Targeting cell death in NAFLD: mechanisms and targeted therapies.

Nonalcoholic fatty liver disease (NAFLD) is a group of chronic liver disease which ranges from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH) and is characterized by lipid accumulation, inflammation activation, fibrosis, and cell death. To date, a number of preclinical studies or clinical trials associated with therapies targeting fatty acid metabolism, inflammatory factors and liver fibrosis are performed to develop effective drugs for NAFLD/NASH. However, few therapies are cell death signaling-targeted even though the various cell death modes are present throughout the progression of NAFLD/NASH. Here we summarize the four types of cell death including apoptosis, necroptosis, pyroptosis, and ferroptosis in the NAFLD and the underlying molecular mechanisms by which the pathogenic factors such as free fatty acid and LPS induce cell death in the pathogenesis of NAFLD. In addition, we also review the effects of cell death-targeted therapies on NAFLD. In summary, our review provides comprehensive insight into the roles of various cell death modes in the progression of NAFLD, which we hope will open new avenues for therapeutic intervention.

Exploring Brominated Aromatic Butenolides from Aspergillus terreus EGF7-0-1 with Their Antifungal Activities.

Fungal diseases could severely harm agricultural productions. To develop new antifungal agents, based on the Global Natural Products Social Molecular Networking, typical bromine isotope peak ratios, and ultraviolet absorptions, cultivation of the soft coral-derived endophytic fungi Aspergillus terreus EGF7-0-1 with NaBr led to the targeted isolation of 14 new brominated aromatic butenolides (1-14) and six known analogues (15-20). Their structures were elucidated by extensive spectroscopic analysis and quantum chemical calculations. Compounds 1-14 exhibited wildly antifungal activities (against Colletotrichum gloeosporioides, Pestalotiopsis microspora, Fusarium oxysporum f. sp. cubense, Botrytis cinerea, and Diaporthe phoenicicola). The bioassay results showed that compounds 1-14 exhibited excellent antifungal activities against C. gloeosporioides, with concentration for 50% of maximal effect (EC50) values from 2.72 to 130.41 nM. The mechanistic study suggests that compound 1 may disrupt nutrient signaling pathways by reducing the levels of metabolites, such as carbohydrates, lipids, and amino acids, leading to an increase in low-density granules and a decrease in high-density granules in the cytoplasm, accompanied by numerous vacuoles, thereby inhibiting the growth of C. gloeosporioides. Monobrominated γ-butenolide 1 may be expected to exploit a novel agriculturally antifungal leading drug. Meanwhile, compound M1 has conformed antifugual activities against C. gloeosporioides by papayas in vivo.

lncSNHG16 promotes hepatocellular carcinoma development by inhibiting autophagy.

OBJECTIVE: To investigate the expression of long non-coding RNA lncSNHG16 in hepatocellular carcinoma (HCC), associations between its expression and patient survival, and its potential role in regulating autophagy in the disease. METHODS: Expression of lncSNHG16 was measured using quantitative real-time PCR in HCC cells in culture and HCC tissues from patients. Effects of lncSNHG16 overexpression were examined in HCC cultures using assays of cell proliferation, wound healing, and migration or invasion in Transwell dishes. Effects of lncSNHG16 overexpression were also examined in subcutaneous tumor in mice. Relationships of lncSNHG16 expression to autophagy and apoptosis in HCC cultures were explored using western blotting and flow cytometry. RESULTS: Higher lncSNHG16 expression in HCC tissues was associated with significantly worse overall and recurrence-free survival of patients. Overexpressing lncSNHG16 in HCC cell culture promoted cell proliferation, migration, and invasion while suppressing apoptosis. lncSNHG16 was associated with upregulation of STAT3 as well as inhibition of autophagy and associated apoptosis. Overexpressing lncSNHG16 accelerated tumor growth and weight in mice. CONCLUSION: The non-coding RNA lncSNHG16 suppresses autophagy and associated apoptosis in HCC, making it a potential therapeutic target.

Identification of a pathogenic variant and pre-implantation genetic testing for a Chinese family affected with split-hand/foot malformation.

Split-hand/foot malformation is a serious congenital limb malformation characterized by syndactyly and underdevelopment of the phalanges and metatarsals. In this study, we reported a case of a fetus with hand-foot cleft deformity. Whole exome and Sanger sequencing were used to filter out candidate gene mutation sites and provide pre-implantation genetic testing(PGT) for family members. Genetic testing results showed that there was a homozygous mutation c.786G>A (p.Trp262*) in the fetal WNT10B, and both parents were carriers of heterozygous mutations. PGT results showed that out of the two blastocysts, one was a heterozygous mutant and the other was a homozygous mutant. All the embryos had diploid chromosomes. The heterozygous embryo was transferred, and a singleton pregnancy was successfully achieved. This study suggests that homozygous mutations in WNT10B are the likely cause of hand-foot clefts in this family. For families with monogenic diseases, preimplantation genetic testing can effectively prevent the birth of an affected child only after identifying the pathogenic mutation.

Encouraging Breastfeeding Without Guilt: A Qualitative Study of Breastfeeding Promotion in the Singapore Healthcare Setting.

Introduction: In Singapore, the healthcare system strongly encourages mothers to breastfeed and breastfeeding initiation is near-universal. However, sustained breastfeeding rates remain low. Little is currently known about how breastfeeding information disseminated in the healthcare setting influences women's breastfeeding experiences. This study explored breastfeeding promotion and educational resources from the perspective of Singaporean mothers and healthcare workers. Methods: Semi-structured interviews with 14 mothers of infants aged 1-5 months and who had used obstetric, maternity, and/or paediatric services in Singapore, and 20 health workers with experience in general, obstetric, maternal, or paediatric care recruited using purposive sampling methods. Interview transcripts were coded using an inductive method. Results: Breastfeeding communications were viewed as too moralized and too focused on nudging women to breastfeed, with relatively little emphasis on timely, practical information or solutions for mothers unable to latch. Hence mothers tended to rely on alternative resources such as blogs. They lacked in-depth knowledge of the benefits of breastfeeding and viewed it as detrimental to maternal mental wellbeing due to the perceived stress and guilt when experiencing difficulties, notably with milk supply and latching, and from the inability to meet breastfeeding expectations. Husbands, older family members, confinement nannies, and employers were considered influential individuals to encourage breastfeeding, but they commonly discouraged breastfeeding due to social and cultural factors which led to supplementation with formula. Conclusion: For better breastfeeding outcomes, future informational sources on breastfeeding should be morally neutral, practical, set realistic expectations for the demands of breastfeeding, and target influential individuals such as family members, confinement nannies and employers.

S-Arylation of Thioic S-Acid Using Thianthrenium Salts via Photoactivation of Electron Donor-Acceptor Complex.

Thioesters make up an important class of bioactive compounds. Due to their chemoselectivity, they have been widely used in the synthesis of a wide range of complex bioactive molecules and natural products. At present, chemists have developed a variety of methods for the preparation of thioester compounds. However, these methods usually require the use of transition metal catalysis or harsh reaction conditions. The strategy of synthesizing thioester compounds via visible light-induced electron donor-acceptor (EDA) complex reactions avoids the problems associated with conventional methods through the development of photocatalysis. Here we report a sustainable method for thiocarbonylating aryl sulfonium salts via a visible light-induced EDA complex process without transition metals.

Impact of High Sodium Diet on Neovascularization and Osseointegration around Titanium Implant: An in Vivo and in Vitro Study.

Objective: A high sodium (HS) diet is believed to affect bone metabolism processes. Clarifying its impact on osseointegration of titanium (Ti) implants holds significant implications for postoperative dietary management of implanted patients. Methods: This investigation probed the impact of sodium ions (Na +) on neovascularization and osteogenesis around Ti implants in vivo, utilizing micro-computed tomography, hematoxylin and eosin staining, and immunohistochemical analyses. Concurrently, in vitro experiments assessed the effects of varied Na + concentrations and exposure durations on human umbilical vein endothelial cells (HUVECs) and MC3T3-E1 cells. Results: In vivo, increased dietary sodium (0.8%-6.0%) led to a substantial decline in CD34 positive HUVECs and new bone formation around Ti implants, alongside an increase in inflammatory cells. In vitro, an increase in Na + concentration (140-150 mmol/L) adversely affected the proliferation, angiogenesis, and migration of HUVECs, especially with prolonged exposure. While MC3T3-E1 cells initially exhibited less susceptibility to high Na + concentrations compared to HUVECs during short-term exposure, prolonged exposure to a HS environment progressively diminished their proliferation, differentiation, and osteogenic capabilities. Conclusion: These findings suggest that HS diet had a negative effect on the early osseointegration of Ti implants by interfering with the process of postoperative vascularized bone regeneration.

Alginate oligosaccharides exert protective effects on hydrogen peroxide-induced senescence in H9C2 cardiomyocytes by regulating the redox state of cells.

Aging is a known independent risk factor for several cardiovascular diseases. Here, we evaluated potential effects and possible mechanisms through which alginate oligosaccharides (AOS) affect hydrogen peroxide (H2O2)-induced senescence in H9C2 cardiomyocytes. A series of AOS molecules, including oligoM, oligoG, M-5, and G-5, were investigated. AOS significantly decreased SA-ß-gal and DAPI-stained positive cells, downregulated p53 and p21 (aging-related markers) expression, and eventually protected H9C2 cells from H2O2-induced senescence. AOS decreased reactive oxygen species and malondialdehyde production, recovered mitochondrial function, and alleviated the oxidative stress state by regulating PGC-1α and NADPH oxidase subunit expression. Furthermore, AOS treatment restored the expression of antioxidant enzymes in senescent H9C2 cells. Thus, our results show in vitro evidence that AOS alleviate senescence in H9C2 cells by regulating the redox state; thus, AOS may be an effective therapeutic agent that could protect against cardiomyocyte senescence.

Enhancing Short-Range Interactions to Broaden the Temperature Range for Coexistence of Antiferroelectricity and Ferroelasticity.

Antiferroelectric (AFE) materials, characterized by double electric hysteresis loops, can be transformed to the ferroelectric (FE) phase under an external electric field, making them promising candidates for electronic energy storage and solid-state refrigeration. Additionally, the field-induced strain in AFE materials is contingent upon the direction of the electric field, rendering it with a switching characteristic. Although AFE materials have made progress in the field of energy storage and negative electrocaloric effect, the coexistence of AFE and ferroelasticity is still rarely reported. Here, two isomorphic organic-inorganic hybrid perovskites, HDAEPbCl4 and HDAEPbBr4 (HDAE is [2-(hydroxydimethylammonio)ethan-1-aminium]), exhibiting FE-AFE-PE (PE is paraelectric) phase transitions, are presented. Remarkably, the temperature range where AFE and ferroelasticity coexist is significantly broadened from 59.9 K to 115.1 K by strengthening short-range forces via halogen substitution. This discovery extends the family of FE, AFE, and ferroelastic materials, contributing to the development of multifunctional materials and advancing multifunctional material development.

Blistering Behavior of Beryllium and Beryllium Alloy under High-Dose Helium Ion Irradiation.

Beryllium (Be) has been selected as the solid neutron multiplier material for a tritium breeding blanket module in ITER, which is also the primary option of the Chinese TBM program. But the irradiation swelling of beryllium is severe under high temperature, high irradiation damage and high doses of transmutation-induced helium. Advanced neutron multipliers with high stability at high temperature are desired for the demonstration power plant (DEMO) reactors and the China Fusion Engineering Test Reactor (CFETR). Beryllium alloys mainly composed of Be12M (M is W or Ti) phase were fabricated by HIP, which has a high melting point and high beryllium content. Beryllium and beryllide (Be12Ti and Be12W) samples were irradiated by helium ion with 30 keV and 1 × 1018 cm-2 at RT. The microstructures of Be, Be12Ti and Be12W samples were analyzed by SEM and TEM before and after ion irradiation. The average size of the first blistering on the surface of Be-W alloy is about 0.8 µm, and that of secondary blistering is about 79 nm. The surface blistering rates of the beryllium and beryllide samples were also compared. These results may provide a preliminary experimental basis for evaluating the irradiation swelling resistance of beryllium alloy.

Intrauterine hyperglycaemia during late gestation caused mitochondrial dysfunction in skeletal muscle of male offspring through CREB/PGC1A signaling.

BACKGROUND: Maternal diabetes mellitus can influence the development of offspring. Gestational diabetes mellitus (GDM) creates a short-term intrauterine hyperglycaemic environment in offspring, leading to glucose intolerance in later life, but the long-term effects and specific mechanism involved in skeletal muscle dysfunction in offspring remain to be clarified. METHODS: Pregnant mice were divided into two groups: The GDM group was intraperitoneally injected with 100 mg/kg streptozotocin on gestational days (GDs) 6.5 and 12.5, while the control (CTR) group was treated with vehicle buffer. Only pregnant mice whose random blood glucose level was higher than 16.8 mmol/L beginning on GD13.5 were regarded as the GDM group. The growth of the offspring was monitored, and the glucose tolerance test was performed at different time points. Body composition analysis and immunohistochemical methods were used to evaluate the development of lean mass at 8 weeks. The exercise capacity and grip strength of the male mouse offspring were assessed at the same period. Transmission electron microscopy was used to observe the morphology inside skeletal muscle at 8 weeks and as a foetus. The genes and proteins associated with mitochondrial biogenesis and oxidative metabolism were investigated. We also coanalyzed RNA sequencing and proteomics data to explore the underlying mechanism. Chromatin immunoprecipitation and bisulfite-converted DNA methylation detection were performed to evaluate this phenomenon. RESULTS: Short-term intrauterine hyperglycaemia inhibited the growth and reduced the lean mass of male offspring, leading to decreased endurance exercise capacity. The myofiber composition of the tibialis anterior muscle of GDM male offspring became more glycolytic and less oxidative. The morphology and function of mitochondria in the skeletal muscle of GDM male offspring were destroyed, and coanalysis of RNA sequencing and proteomics of foetal skeletal muscle showed that mitochondrial elements and lipid oxidation were consistently impaired. In vivo and in vitro myoblast experiments also demonstrated that high glucose concentrations impeded mitochondrial organisation and function. Importantly, the transcription of genes associated with mitochondrial biogenesis and oxidative metabolism decreased at 8 weeks and during the foetal period. We predicted Ppargc1α as a key upstream regulator with the help of IPA software. The proteins and mRNA levels of Ppargc1α in the skeletal muscle of GDM male offspring were decreased as a foetus (CTR vs. GDM, 1.004 vs. 0.665, p = 0.002), at 6 weeks (1.018 vs. 0.511, p = 0.023) and 8 weeks (1.006 vs. 0.596, p = 0.018). In addition, CREB phosphorylation was inhibited in GDM group, with fewer activated pCREB proteins binding to the CRE element of Ppargc1α (1.042 vs. 0.681, p = 0.037), Pck1 (1.091 vs. 0.432, p = 0.014) and G6pc (1.118 vs. 0.472, p = 0.027), resulting in their decreased transcription. Interestingly, we found that sarcopenia and mitochondrial dysfunction could even be inherited by the next generation. CONCLUSIONS: Short-term intrauterine hyperglycaemia significantly reduced lean mass in male offspring at 8 weeks, resulting in decreased exercise endurance and metabolic disorders. Disrupted organisation and function of the mitochondria in skeletal muscle were also observed among them. Foetal exposure to hyperglycaemia decreased the ratio of phosphorylated CREB and reduced the transcription of Ppargc1α, which inhibited the transcription of downstream genes involving in mitochondrial biogenesis and oxidative metabolism. Abnormal mitochondria, which might be transmitted through aberrant gametes, were also observed in the F2 generation.

The de novo missense mutation F224S in GABRB2, identified in epileptic encephalopathy and developmental delay, impairs GABAAR function.

Genetic variants in genes encoding subunits of the γ-aminobutyric acid-A receptor (GABAAR) have been found to cause neurodevelopmental disorders and epileptic encephalopathy. In a patient with epilepsy and developmental delay, a de novo heterozygous missense mutation c.671 T > C (p.F224S) was discovered in the GABRB2 gene, which encodes the ß2 subunit of GABAAR. Based on previous studies on GABRB2 variants, this new GABRB2 variant (F224S) would be pathogenic. To confirm and investigate the effects of this GABRB2 mutation on GABAAR channel function, we conducted transient expression experiments using GABAAR subunits in HEK293T cells. The GABAARs containing mutant ß2 (F224S) subunit showed poor trafficking to the cell membrane, while the expression and distribution of the normal α1 and γ2 subunits were unaffected. Furthermore, the peak current amplitude of the GABAAR containing the ß2 (F224S) subunit was significantly smaller compared to the wild type GABAAR. We propose that GABRB2 variant F224S is pathogenic and GABAARs containing this ß2 mutant reduce response to GABA under physiological conditions, which could potentially disrupt the excitation/inhibition balance in the brain, leading to epilepsy.

Two new types of structures from soft coral-associated epiphytic fungus Aspergillus versicolor CGF9-1-2.

Global Natural Products Social (GNPS) molecular networking platform was applied to discovery the undescribed compounds from the common marine fungi Aspergillus versicolor CGF9-1-2, ultimately resulting in isolation of four new polyketides, decumbenone E (1), decumbenone F (2), 2'-epi-8-O-methylnidurufin (6), (-)-phomoindene A (7), one new nucleoside, 3-methyl-9-(2-methylbutene)-xanthine (8), and five known analogues. Their structures were elucidated based on 1D/2D NMR spectroscopic and HRESIMS data analyses, meanwhile, the absolute configurations of new compounds were established based on the X-ray crystallographic experiments, as well as the electronic circular dichroism (ECD) analysis. All compounds were predicted pharmaceutical chemistry with ten commonly disease-related proteins by molecular docking. In addition, all compounds against TDP1 were performed in vitro, which was consistent with the docking result, and compound 6 shown a weak inhibitory activity.

The effect of the molecular weight of blackberry polysaccharides on gut microbiota modulation and hypoglycemic effect in vivo.

Blackberry polysaccharides with certain molecular weight distribution have good bioactivity. In this research, type 2 diabetes mice were used to investigate the hypoglycemic effect of blackberry polysaccharides with three different molecular weights, BBP (603.59 kDa), BBP-8 (408.13 kDa) and BBP-24 (247.62 kDa), through gut microbiota modulation. Blackberry polysaccharides exhibited stronger hypoglycemic activity after degradation, and the FBG of BBP, BBP-8 and BBP-24 was reduced to 20.21 ± 4.17 mmol L-1, 20.6 ± 7.23 mmol L-1 and 17.32 ± 6.59 mmol L-1 and OGTT-AUC was reduced by 14.76%, 19.80% and 25.04%, respectively, after 8-week intervention. Furthermore, 16S rRNA gene sequencing analysis indicated that BBP, BBP-8 and BBP-24 could reshape the diversity and composition of the gut microbiota. From 0 to 4 weeks, the F/B of BBP, BBP-8 and BBP-24 reduced by 56.44%, 47.19% and 62.04%, reaching 3.39, 6.54, and 3.11 in the 8th week, respectively, which suggested the faster utilization of BBP-24. Moreover, the intervention the three blackberry polysaccharides increased the relative abundance of the targeted beneficial bacteria Oscillospira and Bacteroidaceae Bacteroides and decreased the relative abundance of the pathogenic bacterium Allobaculum. In general, the result demonstrated that blackberry polysaccharides with a lower molecular weight are more easily fermented, making the theoretical basis for the development of blackberry polysaccharides as a probiotic food to rapidly regulate intestinal flora for type 2 diabetes.

Is It Time to Ban Flavored Cigarettes in Asia-Pacific Countries? A Scoping Review.

Flavored cigarettes encourage youth smoking and deter quitting. No country in Asia-Pacific, a region with some of the world's highest smoking rates, has regulated tobacco flavors. We examined market data, academic literature, and gray literature to describe what is known on flavored cigarettes in the Asia-Pacific region. Of the 12 countries for which market data were available, ten had substantial flavored cigarette market shares ranging from 10% to 97%. With no regulations and growing markets for flavor capsule variants, the tobacco industry's ongoing promotion of flavored cigarettes, which targets primarily youth and women, is expected to drive further increases in smoking prevalence. There are significant research and monitoring gaps on the industry's marketing tactics and use of flavored cigarettes in the region. Given the large market shares, Asia-Pacific countries stand to benefit substantially from a tobacco flavors ban.