Precision Clinical Medicine最新文献

The COVID-19 pandemic poses a fundamental challenge to global health. Since the outbreak of SARS-CoV-2, great efforts have been made to identify antiviral strategies and develop therapeutic drugs to combat the disease. There are different strategies for developing small molecular anti-SARS-CoV-2 drugs, including targeting coronavirus structural proteins (e.g. spike protein), non-structural proteins (nsp) (e.g. RdRp, M^pro, PL^pro, helicase, nsp14, and nsp16), host proteases (e.g. TMPRSS2, cathepsin, and furin) and the pivotal proteins mediating endocytosis (e.g. PIKfyve), as well as developing endosome acidification agents and immune response modulators. Favipiravir and chloroquine are the anti-SARS-CoV-2 agents that were identified earlier in this epidemic and repurposed for COVID-19 clinical therapy based on these strategies. However, their efficacies are controversial. Currently, three small molecular anti-SARS-CoV-2 agents, remdesivir, molnupiravir, and Paxlovid (PF-07321332 plus ritonavir), have been granted emergency use authorization or approved for COVID-19 therapy in many countries due to their significant curative effects in phase III trials. Meanwhile, a large number of promising anti-SARS-CoV-2 drug candidates have entered clinical evaluation. The development of these drugs brings hope for us to finally conquer COVID-19. In this account, we conducted a comprehensive review of the recent advances in small molecule anti-SARS-CoV-2 agents according to the target classification. Here we present all the approved drugs and most of the important drug candidates for each target, and discuss the challenges and perspectives for the future research and development of anti-SARS-CoV-2 drugs.

[This corrects the article DOI: 10.1093/pcmedi/pbac007.].

Background: To evaluate the effect of lanosterol on cataractous lens of cynomolgus monkeys using a subconjunctival drug release system.

Methods: Nine elder cynomolgus monkeys were used, consisting of three monkeys without cataract as controls, three monkeys with naturally occurring cortical cataract, and three monkeys with nuclear cataract as intervention groups. Nanoparticulated thermogel with lanosterol and fluorescein was administered by subconjunctival injection in the monkeys with cataract. Fluorescence changes of injected thermogel and cataract progression were observed. Lanosterol concentration in aqueous humor, solubility changes in lens proteins, and oxidative stress levels were analyzed in the lenses of the control and intervention groups.

Results: Injected thermogel showed decreased fluorescence during follow up. Lanosterol concentration in aqueous humor increased in the first 2 weeks and then gradually decreased, which was in accordance with the changes in cortical lens clarity. However, lenses with nuclear opacification showed little change. In the cortical region of lenses with cortical cataract, solubility of α-crystallin was significantly increased after administration of lanosterol, as well as the reduction of oxidative stress.

Conclusions: We demonstrated the effect of lanosterol on cataract progression based on in vivo models of primates. Lanosterol showed a short-term and reliable reversal effect on reducing cataract severity in cortical cataract in the early stages, possibly due to the increase in the solubility of lens proteins and changes in the oxidative stress status. Lanosterol administration using subconjunctival drug release system could be a promising nonsurgical approach for future clinical studies of cataract prevention and treatment.

The dermal papilla cells in hair follicles function as critical regulators of hair growth. In particular, alopecia areata (AA) is closely related to the malfunctioning of the human dermal papilla cells (hDPCs). Thus, identifying the regulatory mechanism of hDPCs is important in inducing hair follicle (HF) regeneration in AA patients. Recently, growing evidence has indicated that 3' untranslated regions (3' UTR) of key genes may participate in the regulatory circuitry underlying cell differentiation and diseases through a so-called competing endogenous mechanism, but none have been reported in HF regeneration. Here, we demonstrate that the 3' UTR of junctional adhesion molecule A (JAM-A) could act as an essential competing endogenous RNA to maintain hDPCs function and promote HF regeneration in AA. We showed that the 3' UTR of JAM-A shares many microRNA (miRNA) response elements, especially miR-221-3p, with versican (VCAN) mRNA, and JAM-A 3' UTR could directly modulate the miRNA-mediated suppression of VCAN in self-renewing hDPCs. Furthermore, upregulated VCAN can in turn promote the expression level of JAM-A. Overall, we propose that JAM-A 3' UTR forms a feedback loop with VCAN and miR-221-3p to regulate hDPC maintenance, proliferation, and differentiation, which may lead to developing new therapies for hair loss.

CD4⁺ T cells are critical to the development of autoimmune disorders. Glucose, fatty acids, and glutamine metabolisms are the primary metabolic pathways in immune cells, including CD4⁺ T cells. The distinct metabolic programs in CD4⁺ T cell subsets are recognized to reflect the bioenergetic requirements, which are compatible with their functional demands. Gut microbiota affects T cell responses by providing a series of antigens and metabolites. Accumulating data indicate that CD4⁺ T cell metabolic pathways underlie aberrant T cell functions, thereby regulating the pathogenesis of autoimmune disorders, including inflammatory bowel diseases, systemic lupus erythematosus, and rheumatoid arthritis. Here, we summarize the current progress of CD4⁺ T cell metabolic programs, gut microbiota regulation of T cell metabolism, and T cell metabolic adaptions to autoimmune disorders to shed light on potential metabolic therapeutics for autoimmune diseases.