BAMBI在小鼠不同类型脂肪组织发育及脂肪细胞分化过程中的差异表达规律

目的研究BAMBI基因在小鼠不同脂肪组织发育过程中的表达规律。方法利用RT-q PCR及Western blot技术检测BAMBI基因在小鼠不同类型脂肪组织、不同发育阶段(胚胎第18天、出生第0天、第21天、第8周和第6个月)及原代前体脂肪细胞分化过程中(分化第0、3、7、11天)的差异表达情况。结果随着脂肪组织的发育,BAMBI m RNA及蛋白的表达量逐渐降低;在发育的同一时间段,BAMBI m RNA在内脏白色脂肪组织较皮下白色脂肪组织表达量高,在棕色脂肪组织中表达量最低;在小鼠前体脂肪细胞诱导分化过程中,BAMBI m RNA表达量呈时间依赖性降低。结论提示BAMBI的差异表达规律与脂肪组织类型、发育阶段以及脂肪细胞分化程度密切相关,其在脂肪组织发育过程中起着重要的作用。

Correlation network analysis shows divergent effects of a long-term,high-fat diet and exercise on early stage osteoarthritis phenotypes in mice

Background:Obesity increases knee osteoarthritis(OA) risk through metabolic,inflammatory,and biomechanical factors,but how these systemic and local mediators interact to drive OA pathology is not well understood.We tested the effect of voluntary running exercise after chronic diet-induced obesity on knee OA-related cartilage and bone pathology in mice.We then used a correlation-based network analysis to identify systemic and local factors associated with early-stage knee OA phenotypes among the different diet and exercise groups.Methods:Male C57 BL/6 J mice were fed a defined control(10% kcal fat) or high fat(HF)(60% kcal fat) diet from 6 to 37 weeks of age.At 25 weeks,one-half of the mice from each diet group were housed in cages with running wheels for the remainder of the study.Histology,micro computed tomography,and magnetic resonance imaging were used to evaluate changes in joint tissue structure and OA pathology.These local variables were then compared to systemic metabolic(body mass,body fat,and glucose tolerance),inflammatory(serum adipokines and inflammatory mediators),and functional(mechanical tactile sensitivity and grip strength) outcomes using a correlation-based network analysis.Diet and exercise effects were evaluated by two-way analysis of variance.Results:An HF diet increased the infrapatellar fat pad size and posterior joint osteophytes,and wheel running primarily altered the subchondral cortical and trabecular bone.Neither HF diet nor exercise altered average knee cartilage OA scores compared to control groups.However,the coefficient of variation was≥25% for many outcomes,and some mice in both diet groups developed moderate OA(>33% maximum score).This supported using correlation-based network analyses to identify systemic and local factors associated with early-stage knee OA phenotypes.In wheel-running cohorts,an HF diet reduced the network size compared to the control diet group despite similar running distances,suggesting that diet-induced obesity dampens the effects of exercise on systemic and local OA-related factors.Each of the 4 diet and activity groups showed mostly unique networks of local and systemic factors correlated with early-stage knee OA.Conclusion:Despite minimal group-level effects of chronic diet-induced obesity and voluntary wheel running on knee OA pathology under the current test durations,diet and exercise substantially altered the relationships among systemic and local variables associated with early-stage knee OA.These results suggest that distinct pre-OA phenotypes may exist prior to the development of disease.

Does ethnicity matter in male hormonal contraceptive efficacy？

The development of male hormonal contraception has progressed significantly during the last three decades. The ultimate goal is to produce an effective, safe and reversible male method of contraception that are within reach of and can be used by all men globally. This review aims to outline the recent developments in male hormonal contraception with special emphasis on how ethnicity influences acceptability, extent of sperm suppression, and rate of recovery of spermatogenesis. Baseline differences in testicular histomorphology and testosterone metabolism between East Asian and Caucasian men have been reported, but whether this contributes significantly to varying degrees of sperm suppression in response to exogenous testosterone therapy is less known. Testosterone alone male hormonal contraceptive regimens are effective and applicable for East Asian men, and less so for Caucasians. Combinations of progestins with androgens are sufficient to optimize effectiveness of suppression and applicability to all ethnicities. New compounds such as steroidal or non-steroidal selective androgen receptor modulators with dual androgenic and progestational activities are potential compounds for further development as male hormonal contraceptive methods. At the present time, combined androgen and progestin contraceptive regimens appear to be effective, safe, reversible and convenient to use for all men with ethnic, cultural and environmental differences. Further refinements on the hormonal agent, methods of delivery, and dose optimization of the androgen relative to the progestin are necessary. This goal mandates further investment and large clinical trials in multiethnic populations to better define safety and efficacy.

A comprehensive cardiotoxicity assay by combining high-throughput multiple ion channel screening with human cardiomyocyte-based action potential validation

OBJECTIVE Cardiotoxicity refers to drug-induced arrhythmia such as Torsades de pointes.Current single ion channel(hERG)-based assay generates-30% false results.The aim is to establish an advanced in vitro cardiotoxicity assay by incorporating high throughput multiple cardiac ion channel screening and human cardiomyocytes-based validation.METHODS Effects of drugs were tested on multiple cell lines expressing hERG,Nav1.5 and Cav1.2 by automated patch clamping.Subsequently,the results were validated with human pluripotent stem cell(hPSC)-derived cardiomyocytes(hPSC-CMs)in which ion currents and action potentials were measured by manual patch clamping.RESULTS We have tested the cardiotoxicity of monomers extracted from various medical herbs.Mitragynine is the major bioactive compound isolated from kratom,a therapeutic herb from the rain forest of South East Asia.As a popular stimulant,it has been associated with a number of acute fatal incidences.We observed a typical torsadogenic hazard of mitragynine.It exerted a strong hERG inhibition in hERG-HEK293 cell line(IC50:5.2 μmol·L-1)and hPSC-CMs(IC50:0.91 μmol·L-1)without affecting other cardiac ion channels.Moreover,it caused a significant prolongation of action potential duration(APD)in hPSC-CMs(a-32.5%increase in APD at 50 and 90%repolarization).On the other hand,deoxylelephantopin,apotential anti-cancer reagent,demonstrated low cardiotoxicity.It exerted a week inhibition on hERG in HEK293 cells with an IC50 of 87.2 μmol·L-1,while the effective concentrations for suppressing the growth of cancer cells ranges from 2 to 20μmol·L-1.At 100μmol·L-1,deoxylelephantopin showed no effects on Cav1.2 and Nav1.5 and it failed to alter APD in hPSC-CMs.CONCLUSION We have successfully tested a newin vitro cardiotoxicity assay strategy which incorporates multiple cardiac ion channels screening and hPSC-CMs validation.This new strategy could facilitate the effective and efficient evaluation of existing and new drugs/reagents for potential pro-arrhythmic risk.

Accelerate the Promotion of Mobile Payments during the COVID-19 Epidemic

COVID-19 is caused by a novel SARS-CoV-2(severe acute respiratory syndrome coronavirus 2).During the COVID-19 epidemic,when people are infected with the virus,they can transmit the virus onto paper or coin money through touch and droplets,potentially making any physical currency a carrier of the virus.Although there is no report confirming that people can become infected with viruses by cash circulation,relevant research on the survival of viruses on solid surfaces supports this hypothesis.Mobile payments can help individuals avoid coming in direct contact with any paper or coin money.Therefore,we strongly recommend the promotion of mobile payments during the COVID-19 epidemic.

Sorting and Processing of the Alzheimer's Disease Amyloid Precursor Protein Mediated by the AP-4 Complex

Proteolytic processing of the transmembrane amyloid precursor protein (APP) to aggregation-prone amyloid-β (Aβ) peptide underlies the development of Alzheimer’s disease.

DNA methylation profile of a hepatosplenic gamma/delta T-cell lymphoma patient associated with response to interferon-α therapy

The 2–5%γδT cells in healthy human peripheral blood recognize nonpeptide antigens,in contrast toαβT cells.1 DistinctγδT-cell malignancies have been identified,with hepatosplenic T-cell lymphoma(γδ-HSTL)being a rare but aggressive(median survival 13 months)subset.2γδ-HSTL usually presents with hepatosplenomegaly without lymphadenopathy,anemia,and thrombocytopenia.It is histologically characterized by the involvement of the hepatic sinusoids,splenic red pulp and bone marrow interstitium,with or without leukemic presentation in peripheral blood.3 A standard treatment regimen is not well established,but therapy mostly includes various chemotherapeutic agents.Notably,interferon-α(IFN-α)has been proven to be effective in some patients withγδ-HSTL,but other patients require allogeneic or autologous stem cell transplantation.

WTAP:a new player in postnatal BAT development

Understanding the mechanisms underlying brown fat development and metabolism can provide unique insights into the regulation of energy homeostasis.In a recent study published in Life Metabolism,Wang et al.established Wilms’tumor 1-associating protein(WTAP),a key component in m6A methyltransferase complex,as a new and essential regulator in the postnatal development and maturation of interscapular brown adipose tissue(iBAT).Interscapular brown adipose tissue(iBAT)is the major organ responsible for nonshivering thermogenesis in rodents[1].

Targeting BMI1 mitigates chemoresistance in ovarian cancer

Resistance to chemotherapy is a prominent clinical problem in high grade serous ovarian cancer(HGSOC).1 An inadequate understanding of adaptive signaling coupled with limited treatment options for a chemoresistant tumor are likely causes for poor outcomes.We previously reported that BMI1,a stem-cell factor is instrumental in regulating chemoresistance.2,3 However,to advance anti-BMI1 therapy from the bench to the bedside,efficacy needs to be tested in patient-derived chemoresistant HGSOC models,which is lacking.

Development and progression of cancer cachexia:Perspectives from bench to bedside

Cancer cachexia(CC)is a devastating syndrome characterized by weight loss,reduced fat mass and muscle mass that affects approximately 80%of cancer patients and is responsible for 22%-30%of cancer-associated deaths.Understanding underlying mechanisms for the development of CC are crucial to advance therapies to treat CC and improve cancer outcomes.CC is a multi-organ syndrome that results in extensive skeletal muscle and adipose tissue wasting;however,CC can impair other organs such as the liver,heart,brain,and bone as well.A considerable amount of CC research focuses on changes that occur within the muscle,but cancer-related impairments in other organ systems are understudied.Furthermore,metabolic changes in organ systems other than muscle may contribute to CC.Therefore,the purpose of this review is to address degenerative mechanisms which occur during CC from a whole-body perspective.Outlining the information known about metabolic changes that occur in response to cancer is necessary to develop and enhance therapies to treat CC.As much of the current evidences in CC are from pre-clinical models we should note the majority of the data reviewed here are from preclinical models.