A new year,a renewed dedication:greetings from Medical Review

As the crisp air of a new year washes over us,carrying with it the scent of possibilities and the whispers of unfinished endeavors,it is time for reflection and,of course,renewed dedication.Here at Medical Review,we stand tall amidst the constant churn of scientific discovery,witnessing firsthand the tireless efforts of researchers,clinicians,and healthcare professionals who relentlessly push the boundaries of medical knowledge.

The complex interplay between aging and cancer:unraveling the clues

Throughout our life journey,two unstoppable forces shape our existence:the specter of aging and cancer.Seemingly unrelated,these phenomena are more intertwined than we might think[1].The incidence and mortality rates of cancer increase exponentially with age,and their underlying causes are both related to cellular dysfunction.Studying these commonalities is not only key to unlocking cancer therapies,but it may also inspire us to find interventions that delay the aging process itself.

GRP75 triggers white adipose tissue browning to promote cancer-associated cachexia

Cachexia,which affects 50–80%of cancer patients,is a debilitating syndrome that leads to 20%of cancer-related deaths.A key feature of cachexia is adipose tissue atrophy,but how it contributes to the development of cachexia is poorly understood.Here,we demonstrate in mouse models of cancer cachexia that white adipose tissue browning,which can be a characteristic early-onset manifestation,occurs prior to the loss of body weight and skeletal muscle wasting.By analysing the proteins differentially expressed in extracellular vesicles derived from cachexia-inducing tumours,we identified a molecular chaperone,Glucose-regulated protein 75(GRP75),as a critical mediator of adipocyte browning.Mechanistically,GRP75 binds adenine nucleotide translocase 2(ANT2)to form a GRP75–ANT2 complex.Strikingly,stabilized ANT2 enhances its interaction with uncoupling protein 1,leading to elevated expression of the latter,which,in turn,promotes adipocyte browning.Treatment with withanone,a GRP75 inhibitor,can reverse this browning and alleviate cachectic phenotypes in vivo.Overall,our findings reveal a novel mechanism by which tumour-derived GRP75 regulates white adipose tissue browning during cachexia development and suggest a potential white adipose tissue-centred targeting approach for early cachexia intervention.

A highly selective C-rhamnosyltransferase from Viola tricolor and insights into its mechanisms

C-Glycosides are important natural products with various bioactivities.In plant biosynthetic pathways,the C-glycosylation step is usually catalyzed by C-glycosyltransferases(CGTs),and most of them prefer to accept uridine 5’-diphosphate glucose(UDP-Glc)as sugar donor.No CGTs favoring UDP-rhamnose(UDP-Rha)as sugar donor has been reported,thus far.Herein,we report the first selective C-rhamnosyltransferase VtCGTc from the medicinal plant Viola tricolor.VtCGTc could efficiently catalyze C-rhamnosylation of 2-hydroxynaringenin 3-C-glucoside,and exhibited high selectivity towards UDP-Rha.Mechanisms for the sugar donor selectivity of VtCGTc were investigated by molecular dynamics(MD)simulations and molecular mechanics with generalized Born and surface area solvation(MM/GBSA)binding free energy calculations.Val144 played a vital role in recognizing UDP-Rha,and the V144T mutant could efficiently utilize UDP-Glc.This work provides a new and efficient approach to prepare flavonoid C-rhamnosides such as violanthin and iso-violanthin.

Drug development accelerated by artificial intelligence

The development of biopharmaceuticals,driven by advances in molecular cell biology,has accelerated in the past few decades.However,this development presents a paradox,namely,that highly developed biotechnology has led to lower success rates in clinical trials and higher costs in developing individual drugs.This huge obstacle has made drug development the exclusive privilege of large companies and has limited opportunities for small companies to develop advanced drugs.There is also a huge difference between developed and developing countries in terms of their capacity for pharmaceutical research and development(R&D),and high barriers limit the development of innovative drugs in developing countries.