FXR agonists for MASH therapy: Lessons and perspectives from obeticholic acid.

Nonalcoholic fatty liver disease, also called metabolic dysfunction-associated steatotic liver disease, is the most common liver disease worldwide and has no approved pharmacotherapy. Due to its beneficial effects on metabolic regulation, inflammation suppression, cell death prevention, and fibrogenesis inhibition, farnesoid X receptor (FXR) is widely accepted as a promising therapeutic target for nonalcoholic steatosis (NASH) or called metabolic dysfunction-associated steatohepatitis (MASH). Many FXR agonists have been developed for NASH/MASH therapy. Obeticholic acid (OCA) is the pioneering frontrunner FXR agonist and the first demonstrating success in clinical trials. Unfortunately, OCA did not receive regulatory approval as a NASH pharmacotherapy because its moderate benefits did not outweigh its safety risks, which may cast a shadow over FXR-based drug development for NASH/MASH. This review summarizes the milestones in the development of OCA for NASH/MASH and discuss its limitations, including moderate hepatoprotection and the undesirable side effects of dyslipidemia, pruritus, cholelithiasis, and liver toxicity risk, in depth. More importantly, we provide perspectives on FXR-based therapy for NASH/MASH, hoping to support a successful bench-to-clinic transition.

Facile nitrogen doping in fungal hyphae-derived biochars via cooperation of microbial culture and pyrolysis for efficient catalytic reduction of 4-nitrophenol.

Manipulating the elemental composition is one major strategy to tune the properties of biochars to endow different functions to meet various application requirements. Compared with the widely reported plants- and manure-based precursors for biochars, microbes-based precursors take the lead in regional independency, rapid growth, morphology uniformity and abundant species with different adjustable elemental composition. In this work, fungal hyphae with massive microtubule structure were selected as a typical microbe precursor to prepare biochars whose catalysis capability was further evaluated by a representative reduction reaction of 4-nitrophenol (4-NP) using sodium borohydride as reductant. By simply increasing the nitrogen concentration in the culturing medium, the fungal hyphae derived biochars with increased nitrogen contents (2.1 wt% → 4.3 wt%) were successfully obtained after pyrolysis, showing almost two times higher catalysis ability (4.75 × 10-2 s-1 → 7.26 × 10-2 s-1) towards 4-nitrophenol. The Arrhenius equation calculation further proved that the more doping of nitrogen would increase the active sites rather than altering the reaction pathway. A high surface area of 997 m2 g-1 at pyrolysis temperature of 800 °C was obtained resulting from the fine microstructure of fungal hyphae. Higher pyrolysis temperature derived biochars remarkably promote their catalysis ability. These results indicated that biochars with controllable nitrogen contents can be prepared by cooperating culturing and pyrolysis processes, which pointed out an easy, rapid, scalable, and promising way to synthesis biochars with tunable functions for different applications.

Self-assembled fungus-biochar composite pellets (FBPs) for enhanced co-sorption-biodegradation towards phenanthrene.

Sorption and biodegradation are two major applicable techniques for organic pollutants removal. However, the desorption risk following the sorption process and the low bioavailability of trace pollutants to microbes are still hindering the efficient removal of pollutants. To take full advantages of both sorption (for contaminant accumulation) and microbial degradation, here we introduce a self-assembly method combining carbonaceous sorbents (i.e., biochars: RS350, RS500, and RS700) with fungal hyphae (Phanerochaete chrysosporium) which can efficiently degrade phenanthrene (PHE), one of the typical polycyclic aromatic hydrocarbons. By cultivating Phanerochaete chrysosporium in biochar-containing medium, fungus-biochar composite pellets (FBPs) were successfully synthesized with a 3D macrostructure of abundant hyphae and uniform pellet size (~2.5 mm in diameter). Benefiting from the high sorption ability of biochars, such FBPs showed up to triple sorption ability and 70 folds faster biodegradation rate than pure fungal pellets. The PHE concentration remaining in solution receiving co-sorption-degradation treatment after 22 d was only one third of that receiving sorption treatment alone. Continuous removal experiment indicated that these composite pellets could hold their removal ability of above 90 % in the first 4 cycles. This study points out a simple and promising self-assembly approach that could be easily scaled up to manufacture FBPs with high removal efficiency, fast biodegradation rate, easy separation ability and long-term stability.

Reduced bioavailability and plant uptake of polycyclic aromatic hydrocarbons from soil slurry amended with biochars pyrolyzed under various temperatures.

Biochar has high potential for organic pollutant immobilization due to its powerful sorption capacity. Nevertheless, potential risks may exist when biochar-sorbed organic pollutants are bioavailable. A direct plant exposure assay in combination with an organic solvent extraction experiment was carried out in this study to investigate the bioavailability of polycyclic aromatic hydrocarbons (PAHs) with the application of pine needle biochars pyrolyzed under different temperatures (100, 300, 400, and 700 °C; referred as P100-P700 accordingly). Biochar reduced solvent extractability and plant uptake of PAHs including naphthalene (Naph), acenaphthene (Acen), phenanthrene (Phen), and pyrene (Pyr), especially for three- and four-ring PAHs (Phen and Pyr) with high-temperature biochar. Plant uptake assay validates with organic solvent extraction for bioavailability assessment. Sorption of PAHs to biochars reduced plant uptake of PAHs in roots and shoots by lowering freely dissolved PAHs. Aging process reduced the bioavailability of PAHs that were bound to biochar. High pyrolysis temperature can be recommended for biochar preparation for purpose of effectively immobilizing PAHs, whereas application of moderate-temperature biochar for PAH immobilization should concern the potential risks of desorption and bioavailability of PAHs.

Clinicopathologic features and molecular analysis of enterovirus 71 infection: report of an autopsy case from the epidemic of hand, foot and mouth disease in China.

A 15-month boy with fatal hand, foot, and mouth disease (HFMD) exhibited atypical symptoms and progressed rapidly to death. An autopsy was performed the next day and tissue sections were stained for histopathological examination. His intestinal samples were tested for enterovirus 71 (EV71), and the whole-genome sequence of EV71 was analyzed. An autopsy revealed that the central nervous system, lungs, and gut displayed severe meningitis and brainstem encephalitis, remarkable pulmonary congestion, edema, moderate inflammatory infiltration, and hemorrhage as well as intestinal mucosal congestion, epithelial necrosis, thinning intestinal wall, and submucosal lymphoid follicular hyperplasia. The heart showed myocardial interstitial congestion, myocardial edema, and some inflammatory infiltrates. There were no significant alterations in the architecture of other organs. EV71 antigen and apoptotic cells were detected in brain, lung and intestine by immunohistochemical staining and TUNEL (TdT-mediated dUTP nick-end labeling) respectively. Intestinal contents and intestinal autopsy samples of this case were positive for EV71, and the EV71 strain was classified as subgenogroup C4. In China, the severe forms of HFMD were mostly caused by EV71 subgenogroup C4 infection. Severe intestinal damages may relate to EV71 subgenogroup C4 infection. Thus, children with severe EV71 HFMD may have serious pathological changes in their central nervous system, lungs, and gut. Physicians should pay special attention to infants with atypical symptoms, particularly in EV71 epidemic areas for early diagnosis and treatment.