Si-Wu-Tang alleviates metabolic dysfunction-associated fatty liver disease by inhibiting ACSL4-mediated arachidonic acid metabolism and ferroptosis in MCD diet-fed mice.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent chronic liver disease worldwide. Si-Wu-Tang (SWT), a traditional Chinese medicine decoction has shown therapeutic effects on various liver diseases. However, the hepatoprotective effects and underlying mechanism of SWT on MAFLD remain unclear. METHODS: First, a methionine-choline-deficient (MCD) diet-fed mice model was used and lipidomic analysis and transcriptomic analysis were performed. The contents of total iron ions, ferrous ions, and lipid peroxidation were detected and Prussian blue staining was performed to confirm the protective effects of SWT against ferroptosis. Finally, chemical characterization and network pharmacological analysis were employed to identify the potential active ingredients. RESULTS: Serological and hepatic histopathological findings indicated SWT's discernible therapeutic impact on MCD diet-induced MAFLD. Lipidomic analysis revealed that SWT improved intrahepatic lipid accumulation by inhibiting TG synthesis and promoting TG transport. Transcriptomic analysis suggested that SWT ameliorated abnormal FA metabolism by inhibiting FA synthesis and promoting FA ß-oxidation. Then, ferroptosis phenotype experiments revealed that SWT could effectively impede hepatocyte ferroptosis, which was induced by long-chain acyl-CoA synthetase 4 (ACSL4)-mediated esterification of arachidonic acid (AA). Finally, chemical characterization and network pharmacological analysis identified that paeoniflorin and other active ingredients might be responsible for the regulative effects against ferroptosis and MAFLD. CONCLUSION: In conclusion, our study revealed the intricate mechanism through which SWT improved MCD diet-induced MAFLD by targeting FA metabolism and ferroptosis in hepatocytes, thus offering a novel therapeutic approach for the treatment of MAFLD and its complications.

Intraoperative hypotension during liver transplantation and postoperative outcomes: Retrospective cohort study.

STUDY OBJECTIVES: Evaluation of the association between intraoperative hypotension (IOH) and important postoperative outcomes after liver transplant such as incidence and severity of acute kidney injury (AKI), MACE and early allograft dysfunction (EAD). DESIGN: Retrospective, single institution study. SETTINGS: Operating room. PATIENTS: 1576 patients who underwent liver transplant in our institution between January 2005 and February 2022. MEASUREMENTS: IOH was measured as the time, area under the threshold (AUT), or time-weighted average (TWA) of mean arterial pressure (MAP) less than certain thresholds (55,60 and 65 mmHg). Associations between IOH exposures and AKI severity were assessed via proportional odds models. The odds ratio from the proportional odds model estimated the relative odds of having higher stage of AKI for higher exposure to IOH. Associations between exposures and MACE and EAD were assessed through logistic regression models. Potential confounding variables including patient baseline and surgical characteristics were adjusted for all models. MAIN RESULTS: The primary analysis included 1576 surgeries that met the inclusion and exclusion criteria. Of those, 1160 patients (74%) experienced AKI after liver transplant surgery, with 780 (49%), 248(16%), and 132 (8.4%) experiencing mild, moderate, and severe injury, respectively. No significant association between hypotension exposure and postoperative AKI (yes or no) nor severity of AKI was observed. The odds ratios (95% CI) of having more severe AKI were 1.02 (0.997, 1.04) for a 50-mmHg·min increase in AUT of MAP <55 mmHg (P = 0.092); 1.03 (0.98, 1.07) for a 15-min increase in time spent under MAP <55 mmHg (P = 0.27); and 1.24 (0.98, 1.57) for a 1 mmHg increase in TWA of MAP <55 mmHg (P = 0.068). The associations between IOH and the incidence of MACE or EAD were not significant. CONCLUSION: Our results did not show the association between IOH and investigated outcomes.

Flooding soil with biogas slurry suppresses root-knot nematodes and alters soil nematode communities.

Root-knot nematodes (RKNs) pose a serious threat to crop production. Flooding soil with biogas slurry, combined with soil heating before crop planting, has the potential for RKN disease suppression. However, the actual effect of this method has not been verified under field conditions. Here, we present the results of a two-year field experiment in a greenhouse demonstrating the control effect on RKN disease and plant growth using this method, as well as its influence on the soil nematode community. Four treatments were set: untreated control (CK), local control method for RKN (CC), soil flooded with 70 % biogas slurry (BS70), and soil flooded with undiluted biogas slurry (BS100). In the first year, all three RKN control treatments significantly reduced the root-knot index (p < 0.05). In the next year, only BS70 and BS100 still presented significantly suppressed effects (p < 0.05), and it was more obvious under BS70 with a relative control effect of 74.6 %. In the first year, BS70 and BS100 significantly inhibited the plant height of watermelon (p < 0.05). In the next year, however, all three RKN control treatments promoted the growth of watermelon, and their stem diameter was significantly greater than that of CK. The application of biogas slurry (BS70 and BS100) significantly increased nematode richness and the Shannon index in the second year (p < 0.05). However, the structure index showed no significant difference among treatments (p > 0.05), indicating that biogas slurry application did not increase the soil food web complex. Principal component analysis showed that the application of biogas slurry changed the nematode community, especially under BS70, which presented a more lasting influence. The high-level input of biogas slurry also caused soil NH4+-N and heavy-metal and arsenic accumulation in the first year, but these soil-pollution risks disappeared in the second year.

Evaluation of an E6/E7 PCR-capillary electrophoresis fragment analysis in the genotyping of human papillomavirus in archival FFPE samples of oropharyngeal cancer.

Accumulating evidence has demonstrated that high-risk human papillomaviruses (HR-HPVs) are involved in the etiology of a subset of oropharyngeal squamous cell carcinoma (OPSCC). In this regard, the International Agency for Research on Cancer (IARC) has recommended direct molecular HPV testing. So far, there is no agreement on the most appropriate method for HPV detection on OPSCC formalin-fixed paraffin-embedded (FFPE) materials. In this study, we aimed to evaluate the performance of the high-sensitive SureX HPV assay in OPSCC FFPE tissues compared with LiPA-25 and p16ink4a immunostaining. A retrospective series of FFPE primary OPSCC cases were diagnosed between 2008 and 2019 and provided by the Henan Cancer Hospital, China. The level of agreement of two assays was determined using Cohen's Kappa (κ) statistics. A total of 230 FFPE OPSCC samples from tumor resections (n = 160) and diagnostic biopsies (n = 70) were detected. Sixty-six (28.7%) and 70 (30.4%) samples were identified as HPV-DNA-positive by LiPA-25 and SureX, respectively, of which HPV16 was largely the most common type (95.5% vs 94.3%). We found a perfect concordance between LiPA-25 and SureX for HPV-DNA status (κ = 0.906, 95% CI: 0.875-0.937) and for HPV16 (κ = 0.925, 95% CI: 0.897-0.953). In addition, SureX and p16ink4a immunostaining had a perfect concordance (κ = 0.917, 95% CI: 0.888-0.946). Moreover, the HPV-driven fraction, based on double positivity for HPV-DNA and p16ink4a, was similar between SureX (63 of 230, 27.4%) and LiPA-25 (60 of 230, 26.1%). Similar results were found in samples from resections and biopsies. SureX and LiPA-25 are comparable. SureX could be used for routine HPV-DNA detection and genotyping on archival OPSCC FFPE tissues.

Pioglitazone-induced alterations of purine metabolism in healthy male subjects.

Pioglitazone is class of thiazolidinediones that activates peroxisome proliferator-activated receptors (PPARs) in adipocytes to improve glucose metabolism and insulin sensitivity and has been used as a treatment for type 2 diabetes. However, the underlying mechanisms of associated pioglitazone-induced effects remain unclear. Our study aimed to investigate endogenous metabolite alterations associated with pioglitazone administration in healthy male subjects using an untargeted metabolomics approach. All subjects received 30 mg of pioglitazone once daily in the assigned sequence and period. Urine samples were collected before pioglitazone administration and for 24 h after 7 days of administration. A total of 1465 compounds were detected and filtered using a coefficient of variance below 30% and 108 metabolites were significantly altered upon pioglitazone administration via multivariate statistical analysis. Fourteen significant metabolites were identified using authentic standards and public libraries. Additionally, pathway analysis revealed that metabolites from purine and beta-alanine metabolisms were significantly altered after pioglitazone administration. Further analysis of quantification of metabolites from purine metabolism, revealed that the xanthine/hypoxanthine and uric acid/xanthine ratios were significantly decreased at post-dose. Pioglitazone-dependent endogenous metabolites and metabolic ratio indicated the potential effect of pioglitazone on the activation of PPAR and fatty acid synthesis. Additional studies involving patients are required to validate these findings.

3D-QSAR-Directed Synthesis of Halogenated Coumarin-3-Hydrazide Derivatives: Unveiling Their Potential as SDHI Antifungal Agents.

The pursuit of new succinate dehydrogenase (SDH) inhibitors is a leading edge in fungicide research and development. The use of 3D quantitative structure-activity relationship (3D-QSAR) models significantly enhances the development of compounds with potent antifungal properties. In this study, we leveraged the natural product coumarin as a molecular scaffold to synthesize 74 novel 3-coumarin hydrazide derivatives. Notably, compounds 4ap (0.28 µg/mL), 6ae (0.32 µg/mL), and 6ah (0.48 µg/mL) exhibited exceptional in vitro effectiveness against Rhizoctonia solani, outperforming the commonly used fungicide boscalid (0.52 µg/mL). Furthermore, compounds 4ak (0.88 µg/mL), 6ae (0.61 µg/mL), 6ah (0.65 µg/mL), and 6ak (1.11 µg/mL) showed significant activity against Colletotrichum orbiculare, surpassing both the SDHI fungicide boscalid (43.45 µg/mL) and the broad-spectrum fungicide carbendazim (2.15 µg/mL). Molecular docking studies and SDH enzyme assays indicate that compound 4ah may serve as a promising SDHI fungicide. Our ongoing research aims to refine this 3D-QSAR model further, enhance molecular design, and conduct additional bioactivity assays.

Controlled delivery of procyanidin through magnesium oxide nanoparticles (MgO NPs) to improve the activity and mineralization of osteoblasts under oxidative stressin vitro.

Excessive reactive oxygen species (ROS) in the microenvironment of osteoporosis (OP) not only accelerate the bone absorption, but also affect the osteogenic and mineralized effect of osteoblasts. Procyanidins (PC) have been reported to have anti-oxidation effects, but low bioavailability. This study aimed to explore the effect of magnesium oxide nanoparticles (MgO-PC NPs)-loaded PC on the osteogenesis and mineralization of osteoblasts that stimulated by H2O2. PC was loaded onto MgO NPs and characterized by transmission electron microscopy, energy dispersive spectroscopy, dynamic light scattering, and Fourier transform infrared spectroscopy. After primary screening by cytotoxicity assay, MgO-PC NPs containing 20 µM of PC were chosen for further studies. In H2O2-stimulated osteoblasts, dichlorodihydrofluorescein diacetate probe, Cell Counting Kit-8, quantitative real-time polymerase chain reaction, alkaline phosphatase staining/activity and Alizarin red staining were used to detect the ROS production, cell viability and osteogenic and mineralized markers of osteoblasts. PC was loaded onto MgO NPs to successfully receive MgO-PC NPs with a diameter of about 144 nm and negative potential. PC can sustain release from MgO-PC NPs for at least 16 d. The controlled release of PC from MgO-PC NPs can effectively eliminate ROS and thereby promoted the cell activity. Most importantly, the osteogenesis and mineralization of osteoblasts under oxidative stress were also significantly reversed by MgO-PC NPS. Thus, these findings indicate that MgO-PC NPs may be developed as a potential therapeutic strategy for OP.

ATR2C ala2 from Arabidopsis-infecting downy mildew requires 4 TIR-NLR immune receptors for full recognition.

Arabidopsis Col-0 RPP2A and RPP2B confer recognition of Arabidopsis downy mildew (Hyaloperonospora arabidopsidis [Hpa]) isolate Cala2, but the identity of the recognized ATR2Cala2 effector was unknown. To reveal ATR2Cala2, an F2 population was generated from a cross between Hpa-Cala2 and Hpa-Noks1. We identified ATR2Cala2 as a non-canonical RxLR-type effector that carries a signal peptide, a dEER motif, and WY domains but no RxLR motif. Recognition of ATR2Cala2 and its effector function were verified by biolistic bombardment, ectopic expression and Hpa infection. ATR2Cala2 is recognized in accession Col-0 but not in Ler-0 in which RPP2A and RPP2B are absent. In ATR2Emoy2 and ATR2Noks1 alleles, a frameshift results in an early stop codon. RPP2A and RPP2B are essential for the recognition of ATR2Cala2. Stable and transient expression of ATR2Cala2 under 35S promoter in Arabidopsis and Nicotiana benthamiana enhances disease susceptibility. Two additional Col-0 TIR-NLR (TNL) genes (RPP2C and RPP2D) adjacent to RPP2A and RPP2B are quantitatively required for full resistance to Hpa-Cala2. We compared RPP2 haplotypes in multiple Arabidopsis accessions and showed that all four genes are present in all ATR2Cala2-recognizing accessions.

Melatonin confers thermotolerance and antioxidant capacity in Chinese cabbage.

Due to the damaging effect of high temperatures on plant development, global warming is predicted to increase agricultural risks. Chinese cabbage holds considerable importance as a leafy vegetable that is extensively consumed and cultivated worldwide. Its year-round production also encounters severe challenges in the face of high temperatures. In this study, melatonin (MT), a pivotal multifunctional signaling molecule that coordinates responses to diverse environmental stressors was used to mitigate the harmful effects of high temperatures on Chinese cabbage. Through the utilization of growth indices, cytological morphology, physiological and biochemical responses, and RNA-Seq analysis, alongside an examination of the influence of crucial enzymes in the endogenous MT synthesis pathway on the thermotolerance of Chinese cabbage, we revealed that MT pretreatment enhanced photosynthetic activity, maintained signaling pathways associated with endoplasmic reticulum protein processing, and preserved circadian rhythm in Chinese cabbage under high temperatures. Furthermore, pretreatment with MT resulted in increased levels of soluble sugar, vitamin C, proteins, and antioxidant enzyme activity, along with decreased levels of malondialdehyde, nitrate, flavonoids, and bitter glucosinolates, ultimately enhancing the capacity of the organism to mitigate oxidative stress. The knockdown of the tryptophan decarboxylase gene, which encodes a key enzyme responsible for MT biosynthesis, resulted in a significant decline in the ability of transgenic Chinese cabbage to alleviate oxidative damage under high temperatures, further indicating an important role of MT in establishing the thermotolerance. Taken together, these results provide a mechanism for MT to improve the antioxidant capacity of Chinese cabbage under high temperatures and suggest beneficial implications for the management of other plants subjected to global warming.

Beneficial effects of time-restricted fasting on cardiovascular disease risk factors: a meta-analysis.

BACKGROUND: Cardiovascular disease continues to be a leading cause of mortality worldwide, highlighting the need to explore innovative approaches to improve cardiovascular health outcomes. Time-restricted fasting (TRF) is a dietary intervention that involves limiting the time window for food consumption. It has gained attention for its potential benefits on metabolic health and weight management. This study aims to investigate the impact of TRF on key risk factors, including body weight, glucose metabolism, blood pressure, and lipid profile. METHODS: We conducted a systematic search in five databases (Scopus, Embase, PubMed, Cochrane, and Web of Science) for relevant studies up to January 2023. After applying inclusion criteria, 12 studies were eligible for analysis. Quality assessment was conducted using the ROB-2.0 tool and ROBINS-I. Risk of bias was mapped using Revman 5.3, and data analysis included Hartung-Knapp adjustment using R 4.2.2. RESULTS: The group that underwent the TRF intervention exhibited a significant decrease in body weight (SMD: -0.22; 95%CI: -0.41, -0.04; P < 0.05) and fat mass (SMD: -0.19; 95%CI: -0.36, -0.02; P < 0.05), while maintaining lean mass (SMD: -0.09; 95%CI: -0.08, 0.26; P > 0.05). CONCLUSION: TRF has shown potential as a treatment strategy for reducing total body weight by targeting adipose tissue, with potential improvements in cardiometabolic function.

Acupuncture and related acupoint therapies for smoking cessation: An umbrella review and updated meta-analysis.

INTRODUCTION: Acupuncture and related acupoint therapies have been widely used for smoking cessation. Some relevant systematic reviews (SRs) have been published. There is a need to summarize and update the evidence to inform practice and decision-making. METHODS: Eight databases were searched from their inception to December 2023. SRs, any randomized controlled trials (RCTs) comparing acupuncture therapies with sham acupuncture, pharmacotherapy, behavioral therapy, or no treatment, were included. The primary outcome was the abstinence rate. AMSTAR-2 was employed to assess the quality of SRs. An updated meta-analysis was conducted based on SRs and RCTs. Data were synthesized using risk ratios (RR) with 95% confidence intervals (CIs). The GRADE approach was employed to assess the certainty of the updated evidence. RESULTS: Thirteen SRs and 20 RCTs outside of the SRs were identified. The SRs were of low or very low quality by AMSTAR-2. Sixteen (80%) RCTs were at high risk of performance bias. Eight acupuncture and related acupoint therapies were involved. The short-term (≤6 months) abstinence rate outcome was summarized as follows. Most SRs suggested that filiform needle acupuncture or acupressure had a better effect than sham acupuncture, but the findings were inconsistent. The updated meta-analysis also suggested that filiform needle acupuncture was more effective than sham acupuncture (RR=1.44; 95% CI: 1.02-2.02; I2 = 66%; low certainty; 9 RCTs, n=1358). Filiform needle acupuncture combined with acupressure was comparable to nicotine patches (RR=0.99; 95% CI: 0.74-1.32; low certainty; 6 RCTs, n= 524). Acupressure was superior to counseling (RR=1.46; 95% CI: 1.14-1.87; I2=5%; low certainty; 8 RCTs, n=595). No serious adverse events were reported in these SRs or RCTs. CONCLUSIONS: Low certainty evidence suggests that filiform needle acupuncture and auricular acupressure appear to be safe and effective in achieving short-term smoking cessation. However, long-term follow-up data are needed.

Impact of high-performance human papillomavirus testing to improve cervical cancer screening in China: a prospective population-based multicentre cohort study.

OBJECTIVES: The aim of the study was to evaluate the clinical performance of HBRT-H14, a real-time PCR-based assay that separates human papillomavirus (HPV) 16 and HPV18 from 12 other high-risk (HR) HPV types, in population according to Chinese guideline. METHODS: A total of 9829 eligible women aged 21-64 years from Henan, Shanxi, and Guangdong provinces were performed by HBRT-H14 testing and liquid-based cytology (LBC) screening at baseline and followed up for 3-year. The sensitivity, specificity, positive predictive value (absolute risk), and negative predictive value of LBC diagnosis and HPV testing were calculated for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) Lesions. RESULTS: At baseline, 80 (0.81%) participants were diagnosed with CIN2+. HR-HPV with reflex LBC had a significantly higher sensitivity (78/80, 97.50% [95% CI, 91.34-99.31%] vs. 62/80, 77.50% [67.21-85.27%], McNemar's test p < 0.001), and a slightly lower specificity (8528/9749, 87.48% [86.80-88.12%] vs. 8900/9749, 91.29% [90.72-91.83%], McNemar's test p < 0.001) than LBC with reflex HR-HPV for CIN2+. 7832 (79.6%) participants completed 3-year follow-up and 172 (2.20%) participants were cumulatively diagnosed with CIN2+. Compared with LBC with reflex HR-HPV, HR-HPV with reflex LBC significantly increased the sensitivity (161/172, 93.60% [88.91-96.39%] vs. 87/172, 50.58% [43.18-57.96%], McNemar's test p < 0.001), but marginally decreased the specificity (6776/7660, 88.46% [87.72-89.16%] vs. 6933/7660, 90.51% [89.83-91.15], McNemar's test p < 0.001). In addition, the absolute 3-year risk of CIN2+ in HPV16/18-positive individuals was as high as 33% (80/238), whereas the risk in the HPV-negative population was only 0.16% (11/6787), much lower than those in the negative for intraepithelial lesion or malignancy population (1.21%, 85/7018). Moreover, similar results were found in women ≥30 years old. DISCUSSION: The study has indicated that HBRT-14 has a reliable clinical performance for use in cervical screening. The validated HPV test would improve the quality of population screening.

Functional differentiation of olive PLP_deC genes: insights into metabolite biosynthesis and genetic improvement at the whole-genome level.

KEY MESSAGE: This study identified 16 pyridoxal phosphate-dependent decarboxylases in olive at the whole-genome level, conducted analyses on their physicochemical properties, evolutionary relationships and characterized their activity. Group II pyridoxal phosphate-dependent decarboxylases (PLP_deC II) mediate the biosynthesis of characteristic olive metabolites, such as oleuropein and hydroxytyrosol. However, there have been no report on the functional differentiation of this gene family at the whole-genome level. This study conducted an exploration of the family members of PLP_deC II at the whole-genome level, identified 16 PLP_deC II genes, and analyzed their gene structure, physicochemical properties, cis-acting elements, phylogenetic evolution, and gene expression patterns. Prokaryotic expression and enzyme activity assays revealed that OeAAD2 and OeAAD4 could catalyze the decarboxylation reaction of tyrosine and dopa, resulting in the formation of their respective amine compounds, but it did not catalyze phenylalanine and tryptophan. Which is an important step in the synthetic pathway of hydroxytyrosol and oleuropein. This finding established the foundational data at the molecular level for studying the functional aspects of the olive PLP_deC II gene family and provided essential gene information for genetic improvement of olive.

Pattern of multiple human papillomavirus infection and type competition: An analysis in healthy Chinese women aged 18-45 years.

To assess the pattern of multiple human papillomavirus infection to predict the type replacement postvaccination. A total of 7372 women aged 18-45y from a phase III trial of an Escherichia coli-produced HPV-16/18 vaccine were analyzed at enrollment visit before vaccination. Hierarchical multilevel logistic regression was used to evaluate HPV vaccine type and nonvaccine-type interactions with age as a covariate. Binary logistic regression was construed to compare multiple infections with single infections to explore the impact of multiple-type infections on the risk of cervical disease. Multiple HPV infections were observed in 25.2% of HPV-positive women and multiple infections were higher than expected by chance. Statistically significant negative associations were observed between HPV16 and 52, HPV18 and HPV51/52/58, HPV31 and HPV39/51/52/53/54/58, HPV33 and HPV52/58, HPV58 and HPV52, HPV6 and HPV 39/51/52/53/54/56/58. Multiple HPV infections increased the risk of CIN2+ and HSIL+, with the ORs of 2.27(95%CI: 1.41, 3.64) and 2.26 (95%CI: 1.29, 3.95) for multiple oncogenic HPV infection separately. However, no significant evidence for the type-type interactions on risk of CIN2+ or HSIL+. There is possibility of type replacement between several pairs of vaccine and nonvaccine HPV type. Multiple HPV infection increased the risk of cervical disease, but coinfection HPV types seem to follow independent disease processes. Continued post-vaccination surveillance for HPV 51/52/58 types and HPV 39/51 types separately was essential after the first and second generation of HPV vaccination implementation in China.

Si-Wu-Tang attenuates hepatocyte PANoptosis and M1 polarization of macrophages in non-alcoholic fatty liver disease by influencing the intercellular transfer of mtDNA.

ETHNOPHARMACOLOGICAL RELEVANCE: Non-alcoholic fatty liver disease (NAFLD) represents a burgeoning challenge for public health with potential progression to malignant liver diseases. PANoptosis, an avant-garde conceptualization of cell deaths, is closely associated with mitochondrial damage and linked to multiple liver disorders. Si-Wu-Tang (SWT), a traditional Chinese herbal prescription renowned for regulating blood-related disorders and ameliorating gynecological and hepatic diseases, has been demonstrated to alleviate liver fibrosis by regulating bile acid metabolism and immune responses. AIM OF THE STUDY: However, the mechanisms by which mtDNA is released from PANoptotic hepatocytes, triggering macrophage activation and hepatitis and whether this process can be reversed by SWT remain unclear. MATERIALS AND METHODS: Here, sophisticated RNA-sequencing complemented by molecular approaches were applied to explore the underlying mechanism of SWT against NAFLD in methionine/choline-deficient diet (MCD)-induced mice and relative in vitro models. RESULTS: We revealed that SWT profoundly repaired mitochondrial dysfunction, blocked mitochondrial permeability transition and mtDNA released to the cytoplasm, subsequently reversing hepatocyte PANoptosis and macrophage polarization both in MCD-stimulated mice and in vitro. Mechanically, loaded lipids dramatically promoted the opening of mPTP and oligomerization of VDAC2 to orchestrate mtDNA release, which was combined with ZBP1 to promote hepatocyte PANoptosis and also taken by macrophages to trigger M1 polarization via the FSTL1 and PKM2 combination. SWT effectively blocked NOXA signaling and reversed all these detrimental outcomes. CONCLUSION: Our findings show that SWT protects against hepatitis-mediated hepatocyte PANoptosis and macrophage M1 polarization by influencing intrahepatic synthesis, release and intercellular transfer of mtDNA, suggesting a potential therapeutic strategy for ameliorating NAFLD.

Novel 5-Sulfonyl-1,3,4-thiadiazole-Substituted Flavonoids as Potential Bactericides and Fungicides: Design, Synthesis, Three-Dimensional Quantitative Structure-Activity Relationship Studies.

Flavonoids, ubiquitous natural products, provide sources for drug discovery owing to their structural diversity, broad-spectrum pharmacological activity, and excellent environmental compatibility. To develop antibacterial and antifungal agents with novel mechanisms of action and innovative structures, a series of novel 5-sulfonyl-1,3,4-thiadiazole-substituted flavonoids were designed and synthesized, and their biological activities against seven agriculturally common phytopathogenic microorganisms were evaluated. The results of the antimicrobial bioassay showed that most of the target compounds displayed excellent inhibitory effects against Xanthomonas oryzae, Rhizoctonia solani, and Colletotrichum orbiculare. Compounds 1, 3, 7, 9, 13, and 14 exhibited remarkable antibacterial activity against X. oryzae pv. oryzae with EC50 values below 10 µg/mL, which were superior to bismerthiazol (70.89 µg/mL). Compound 2 (EC50 = 0.41 µg/mL) displayed the most effective inhibitory potency against R. solani in vivo, comparable protective effects with the positive control carbendizam. Preliminary mechanistic studies indicated that compound 2 induced disordered entanglement of hyphae, shrinkage of hyphal surfaces, extravasation of cellular contents, and vacuole swelling and rupture, which disrupted normal hyphal growth. Subsequently, compounds 35-53 with good antifungal activity were designed and synthesized based on reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) models. Compound 49 showed high efficacy and superior antifungal activity against R. solani, with an EC50 value of 0.28 µg/mL and a half-maximal effective concentration of 0.46 µg/mL.

Veterans Crisis Line Contacts After the 988 Suicide and Crisis Lifeline Rollout.

INTRODUCTION: This study identifies changes in Veterans Crisis Line (VCL) contact volume following the 988 National Suicide Prevention Hotline rollout, and examines changes in contact volume for self-identified Veterans. METHODS: VCL's Medora database was analyzed from July 2018 to June 2023, fitting linear interrupted time series models to forecast trends after the July 2022 rollout of the 988 Suicide Prevention Hotline. Data analysis was performed from 2023 to 2024. RESULTS: After the 988 rollout, average monthly VCL contact volume increased by 5,388 contacts (8.2%). The number of contacts self-identifying as Veterans increased by 2,739 (6.2%), while the percentage of self-identifying Veteran contacts who could be linked to VHA records declined by 3.8%. CONCLUSIONS: The 988 rollout was associated with increased VCL contact volume and broad changes in the profile of users. This underscores the importance of crisis services in adapting to dynamic user needs and highlights the potential of national suicide prevention initiatives to reach diverse populations.

Chinese medicine Phragmites communis (Lu Gen) for acute respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials.

Background: Acute respiratory tract infections (ARTIs) are the most common cause of morbidity and mortality worldwide, with most people experiencing at least one episode per year. Current treatment options are mainly symptomatic therapy. Antivirals, antibiotics, and glucocorticoids are of limited benefit for most infections. Traditional Chinese medicine has shown potential benefits in the treatment of ARTIs. Objective: The objective of this study was to determine the efficacy, effectiveness, and safety of Phragmites communis Trin. (P. communis, a synonym of Phragmites australis (Cav.) Trin. ex Steud) as monotherapy or as part of an herb mixture for ARTIs. Method: Eight databases and two clinical trial registries were searched from inception to 8 February 2023 for randomized controlled trials (RCTs) evaluating any preparation involving P. communis without language restrictions. The Risk of Bias Tool 2.0 was used to assess the risk of bias of the included trials. RevMan 5.3 software was used for data analyses with effects estimated as risk ratios (RRs), mean differences (MDs), or standardized mean differences (SMDs) with 95% confidence intervals (CIs). The online GRADEpro tool was used to assess the certainty of the evidence, if available. Results: Forty-two RCTs involving 6,879 patients with ARTIs were included, with all trials investigating P. communis as part of an herbal mixture. Of the included trials, the majority (38/42) were considered high risk. Compared to the placebo, P. communis preparations improved the cure rate [RR = 1.60, 95% CI (1.13, 2.26)] and fever clearance time [MD = -2.73 h, 95% CI (-4.85, -0.61)]. Compared to usual care alone, P. communis preparations also significantly improved the cure rate [RR = 1.57, 95% CI (1.36, 1.81)] and fever clearance time [SMD = -1.24, 95% CI (-2.37, -0.11)]. P. communis preparations plus usual care compared to usual care alone increased the cure rate [RR = 1.55, 95% CI (1.35, 1.78)], shortened the fever clearance time [MD = -19.31 h, 95% CI (-33.35, -5.27)], and improved FEV1 [ MD = 0.19 L, 95% CI (0.13, 0.26)] and FVC [ MD = 0.16 L, 95% CI (0.03, 0.28)]. Conclusion: Low- or very low-certainty evidence suggests that P. communis preparations may improve the cure rate of ARTIs, shorten the fever clearance time in febrile patients, and improve the pulmonary function of patients with acute exacerbation of chronic obstructive pulmonary disease or chronic bronchitis. However, these findings are inconclusive and need to be confirmed in rigorously designed trials. Systematic review registration: PROSPERO, identifier CRD42021239936.

Double-blinded, randomized clinical trial of Gegen Qinlian decoction pinpoints Faecalibacterium as key gut bacteria in alleviating hyperglycemia.

Background: Accumulating evidence suggests that metabolic disorders, including type 2 diabetes mellitus (T2DM), can be treated with traditional Chinese medicine formulas, such as the Gegen Qinlian decoction (GQD). This study elucidates the mechanisms by which gut microbes mediate the anti-diabetic effects of GQD. Methods: We conducted a double-blind randomized clinical trial involving 120 untreated participants with T2DM. During the 12-week intervention, anthropometric measurements and diabetic traits were recorded every 4 weeks. Fecal microbiota and serum metabolites were measured before and after the intervention using 16S rDNA sequencing, liquid chromatography-mass spectrometry, and Bio-Plex panels. Results: Anti-diabetic effects were observed in the GQD group in the human trial. Specifically, glycated hemoglobin, fasting plasma glucose, and two-hour postprandial blood glucose levels were significantly lower in the GQD group than in the placebo group. Additionally, Faecalibacterium was significantly enriched in the GQD group, and the short-chain fatty acid levels were higher and the serum inflammation-associated marker levels were lower in the GQD group compared to the placebo group. Moreover, Faecalibacterium abundance negatively correlated with the levels of serum hemoglobin, fasting plasma glucose, and pro-inflammatory cytokines. Finally, the diabetes-alleviating effect of Faecalibacterium was confirmed by oral administration of Faecalibacterium prausnitzii (DSMZ 17677) in T2DM mouse model. Conclusions: GQD improved type 2 diabetes primarily by modulating the abundance of Faecalibacterium in the gut microbiota, alleviating metabolic disorders and the inflammatory state. Trial registration: Registry No. ChiCTR-IOR-15006626.

Design, Synthesis, Antifungal Activity, and 3D-QASR of Novel Oxime Ether-Containing Coumarin Derivatives as Potential Fungicides.

Structural modification of natural products is an effective approach for improving antifungal activity and has, therefore, been used extensively in the development of new agrochemical products. In this work, a series of novel coumarin derivatives containing oxime ether structures were designed, synthesized, and evaluated for antifungal activity. Some of the designed compounds exhibited promising antifungal activities against tested fungi, and compounds 4a, 4c, 5a, and 6b had EC50 values equivalent to those of commercial fungicides. Compound 6b was the most promising candidate fungicide against Rhizoctonia solani (EC50 = 0.46 µg/mL). In vivo antifungal bioassays suggested that compounds 5a and 6b could serve as novel agricultural antifungals. Furthermore, microscopy demonstrated that compound 6b induced the sprawling growth of hyphae, distorted the outline of cell walls, and reduced mitochondrial numbers. Additionally, the effects of the substituent steric, electrostatic, hydrophobic, and hydrogen-bond fields were elucidated using an accurate and reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) model. The results presented here will guide the discovery of potential novel fungicides for plant disease control in agriculture.