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Small molecule conjugates with selective estrogen receptor β agonism promote anti-aging benefits in metabolism and skin recovery

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2137-2152页

作者： tarik.zahr Vijay K.Boda Jian Ge Lexiang Yu Zhongzhi Wu Jianwen Que Wei Li Li Qiang Naomi Berrie Diabetes Center Columbia UniversityNew YorkNY 10032USA Department of Molecular Pharmacology and Therapeutics Columbia UniversityNew YorkNY 10032USA Department of Pharmaceutical Sciences College of PharmacyUniversity of Tennessee Health Science CenterMemphisTN 38163USA Drug Discovery Center College of PharmacyUniversity of Tennessee Health Science CenterMemphisTN 38163USA Division of Digestive and Liver Diseases Columbia UniversityNew YorkNY 10032USA Center for Human Development Columbia UniversityNew YorkNY 10027USA Department of Pathology and Cell Biology Columbia UniversityNew YorkNY 10032USA Department of Medicine Columbia UniversityNew YorkNY 10032USA

Estrogen is imperative to mammalian reproductivity,metabolism,and ***,the hormone activating estrogen receptor(ERs)αcan cause major safety concerns due to the enrichment of ERαin female tissues and certain *** contrast,ERβis more broadly expressed in metabolic tissues and the ***,it is desirable to generate selective ERβagonist conjugates for maximizing the therapeutic effects of ERs while minimizing the risks of ERα***,we report the design and production of small molecule conjugates containing selective non-steroid ERβagonists Gtx878 or *** of aged mice with our synthesized conjugates improved aging-associated declines in insulin sensitivity,visceral adipose integrity,skeletal muscle function,and skin health,with validation in *** further uncovered the benefits of ERβconjugates in the skin using two inducible skin injury mouse models,showing increased skin basal cell proliferation,epidermal thickness,and wound ***,our ERβ-selective agonist conjugates offer novel therapeutic potential to improve aging-associated conditions and aid in rejuvenating skin health.

关键词： Estrogen receptorβ Aging Metabolism Skin injury Muscle metabolism Small molecule conjugates Regeneration Adiposity

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The polarizable and reprogrammable identity of Kupffer cells in Nonalcoholic Steatohepatitis

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Medical Review 2022年第4期2卷 324-327页

作者： tarik.zahr Kevin Sun Li Qiang Naomi Berrie Diabetes Center Columbia University1150 St.Nicholas AveNew YorkNY 10032USA Department of Molecular Pharmacology and Therapeutics Columbia UniversityNew YorkNYUSA Department of Pathology and Cell Biology Columbia UniversityNew YorkNY 10032USA

Kupffer cells(KCs)are the resident macrophages of the liver with similar origins to myeloid-derived *** differentiated,KCs exhibit distinct cellular machinery capable of longevity and self-renewal,making them a crucial player in promoting effective intrahepatic ***,this gets compromised in disease states like Nonalcoholic Steatohepatitis(NASH),where the loss of embryo-derived KCs(EmKCs)is *** this,other KC-like and KC-derived populations start to form and contribute to a variety of roles in NASH pathogenesis,often adopting a NASH-associated molecular *** we offer a brief overview of recent reports describing KC polarization and reprogramming in the *** describe the complexities of KC cellular identity,their proposed ability to reprogram to fibroblast-like and endothelial-like cells,and the potential implications in NASH.

关键词： Kupffer cells macrophages Nonalcoholic Steatohepatitis polarization reprogramming

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Acetylation of PPARγin macrophages promotes visceral fat degeneration in obesity

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Life Metabolism 2022年第3期1卷 258-269页

作者： Nicole Aaron tarik.zahr Ying He Lexiang Yu Brent Mayfield Utpal BPajvani Li Qiang Naomi Berrie Diabetes Center Columbia UniversityNew YorkNYUSA Department of Pharmacology Columbia UniversityNew YorkNYUSA Department of Pathology and Cell Biology Columbia UniversityNew YorkNYUSA Department of Genetics and Development Columbia UniversityNew YorkNYUSA Department of Medicine Columbia UniversityNew YorkNYUSA

Obesity is characterized by chronic,low-grade inflammation,which is driven by macrophage infiltration of adipose ***γ is well established to have an anti-inflammatory function in macrophages,but the mechanism that regulates its function in these cells remains to be fully ***γundergoes post-translational modifications(PTMs),including acetylation,to mediate ligand responses,including on metabolic ***,we report that PPARγacetylation in macrophages promotes their infiltration into adipose tissue,exacerbating metabolic *** generated a mouse line that expresses a macrophage-specific,constitutive acetylation-mimetic form of PPARγ(K293Q^(flox/flox):LysM-cre,mK293Q)to dissect the role of PPARγacetylation in *** highfat diet feeding to stimulate macrophage infiltration into adipose tissue,we assessed the overall metabolic profile and tissue-specific phenotype of the mutant mice,including responses to the PPARγagonist ***-specific PPARγK293Q expression promotes proinflammatory macrophage infiltration and fibrosis in epididymal white adipose tissue,but not in subcutaneous or brown adipose tissue,leading to decreased energy expenditure,insulin sensitivity,glucose tolerance,and adipose tissue ***,mK293Q mice are resistant to Rosiglitazone-induced improvements in adipose tissue *** study reveals that acetylation is a new layer of PPARγregulation in macrophage activation,and highlights the importance and potential therapeutic implications of such PTMs in regulating metabolism.

关键词： PPARγacetylation adipose tissue remodeling macrophage inflammation fibrosis

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A Concise History of Islamic Medicine: An Introduction to the Origins of Medicine in Islamic Civilization, Its Impact on the Evolution of Global Medicine, and Its Place in the Medical World Today

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International Journal of Clinical Medicine 2022年第4期13卷 180-197页

作者： Homayun Shahpesandy tarik Al-Kubaisy Rosemary Mohammed-Ali Ahmed Oladosu Rachael Middleton Nermin Saleh Ash Villa Willoughby Road Greylees Sleaford NG34 8QA Lincolnshire Partnership NHS Foundation Trust UK Early Intervention Psychosis Team Meridian House Normanby Road Scunthorpe North Lincolnshire DN15 8QZ Rotherham Don-caster and South Humber NHS Foundation Trust UK The Hartsholme Centre Long Leys Road Lincoln LN1 1FS Lincolnshire NHS Foundation Trust UK Carlholme Court Long Leys Road Lincoln LN1 1FS Lincolnshire NHS Foundation Trust UK

The practice of medicine in Muslim nations dates to the millennia before the advent of the religion of Islam. As far as the pre-Islamic period is concerned, what evidence is available indicates the medical evolution began nearly 6000 years ago in Mesopotamia, where medicine for the first time in history became a recognised profession. In ancient Egypt, it was practised by priest-physicians who demonstrated astonishing knowledge in various medical subjects. The origins of medicine in ancient Persia (Afghanistan, Iran, and parts of Central Asia) span the 6th century B.C. and to the Zoroastrian religious book of Avesta, which delved into such topics as preventive and clinical medicine. In reference to the account of medicine in the Arab peninsula, limited information exists. In terms of post-Islamic ages, the foundations of Islamic science were laid during the reign of the second Abbasid Caliph, al-Mansur, and the establishment of Baghdad as its capital in 762 A.D., when the Arabic translation movement commenced. During the next six centuries, medicine and other fields of science flourished, and prominent physicians such as the Bukht Yishu family, Razī, Majūsī, Avicenna, Jorjanī, Al-zahrāwī, and other scientists emerged. In both the pre- and post-Islamic ages, Islamic medicine was heavily influenced by Mesopotamian, Egyptian, Persian, Indian, and, predominantly, Greek medicine. Nevertheless, the advancements and innovations in medical science and healthcare systems that were achieved during the early and medieval Islamic ages have indubitably made an invaluable contribution to the evolution of medicine throughout the world, and to the invention of numerous procedures and practices which are still widely performed today. Hence, the value of comprehending the pivotal role Islamic medicine played (and indeed still plays) in the progression of medical practice across the globe cannot be overstated.

关键词： History of Medicine Islamic Civilisation Balkhi Razi Avicenna

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