Objective: Prostate cancer (PCa) is the most common malignant tumor diagnosed in men in developed countries. In developing countries, the PCa morbidity and mortality rates are also increasing rapidly. Since androgen receptor (AR) is a key driver and plays a critical role in the regulation of PCa development, AR-targeted agents provide a key component of current therapy regimens. However, even new-generation AR antagonists are prone to drug resistance, and there is currently no effective strategy for overcoming advanced PCa aggressiveness, including drug-resistance progression. The aim of this study was to evaluate the potential efficacy and novel therapy strategy of proxalutamide (a newly developed AR antagonist) in PCa. Methods: Four PCa cell lines with various biological heterogeneities were utilized in this study, namely, androgen-sensitive/-insensitive with/without AR expression. Proliferation, migration and apoptosis assays in PCa cells were used to evaluate the effective therapeutic activity of proxalutamide. The changes in lipid droplet accumulation and lipidomic profiles were analyzed to determine the influence of proxalutamide on lipogenesis in PCa cells. The molecular basis of the effects of proxalutamide on lipogenesis and the AR axis was then further investigated. Results: Proxalutamide significantly inhibited the proliferation and migration of PCa cells, and its inhibitory effect was superior to that of enzalutamide (Enz, second-generation AR antagonist). Proxalutamide induced the caspase-dependent apoptosis of PCa cells. Proxalutamide significantly diminished the level of lipid droplets in PCa cells, changed the lipid profile of PCa cells and reduced the content of most lipids (especially triglycerides) in PCa cells. Proxalutamide attenuated de novo lipogenesis by inhibiting the expression of ATP citrate lyase (ACL), acetyl CoA carboxylase (ACC), fatty acid synthase (FASN) and sterol regulatory element-binding protein-1 (SREBP-1). Moreover, proxalutamide also decreased AR expression in PCa cells, and its inhibitory effect on lipogenesis did not depend on its ability to down-regulate AR expression. However, Enz had no effect on AR expression, lipid accumulation or lipid de novo synthesis in PCa cells. Conclusions: By co-targeting the AR axis and endogenous adipogenesis, a novel and promising strategy was established for proxalutamide to combat the progress of PCa. The unique effect of proxalutamide on the metabolic reprogramming of PCa provides a potential solution to overcome the resistance of current AR-targeted therapy, which will help to effectively prolong its clinical service life.

Wushanicaritin, a natural polyphenol compound, exerts many biological activities. This study aimed to characterize wushanicaritin glucuronidation by pooled human liver microsomes (HLM), human intestine microsomes and individual uridine diphosphate-glucuronosyltransferase (UGT) enzyme. Glucuronidation rates were determined by incubating wushanicaritin with uridine diphosphoglucuronic acid-supplemented microsomes. Kinetic parameters were derived by appropriate model fitting. Reaction phenotyping, the relative activity factor (RAF) and activity correlation analysis were performed to identify the main UGT isoforms. Wushanicaritin glucuronidation in HLM was efficient with a high CL_int (intrinsic clearance) value of 1.25 and 0.69 mL/min/mg for G1 and G2, respectively. UGT1A1 and 1A7 showed the highest activities with the intrinsic clearance (CL_int) values of 1.16 and 0.38 mL/min/mg for G1 and G2, respectively. In addition, G1 was significantly correlated with β-estradiol glucuronidation (r = 0.847; p = 0.0005), while G2 was also correlated with chenodeoxycholic acid glucuronidation (r = 0.638, p = 0.026) in a bank of individual HLMs (n = 12). Based on the RAF approach, UGT1A1 contributed 51.2% for G1, and UGT1A3 contributed 26.0% for G2 in HLM. Moreover, glucuronidation of wushanicaritin by liver microsomes showed marked species difference. Taken together, UGT1A1, 1A3, 1A7, 1A8, 1A9 and 2B7 were identified as the main UGT contributors responsible for wushanicaritin glucuronidation.

Tobacco is a major environmental pollutant, and smoking is a recognized risk factor for non-alcoholic fatty liver disease (NAFLD). However, the global epidemiological burden of smoking-related NAFLD remains unclear. This study aimed to quantify the burden of NAFLD attributable to smoking from 1990 to 2021, focusing on disability-adjusted life years (DALYs), mortality rates, and temporal trends. Data were extracted from the Global Burden of Disease Study 2021 and analyzed at global, regional, and national levels. Age, sex, region, and socio-demographic index (SDI) were included. Key measures included age-standardized DALY rates (ASDR), age-standardized mortality rates (ASMR), and average annual percentage changes (AAPCs). Trends were further stratified by age, sex, and SDI. Globally, the ASMR of NAFLD attributable to smoking demonstrated a upward trend (AAPC_ASMR=0.27[95 % CI, 0.17-0.37], P < 0.001). The most substantial increases from 1990 to 2021 were observed in Australasia and Southern Latin America. The AAPC for ASDR was 2.89[95 %CI, 2.5-3.29] and 2.84[95 %CI, 2.16-3.52], respectively. The burden was significantly higher in males, with DALY rates rising with age and peaking at 65-69 years (8.84/100,000; 95 % UI: 2.77-15.69). An inverse U-shaped association between SDI and disease burden was noted. Join-point analysis revealed increasing trends in low-medium SDI regions and among females in high-SDI regions. Despite declining smoking prevalence, the burden of smoking-related NAFLD continues to rise, especially in low-middle income regions and high-income females. Strengthened tobacco control and targeted NAFLD prevention strategies are urgently needed.

Occult hepatitis B virus infection (OBI) carries high risk of transmissibility and pathogenicity. Mutations in the S gene are considered major contributors to OBI development. Our previous study identified the C138R mutation in the S gene of OBI patients. This study aimed to investigate the impact of the C138R mutation on HBsAg function and its mechanisms leading to OBI. Full-length hepatitis B virus (HBV) plasmids (HBV 1.3, genotype B) and mutant plasmids (HBV C138R) were constructed, along with HA-tagged wild-type (sWT) and mutant (sC138R) S protein expression plasmids. The effects of the C138R mutation on HBsAg antigenicity, secretion, and dimer formation were evaluated through in vitro cell transfection and in vivo hydrodynamic tail vein injection in mice. The C138R mutation markedly reduced intra- and extracellular HBsAg levels without affecting HBV transcription, replication, or other viral protein expression. HA-tag assays indicated that this reduction resulted from impaired antigenicity. Several commercial ELISA kits results and HA levels in cell supernatants demonstrated that the C138R mutation also impaired HBsAg secretion. Similarly, the C107R mutation significantly decreased both HBsAg antigenicity and secretion. Non-reducing WB assays and Alphafold 3-based structural predictions revealed that the C138R mutation lead to the formation of aberrant HBsAg dimers. These findings were confirmed in the HBV mouse model. The C138R mutation contributed to OBI by simultaneously impairing HBsAg antigenicity and secretion. Disruption of the disulfide bond between aa107 and aa138, resulting in the formation of structurally abnormal dimers, represented the primary mechanism underlying HBsAg dysfunction caused by this mutation.

Background: Primary hypertrophic osteoarthropathy (PHO) is a rare genetic disorder classified into clinical subtypes and genetic subtypes. Previous clinical studies have primarily focused on case reports and family analyses, largely characterizing the genetic subtypes. However, there remains a long-standing gap in understanding the characteristics of the different clinical subtypes of PHO. This study aimed to determine the distribution of the three clinical subtypes of PHO and compare their clinical characteristics using a large global sample. Methods: A systematic literature search was conducted in multiple databases to categorize cases into complete form (CO), incomplete form (IN), and fruste form (FR). Statistical analyses were performed to assess clinical differences in a retrospective study design. Results: Males predominated across all subtypes, whereas females were most prevalent in IN patients (51.1%). IN patients had the highest family history rate (62.1%). Age at onset peaked in adolescence for CO and FR patients, while IN patients exhibited bimodal peaks in early childhood and adolescence. Congenital diseases were more frequent in IN patients (7.8%, P = 0.021), while CO patients had a higher prevalence of digestive system diseases (12.2%, P = 0.007). Urinary prostaglandin E2 (PGE2) and PGE Metabolite (PGEM) were consistently elevated in CO and FR patients. In IN patients, urinary PGE2 levels were also increased, but the urinary PGEM levels showed equal proportions of elevation and reduction. Genetic analysis revealed that solute carrier organic anion transporter family member 2A1 (SLCO2A1) mutations were predominant in CO (95 cases, 73.1%) and FR (22 cases, 57.9%) patients, whereas hydroxyprostaglandin dehydrogenase (HPGD) mutations were most frequently associated with IN (25 cases, 73.5%). Conclusions: The three clinical subtypes of PHO exhibited distinct characteristics with no clear correlation between clinical and genetic subtypes. These findings highlighted the clinical significance of PHO typing and provided valuable insights for diagnosis, differential diagnosis and subtype-specific management strategies.