes in Hutchinson-Gilford progeria syndrome dermal fibroblasts. Exp Dermatol. 2017 Feb 13. doi: 10.1111/exd.13323. [Epub ahead of print].
Egesipe AL, Blondel S, Cicero AL, et al. Metformin decreases progerin expression and alleviates pathological defects of Hutchinson-Gilford progeria syndrome cells. NPJ Aging Mech Dis. 2016 Nov 10;2:16026.
Sato A, Sunayama J, Okada M, et al. Glioma-initiating cell elimination by metformin activation of FOXO3 via AMPK. Stem Cells Transl Med 2012;1(11):811–24.
Descours B, Petitjean G, López-Zaragoza JL, et al. CD32a is a marker of a CD4 T-cell HIV reservoir harbouring replication-competent proviruses. Nature. 2017 Mar 23;543(7646):564-567.
Wu Y, Chen M, Wu P, Chen C, Xu ZP, Gu W. Increased PD-L1 expression in breast and colon cancer stem cells. Clin Exp Pharmacol Physiol. 2017 May;44(5):602-604.
Kurimoto R, Iwasawa S, Ebata T, et al. Drug resistance originating from a TGF-β/FGF-2-driven epithelial-to-mesenchymal transition and its reversion in human lung adenocarcinoma cell lines harboring an EGFR mutation. Int J Oncol. 2016 May;48(5):1825-36.
Lastwika KJ, Wilson W 3rd, Li QK, et al. Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer. Cancer Res. 2016 Jan 15;76(2):227-38.
Chiao YA, Kolwicz SC, Basisty N, et al. Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts. Aging (Albany NY). 2016 Feb;8(2):314-27.
Scharping NE, Menk AV, �� Whetstone RD, Zeng X, Delgoffe GM. Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia. Cancer Immunol Res. 2017 Jan;5(1):9-16.
Rao E, Zhang Y, Zhu G, et al. Deficiency of AMPK in CD8+ T cells suppresses their anti-tumor function by inducing protein phosphatase-mediated cell death. Oncotarget 2015;6(10):7944–58.
Eikawa S, Nishida M, Mizukami S, Yamazaki C, Nakayama E, Udono H. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1809-14.
Chamoto K, Chowdhury PS, Kumar A, et al. Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity. Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):E761-E770.
Sena LA, Li S, Jairaman A, et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity. 2013 Feb 21;38(2):225-36.
Zhong X, Xiu LL, Wei GH, et al. Bezafibrate enhances proliferation and differentiation of osteoblastic MC3T3-E1 cells via AMPK and eNOS activation. Acta Pharmacol Sin. 2011 May;32(5):591-600.
Kim TH, Eom JS, Lee CG, Yang YM, Lee YS, Kim SG. An active metabolite of oltipraz (M2) increases mitochondrial fuel oxidation and inhibits lipogenesis in the liver by dually activating AMPK. Br J Pharmacol. 2013 Apr;168(7):1647-61.
LaRosa C, Downs SM. Stress stimulates AMP-activated protein kinase and meiotic resumption in mouse oocytes. Biol Reprod. 2006 Mar;74(3):585-92.
Calle-Guisado V, de Llera AH, Martin-Hidalgo D, et al. AMP-activated kinase in human spermatozoa: identification, intracellular localization, and key function in the regulation of sperm motility. Asian J Androl. 2016 Sep 27. doi: 10.4103/1008-682X.185848. [Epub ahead of print].
de Lamirande E, Tsai C, Harakat A, Gagnon C. Involvement of reactive oxygen species in human sperm arcosome reaction induced by A23187, lysophosphatidylcholine, and biological fluid ultrafiltrates. J Androl. 1998 Sep-Oct;19(5):585-94.
Deemeh MR, Tavalaee M, Nasr-Esfahani MH. Health of children born through artificial oocyte activation: a pilot study. Reprod Sci. 2015 Mar;22(3):322-8.
Tamás P, Hawley SA, Clarke RG, et al. Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J Exp Med. 2006 Jul 10;203(7):1665-70.
Spina CA, Anderson J, Archin NM, et al. An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients. PLoS Pathog 2013;9(12):e1003834.
Finley J. Facilitation of hippocampal long-term potentiation and reactivation of latent HIV-1 via AMPK activation: Common mechanism of action linking learning, memory, and the potential eradication of HIV-1. Med Hypotheses. Manuscript submitted.
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AMPK activator Metformin shown for the first time to destabilize latent HIV-1 reservoir in chronic HIV-1 patients & lower immune checkpoint PD-1
Goldsmith Content Providers: CDC/ C. Goldsmith, P. Feorino, E. L. Palmer, W. R. McManus [Public domain], via Wikimedia Commons; CC BY 2.5 (http://creativecommons.org/licenses/by/2.5)], via Wikimedia Commons; By NASA [Public domain], via Wikimedia
At the International AIDS Society’s (IAS) HIV Cure and Cancer Forum held in Paris, France in July of 2017, researchers from the University of Hawaii demonstrated for the first time that the anti-diabetic drug and AMPK activator metformin not only decreased the percentage of CD4+ T cells expressing the immune checkpoint receptors PD-1, TIGIT, and TIM-3 but also destabilized the viral reservoir in chronically-infected HIV-1 patients, indicating that metformin may indeed contribute to HIV-1 eradication by reactivating CD4+ T cells latently-infected with HIV-1 [1-3]. Current antiretroviral drugs selectively targets only replicating viruses capable of inducing viral gene expression in activated CD4+ T cells [4]. However, a method known as the “shock and kill” approach in HIV-1 cure research involves the reactivation of a small subset of primarily CD4+ memory T cells latently infected with HIV-1 (dormant) with various agents/drugs (i.e. “shock”) and is thought to facilitate virus-induced cell death or immune recognition and destruction of the virus (i.e. “kill”) [4]. Immune checkpoint receptors including PD-1 are considered markers of T cell exhaustion and have also previously been found to be positively associated with T cells that harbor latent HIV-1 [5,6].
As the inhibition of PD-1/PD-L1 significantly enhances CD8+ T cell-mediated immunological responses to both viruses and cancer cells, the finding that metformin decreases PD-1 and destabilizes the latent viral reservoir in chronically-infected HIV-1 patients provides additional evidence and supports several recent publications in which I proposed for the first time that AMPK, which is critical for T cell activation, links the reactivation of latent HIV-1 with the differentiation and/or apoptosis of cancer stem cells and the amelioration of accelerated cellular aging defects in Hutchinson-Gilford progeria syndrome (HGPS) [4,7-10]. Because metformin has recently been shown to improve accelerated aging defects in cells derived from HGPS patients, decrease PD-1 expression on T cells, and potently induce cancer stem cell differentiation and/or apoptosis (e.g. glioblastoma), AMPK activation may indeed lead to the inhibition of tumorigenesis, viral eradication, and mitigation of accelerated aging [1,11-13].
At the IAS HIV Cure and Cancer Forum, Chew et al. presented data from an open label, 24 week clinical trial in which metformin (500 mg increasing to 1000 mg at week 4) was administered to 12 HIV-1 positive patients who were on antiretroviral therapy for greater than a year with plasma HIV RNA less than 50 copies/ml [1]. A non-metformin treated observational arm was also included. Compared to the observational arm, metformin-treated patients exhibited a significant 24 week decease in the change of single positive PD-1+, dual expressing TIGIT+PD-1+, and triple expressing TIGIT+PD-1+TIM-3+ CD4 T cells [1]. Strikingly, although integrated HIV DNA (an indicator of HIV-1 latency) in T cells remained remarkably stable in the 3 subjects in the observation arm, a variance in integrated HIV DNA was observed in metformin-treated patients, indicating that the viral reservoir had been destabilized. Interestingly, the authors also noted a statistically significant decrease in CD32a in metformin-treated patients [1]. CD32a is a surface receptor protein in immune cells that has recently been demonstrated as a reliable marker of CD4+ T cell reservoirs in HIV-1 infected patients harboring replication-competent proviruses, providing compelling evidence that metformin-induced AMPK activation may promote viral eradication by inducing reactivation of latent HIV-1, as evidenced by reductions in PD-1, TIGIT, TIM-3, and CD32a, all markers of CD4+ T cell latent HIV-1 reservoirs [1,14].
In addition to inducing latent HIV-1 reactivation, metformin-induced AMPK activation may also mitigate T cell exhaustion and enhance the immunological response of cytotoxic CD8+ T cells to viruses and cancer cells. Indeed, PD-L1, a ligand that binds to the PD-1 receptor on T cells, has been found on breast and colon cancer stem cells and metformin, AICAR (an AMPK activator), and rapamycin (a macrolide that activates AMPK in vivo) have each been shown to decrease PD-L1 expression on human lung cancer cells [15-18]. Intriguingly, metformin has also been shown to improve intratumoral T cell function and tumor clearance in mice by potentiating PD-1 blockade and significantly increasing the number of activated CD8+ T cells [19].
Moreover, as AMPK is critical for T cell activation and AMPK inhibition during T cell activation leads to T cell death, recent studies indicating that AMPK activators decrease PD-1 expression on T cells and enhance CD8+ T cell-mediated immunological responses strongly suggests that AMPK represents a central node linking latent HIV-1 reactivation with T cell-mediated virus and cancer cell elimination (i.e. immunotherapy) [20]. Eikawa et al. for example showed that metformin enabled normal mice (but not T cell-deficient mice) to reject solid tumors by increasing the number of CD8+ tumor-infiltrating lymphocytes (TILs) and protecting them from exhaustion in an AMPK-dependent manner [21]. Perhaps most convincingly, Chamoto et al. demonstrated in a model using mouse colon cancer MC38 cells that PD-1 blockade (using a PD-L1 inhibitor) led to activation of mitochondria in tumor-reactive cytotoxic CD8+ T lymphocytes, evidenced by increased mitochondrial ROS (i.e. superoxide), larger mitochondrial mass, and higher mitochondrial membrane potential [22].
As mitochondria-derived ROS have previously been shown to be critical, if not indispensable for T cell activation, the combination of a PD-L1 inhibitor/mAb with Luperox (a ROS precursor) greatly enhanced the antitumor activity and survival of tumor-bearing mice [22,23]. Interestingly, the mitochondrial uncouplers FCCP and DNP also extended the survival time of PD-L1 mAb-treated animals, which was mitigated by the ROS scavenger MnTBAP [22]. As ROS have been independently shown to induce AMPK activation and AMPK is essential for T cell activation, the PD-L1 mAb alone induced AMPK activation and the combination of mitochondrial uncouplers with the PD-L1 mAb also further enhanced AMPK activation in CD8+ T cells, indicating that AMPK is essential for enhanced CD8+ T cell activation by PD-1 blockade, ROS generators, and mitochondrial uncouplers [4,22]. Indeed, the authors also showed that the AMPK activator A769662 further enhanced the antitumor activity by PD-L1 mAb treatment and improved animal survival. Additionally, oltipraz and bezafibrate, two compounds that also activate AMPK, strongly enhanced tumor-growth suppression and animal-survival by anti–PD-L1 treatment [22,24,25].
Such data, combined with the recent findings from the IAS HIV Cure and Cancer forum showing that metformin decreases the percentage of CD4+ T cells expressing PD-1, TIGIT, and TIM-3 and destabilizes the viral reservoir in chronically-infected HIV-1 patients, indicates that AMPK activation likely links the reactivation of latent HIV-1 with the facilitation of CD8+ T cell-mediated virus and cancer cell killing, potentially leading to HIV-1 eradication and cancer stem cell elimination, a hypothesis I initially proposed in May of 2017 [4].
Furthermore, AMPK activation also promotes oocyte meiotic induction and maturation (processes that are critical for efficient oocyte activation) and AMPK has recently been found localized across the entire acrosome in human spermatozoa [10,26,27]. The induction of cellular stress (e.g. increases in ROS, intracellular Ca2+, and/or AMP(ADP)/ATP ratio increase), which activates AMPK, also promotes oocyte meiotic induction/maturation, oocyte activation, and the acrosome reaction in human sperm, processes critical for the creation of all human life [26,28,29]. Indeed, the calcium ionophore ionomycin, which activates AMPK, is commonly used to promote latent HIV-1 reactivation and is extensively used to activate human oocytes, creating normal healthy children [29-31]. Such evidence further substantiates the novel and provocative assertion that AMPK activation links the amelioration of pathological cellular defects in Hutchinson-Gilford progeria syndrome with HIV-1 latency, adult and cancer stem cells, learning and memory, and the creation of all human life [4,8-10,32].
https://www.linkedin.com/pulse/ampk-activator-metformin-shown-first-time-destabilize-finley
References
G.M. Chew, D.C. Chow, S.A. Souza, et al. Impact of adjunctive metformin therapy on T cell exhaustion and viral persistence in a clinical trial of HIV-infected adults on suppressive ART. Journal of Virus Eradication 2017; 3 (Supplement 1): 6–19.
http://viruseradication.com/supplement-details/Abstracts_of_the_IAS_HIV_Cure_and_Cancer_Forum_2017/
http://www.iasociety.org/HIV-Programmes/Towards-an-HIV-Cure/Events/HIV-Cure-Cancer-Forum
Finley J. Elimination of cancer stem cells and reactivation of latent HIV-1 via AMPK activation: Common mechanism of action linking inhibition of tumorigenesis and the potential eradication of HIV-1. Med Hypotheses. 2017 Jul;104:133-146.
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