Lian-Mei-Yin formula alleviates diet-induced hepatic steatosis by suppressing Yap1/FOXM1 pathway-dependent lipid synthesis.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with a global prevalence of 25%. Patients with NAFLD are more likely to suffer from advanced liver disease, cardiovascular disease, or type II diabetes. However, unfortunately, there is still a shortage of FDA-approved therapeutic agents for NAFLD. Lian-Mei-Yin (LMY) is a traditional Chinese medicine formula used for decades to treat liver disorders. It has recently been applied to type II diabetes which is closely related to insulin resistance. Given that NAFLD is another disease involved in insulin resistance, we hypothesize that LMY might be a promising formula for NAFLD therapy. Herein, we verify that the LMY formula effectively reduces hepatic steatosis in diet-induced zebrafish and NAFLD model mice in a time- and dose-dependent manner. Mechanistically, LMY suppresses Yap1-mediated Foxm1 activation, which is crucial for the occurrence and development of NAFLD. Consequently, lipogenesis is ameliorated by LMY administration. In summary, the LMY formula alleviates diet-induced NAFLD in zebrafish and mice by inhibiting Yap1/Foxm1 signaling-mediated NAFLD pathology.

Marinimicrococcus flavescens gen. nov., sp. nov., a new member of the family Geminicoccaceae, isolated from a marine sediment of the South China Sea.

A Gram-stain-negative, catalase-positive and oxidase-positive, nonmotile, aerobic, light yellow, spherical-shaped bacterial strain with no flagella, designated strain YIM 152171T, was isolated from sediment of the South China Sea. Colonies were smooth and convex, light yellow and circular, and 1.0-1.5×1.0-1.5 µm in cell diameter after 7 days of incubation at 28°C on YIM38 media supplemented with sea salt. Colonies could grow at 20-45°C (optimum 28-35°C) and pH 6.0-11.0 (optimum, pH 7.0-9.0), and they could proliferate in the salinity range of 0-6.0 % (w/v) NaCl. The major cellular fatty acids were summed feature 8 (C18 : 1 ω7c/C18 : 1 ω6c), C18 : 1 ω7c 11-methyl, C16 : 0, C16 : 1 ω11c, C16 : 1 ω5c, C17 : 1 ω6c and C18 : 1 ω5c. The respiratory quinone was ubiquinone 10, and the polar lipid profile included diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, phosphatidylinositol mannoside, one unidentified phospholipid and one unidentified aminolipid. Phylogenetic analyses based on the 16S rRNA gene sequences placed strain YIM 152171T within the order Rhodospirillales in a distinct lineage that also included the genus Geminicoccus. The 16S rRNA gene sequence similarities of YIM 152171T to those of Arboricoccus pini, Geminicoccus roseus and Constrictibacter antarcticus were 92.17, 89.25 and 88.91 %, respectively. The assembled draft genome of strain YIM 152171T had 136 contigs with an N50 value of 134704 nt, a total length of 3 001 346 bp and a G+C content of 70.27 mol%. The phylogenetic, phenotypic and chemotaxonomic data showed that strain YIM 152171T (=MCCC 1K08488T=KCTC 92884T) represents a type of novel species and genus for which we propose the name Marinimicrococcus gen. nov., sp. nov.

Exogenous methionine contributes to reversing the resistance of Streptococcus suis to macrolides.

Streptococcus suis (S. suis) has been increasingly recognized as a porcine zoonotic pathogen that threatens the health of both pigs and humans. Multidrug-resistant Streptococcus suis is becoming increasingly prevalent, and novel strategies to treat bacterial infections caused by these organisms are desperately needed. In the present study, an untargeted metabolomics analysis showed that the significant decrease in methionine content and the methionine biosynthetic pathway were significantly affected by the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis in drug-resistant S. suis. The addition of L-methionine restored the bactericidal activity of macrolides, doxycycline, and ciprofloxacin on S. suis in vivo and in vitro. Further studies showed that the exogenous addition of methionine affects methionine metabolism by reducing S-adenosylmethionine synthetase activity and the contents of S-adenosylmethionine, S-adenosyl homocysteine, and S-ribose homocysteine. Methionine can decrease the total methylation level and methylesterase activity in multidrug resistant S. suis. The drug transport proteins and efflux pump genes were significantly downregulated in S. suis by exogenous L-methionine. Moreover, the exogenous addition of methionine can reduce the survival of S. suis by affecting oxidative stress and metal starvation in bacteria. Thus, L-methionine may influence the development of resistance in S. suis through methyl metabolism and metal starvation. This study provides a new perspective on the mitigation of drug resistance in S. suis.IMPORTANCEBacterial antibiotic resistance has become a severe threat to human and animal health. Increasing the efficacy of existing antibiotics is a promising strategy against antibiotic resistance. Here, we report that L-methionine enhances the efficacy of macrolides, doxycycline, and ciprofloxacin antibiotics in killing Streptococcus suis, including multidrug-resistant pathogens. We investigated the mechanism of action of exogenous methionine supplementation in restoring macrolides in Streptococcus suis and the role of the methionine cycle pathway on methylation levels, efflux pump genes, oxidative stress, and metal starvation in Streptococcus suis. It provides a theoretical basis for the rational use of macrolides in clinical practice and also identifies a possible target for restoring drug resistance in Streptococcus suis.

Hedscandines A-C, three undescribed indole alkaloids from Hedyotis scandens with their anti-MRSA activity.

Hedscandines A-C (1-3), three undescribed indole alkaloids were isolated from Hedyotis scandens Roxb, a traditional Chinese medicine widely used in the treatment of respiratory ailments. Their structures were elucidated by extensive spectroscopic data and electronic circular dichroism calculation. Hedscandine A (1), possessed a unique carbon skeleton with a 1,4-oxazonin-2(3H)-one core system and displayed a rapid bactericidal activity against MRSA with a MIC value of 16 µg/mL. Mechanistic studies showed that compound 1 could disrupt the integrity of bacterial cell membranes and thus lead to bacterial death.

Fangji Huangqi decoction ameliorates membranous nephropathy through the upregulation of BNIP3-mediated mitophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Fangji Huangqi Decoction (FJHQ), a traditional Chinese medicinal formula outlined in Zhang Zhongjing's "Jin Gui Yao Lue" during the Han Dynasty, is often used to treat conditions characterized by symptoms like edema and dysuria, including membranous nephropathy (MN). Despite its proven clinical effectiveness, the exact mechanisms through which FJHQ acts on MN remain elusive. AIM OF THE STUDY: This study aimed to investigate whether FJHQ enhances BNIP3-mediated mitophagy in podocytes by promoting BNIP3 expression and whether this improvement leads to the amelioration of MN. MATERIALS AND METHODS: In this study, by establishing passive Heymann nephritis (PHN) rats, an experimental rat model of MN induced by sheep anti-rat Fx1A serum, we evaluated the effects of FJHQ in vivo. In vitro experiments were carried out by treating primary podocytes with experimental rat serum. Furthermore, the potential mechanism by which FJHQ acts through BNIP3 was further examined by transfecting primary podocytes with the siRNA of BNIP3 or the corresponding control vector. RESULTS: After 4 weeks, significant kidney damage was observed in the rats in the model group, comparatively, FJHQ markedly decreased urine volume, 24-h urinary protein, blood urea nitrogen (BUN), creatinine (Scr), and increased serum total albumin (ALB). Histology showed that FJHQ caused significant improvements in glomerular hyperplasia, and IgG immune complex deposition in MN rats. JC-1 fluorescence labelling and flow cytometry analysis showed that FJHQ could significantly increase mitochondrial membrane potential in vivo. In the mitochondria of MN model rats, FJHQ was able to down-regulate the expression of P62 and up-regulate the expression of BNIP3, LC3B, and LC3 II/LC3 I, according to Western blot and immunofluorescence studies. Furthermore, FJHQ has been shown to significantly up-regulate mitochondrial membrane potential, down-regulate P62 expression in mitochondria, and up-regulate the expression of BNIP3, LC3B, and LC3 II/LC3 I in mitochondria at the cellular level. After the administration of the autophagy inhibitor chloroquine, the serum of rats treated with FJHQ further increased the expression of LC3 II/LC3 I in primary podocytes, showing higher autophagy flow. After the interference of BNIP3 in podocytes, the effect of FJHQ on mitochondrial membrane potential and autophagy-related proteins almost disappeared. CONCLUSION: FJHQ enhanced mitophagy in podocytes by promoting the expression of BNIP3, thereby contributing to the amelioration of MN. This work reveals the possible underlying mechanism by which FJHQ improves MN and provides a new avenue for MN treatment.

Associations of Habitual Calcium Supplementation With Risk of Cardiovascular Disease and Mortality in Individuals With and Without Diabetes.

OBJECTIVE: To prospectively examine the associations of habitual calcium supplementation with cardiovascular disease (CVD) events and mortality in individuals with and without diabetes. RESEARCH DESIGN AND METHODS: The main analysis included 434,374 participants from the UK Biobank. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs. Interactions of calcium supplement use with diabetes status were tested on multiplicative and additive scales. RESULTS: Over a median follow-up of 8.1 and 11.2 years, 26,374 incident CVD events and 20,526 deaths were documented, respectively. After multivariable adjustment, habitual calcium supplementation was significantly associated with higher risks of CVD incidence (HR 1.34; 95% CI 1.14, 1.57), CVD mortality (HR 1.67; 95% CI 1.19, 2.33), and all-cause mortality (HR 1.44; 95% CI 1.20, 1.72) in participants with diabetes, whereas no significant association was observed in participants without diabetes (HR 0.97 [95% CI 0.92, 1.03] for CVD incidence; HR 1.05 [95% CI 0.90, 1.23] for CVD mortality; HR 1.02 [95% CI 0.96, 1.09] for all-cause mortality). Significant multiplicative and additive interactions were found between habitual calcium supplementation and diabetes status on risks of CVD events and mortality (all Pinteraction < 0.05). In contrast, no significant interactions were observed between dietary or serum calcium and diabetes status. CONCLUSIONS: Habitual use of calcium supplements was significantly associated with higher risk of CVD events and mortality in people with diabetes but not in people without diabetes. Further studies are needed to balance potentially adverse effects of calcium supplement against likely benefits, particularly among patients with diabetes.

Genetically engineered probiotics for an optical imaging-guided tumor photothermal therapy/immunotherapy.

Bacteria-based cancer therapy (BCT) has been extensively investigated because of the tumor targeting and antitumor immunity activating abilities of bacteria over traditional nanodrugs, but their potential systemic toxicity poses a challenge. Therefore, it is important to visualize the precise localization and real-time distribution of bacteria in vivo to guide the treatment. Herein, biogenetically engineered Escherichia coli Nissle 1917 (EcN) were constructed to highly express tyrosinase to intracellularly generate cyanine 5-labeled melanin-like polymers (Cy5-Mel), thus endowing them with a bright fluorescence and an excellent photothermal performance upon NIR laser irradiation, thereby inducing the intense immunogenic death of tumor cells and release of tumor-associated antigens. Acting as adjuvants, bacteria can greatly stimulate the maturation of dendritic (DC) cells. The in vivo behaviors of these bacteria was monitored via noninvasive optical imaging when they were intravenously administrated to tumor-bearing mice. From this, NIR exposure on tumor sites was carried out at an appropriate time point to induce the damage to tumor cells and for the modulation of tumor immune microenvironments. Thus, via a simple bioengineering strategy, a promising bacteria-based theranostic platform was constructed for tumor treatment.

Prevention of the Lachnum polysaccharide and its selenium derivatives on cisplatin-induced acute kidney injury in mice.

To investigate the renal protective effects of the polysaccharide LEP-1a and derivatives of selenium (SeLEP-1a) from Lachnum YM38, cisplatin (CP) was used to establish an acute kidney model. LEP-1a and SeLEP-1a could effectively reverse the decrease in renal index and improved renal oxidative stress. LEP-1a and SeLEP-1a significantly reduced the contents of the inflammatory cytokines. They could inhibit the release of cyclooxygenase 2 (COX-2) and nitric oxide synthase (iNOS) and increase the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1). At the same time, the PCR results indicated that SeLEP-1a could significantly inhibit the mRNA expression levels of toll-like receptor 4 (TLR4), nuclear factor-kB (NF-κB) p65 and inhibitor of kappa B-alpha (IκBα). Western blot analysis showed that LEP-1a and SeLEP-1a significantly downregulated the expression levels of Bcl-2-associated X protein (Bax) and cleaved caspase-3 and upregulated phosphatidylinositol 3-kinase (p-PI3K), protein kinase B (p-Akt) and B-cell lymphoma 2 (Bcl-2) protein expression levels in the kidney. LEP-1a and SeLEP-1a could improve CP-induced acute kidney injury by regulating the oxidative stress response, NF-κB-mediated inflammation and the PI3K/Akt-mediated apoptosis signalling pathway.

Comprehensive multicomponent characterization and quality assessment of Xiaoyao Wan by UPLC-Q-Orbitrap-MS, HS-SPME-GC-MS and HS-GC-IMS.

Xiaoyao Wan (XYW) is a prescription medicine of traditional Chinese medicine (TCM) with the effects of "soothing the liver and relieving depression," and "strengthening spleen and nourishing blood". XYW has been widely concerned in the treatment of depression and has become one of the commonly used classic formulas in clinical practice. However, the pharmacodynamic substance basis and the quality control studies of XYW are hitherto quite limited. Here, we aim to fully utilize an advanced ultra - performance liquid chromatography-quadrupole - Orbitrap mass spectrometry (UPLC-Q-Orbitrap-MS), headspace-solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS) and headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS) technique to deep characterization of the pharmacological substance basis and quantitatively evaluate the quality of XYW. Firstly, 299 compounds were identified or tentatively characterized, including 198 non-volatile organic compounds (n-VOCs) and 101 volatile organic compounds (VOCs). Secondly, principal component analysis (PCA) and hierarchical cluster analysis (HCA) was used to analyze quality differences in XYW at different manufacturers. Thirdly, a parallel reaction monitoring (PRM) method was established and validated to quantify the fourteen major effective substances in different manufacturers of XYW, which were chosen as the benchmarked substances to evaluate the quality of XYW. In conclusion, this study shows that the strategy provides a useful method for quality control of TCM and offers a practical workflow for exploring the quality consistency of TCM.

Chromosome-scale genome assembly of sweet tea (Lithocarpus polystachyus Rehder).

Lithocarpus, with >320 species, is the second largest genus of Fagaceae. However, the lack of a reference genome limits the molecular biology and functional study of Lithocarpus species. Here, we report the chromosome-scale genome assembly of sweet tea (Lithocarpus polystachyus Rehder), the first Lithocarpus species to be sequenced to date. Sweet tea has a 952-Mb genome, with a 21.4-Mb contig N50 value and 98.6% complete BUSCO score. In addition, the per-base consensus accuracy and completeness of the genome were estimated at 60.6 and 81.4, respectively. Genome annotation predicted 37,396 protein-coding genes, with repetitive sequences accounting for 64.2% of the genome. The genome did not undergo whole-genome duplication after the gamma (γ) hexaploidy event. Phylogenetic analysis showed that sweet tea diverged from the genus Quercus approximately at 59 million years ago. The high-quality genome assembly and gene annotation resources enrich the genomics of sweet tea, and will facilitate functional genomic studies in sweet tea and other Fagaceae species.

Effects of a multilevel intervention of resistance training with or without beta-hydroxy-beta-methylbutyrate in medical ICU patients during entire hospitalisation: a four-arm multicentre randomised controlled trial.

BACKGROUND: Intensive care unit-acquired weakness (ICU-AW) is a prevalent and severe issue among ICU patients. Resistance training and beta-hydroxy-beta-methylbutyrate (HMB) intervention have demonstrated the potential to enhance muscle function in patients with sarcopenia and in older adults. The purpose of this study was to determine whether resistance training and/or HMB administration would improve physical function, muscle strength, and quality of life in medical ICU patients. METHODS: In this multicentre, four-arm, single-blind randomised control trial, a total of 112 adult patients with internal medical diagnoses admitted to the ICU were enrolled. These participants were then randomly assigned to one of four treatment groups: the resistance training group received protocol-based multilevel resistance exercise, the HMB group received 3 g/day of HMBCa, combination group and control groups received standard care, from the ICU to the general ward until discharge. The primary outcomes assessed at discharge included six-minute walking distance (6MWD) and short physical performance battery (SPPB). Secondary outcomes measured included muscle mass, MRC score, grip strength, and health reports quality of life at different time points. Data analysis was performed using a generalised linear mixed model, adhering to the principles of intention-to-treat analysis. RESULTS: Resistance training and combination treatment groups exhibited significant increases in SPPB scores (3.848 and 2.832 points, respectively) compared to the control group and substantial improvements in 6WMD (99.768 and 88.577 m, respectively) (all with P < 0.01). However, no significant changes were observed in the HMB group. Muscle strength, as indicated by MRC and grip strength tests conducted at both ICU and hospital discharge, showed statistically significant improvements in the resistance training and combination groups (P < 0.05). Nevertheless, no significant differences were found between the treatment groups and usual care in terms of 60-day mortality, prevalence of ICU-AW, muscle mass, quality of life, or other functional aspects. CONCLUSIONS: Resistance training with or without beta-hydroxy-beta-methylbutyrate during the entire hospitalisation intervention improves physical function and muscle strength in medical ICU patients, but muscle mass, quality of life, and 60-day mortality were unaffected. TRIAL REGISTRATION: ChiCTR2200057685 was registered on March 15th, 2022.

Protective effects of Radix Stellariae extract against Alzheimer's disease via autophagy activation in Caenorhabditis elegans and cellular models.

Enhancing the clearance of proteins associated with Alzheimer's disease (AD) emerges as a promising approach for AD therapeutics. This study explores the potential of Radix Stellariae, a traditional Chinese medicine, in treating AD. Utilizing transgenic C. elegans models of AD, we demonstrated that a 75% ethanol extract of Radix Stellariae (RSE) (at 50 µg/mL) effectively diminishes Aß and Tau protein expression, and alleviates their induced impairments including paralysis, behavioral dysfunction, neurotoxicity, and ROS accumulation. Additionally, RSE enhances the stress resistance of C. elegans. Further investigations revealed that RSE promotes autophagy, a critical cellular process for protein degradation, in these models. We found that inhibiting autophagy-related genes negated the neuroprotective effects of RSE, suggesting a central role for autophagy in the actions of RSE. In PC-12 cells, we observed that RSE not only inhibited Aß fibril formation but also promoted the degradation of AD-related proteins and reduced their cytotoxicity. Mechanistically, RSE was found to induce autophagy via modulating PI3K/AKT/mTOR and AMPK/mTOR signaling pathways. Importantly, inhibiting autophagy counteracted the beneficial effects of RSE on the clearance of AD-associated proteins. Moreover, we identified Dichotomine B, a ß-carboline alkaloid, as a key active constituent of RSE in mitigating AD pathology in C. elegans at concentrations ranging from 50 to 1000 µM. Collectively, our study presents novel discoveries that RSE alleviates AD pathology and toxicity primarily by inducing autophagy, both in vivo and in vitro. These findings open up new avenues for exploring the therapeutic potential of RSE and its active component, Dichotomine B, in treating neurodegenerative diseases like AD.

Ameliorative effect of Luffa cylindrica fruits on Caenorhabditis elegans and cellular models of Alzheimer's disease-related pathology via autophagy induction.

BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder without an effective cure. Natural products, while showing promise as potential therapeutics for AD, remain underexplored. AIMS: This study was conducted with the goal of identifying potential anti-AD candidates from natural sources using Caenorhabditis elegans (C. elegans) AD-like models and exploring their mechanisms of action. MATERIALS & METHODS: Our laboratory's in-house herbal extract library was utilized to screen for potential anti-AD candidates using the C. elegans AD-like model CL4176. The neuroprotective effects of the candidates were evaluated in multiple C. elegans AD-like models, specifically targeting Aß- and Tau-induced pathology. In vitro validation was conducted using PC-12 cells. To investigate the role of autophagy in mediating the anti-AD effects of the candidates, RNAi bacteria and autophagy inhibitors were employed. RESULTS: The ethanol extract of air-dried fruits of Luffa cylindrica (LCE), a medicine-food homology species, was found to inhibit Aß- and Tau-induced pathology (paralysis, ROS production, neurotoxicity, and Aß and pTau deposition) in C. elegans AD-like models. LCE was non-toxic and enhanced C. elegans' health. It was shown that LCE activates autophagy and its anti-AD efficacy is weakened with the RNAi knockdown of autophagy-related genes. Additionally, LCE induced mTOR-mediated autophagy, reduced the expression of AD-associated proteins, and decreased cell death in PC-12 cells, which was reversed by autophagy inhibitors (bafilomycin A1 and 3-methyladenine). DISCUSSION: LCE, identified from our natural product library, emerged as a valuable autophagy enhancer that effectively protects against neurodegeneration in multiple AD-like models. RNAi knockdown of autophagy-related genes and cotreatment with autophagy inhibitors weakened its anti-AD efficacy, implying a critical role of autophagy in mediating the neuroprotective effects of LCE. CONCLUSION: Our findings highlight the potential of LCE as a functional food or drug for targeting AD pathology and promoting human health.

Tanshinone IIA inhibited intermittent hypoxia induced neuronal injury through promoting autophagy via AMPK-mTOR signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Chronic intermittent hypoxia (CIH) is the primary pathophysiological process of obstructive sleep apnea (OSA) and is closely linked to neurocognitive dysfunction. Tanshinone IIA (Tan IIA) is extracted from Salvia miltiorrhiza Bunge and used in Traditional Chinese Medicine (TCM) to improve cognitive impairment. Studies have shown that Tan IIA has anti-inflammatory, anti-oxidant, and anti-apoptotic properties and provides protection in intermittent hypoxia (IH) conditions. However, the specific mechanism is still unclear. AIM OF THE STUDY: To assess the protective effect and mechanism of Tan IIA treatment on neuronal injury in HT22 cells exposed to IH. MATERIALS AND METHODS: The study established an HT22 cell model exposed to IH (0.1% O2 3 min/21% O2 7 min for six cycles/h). Cell viability was determined using the Cell Counting Kit-8, and cell injury was determined using the LDH release assay. Mitochondrial damage and cell apoptosis were observed using the Mitochondrial Membrane Potential and Apoptosis Detection Kit. Oxidative stress was assessed using DCFH-DA staining and flow cytometry. The level of autophagy was assessed using the Cell Autophagy Staining Test Kit and transmission electron microscopy (TEM). Western blot was used to detect the expressions of the AMPK-mTOR pathway, LC3, P62, Beclin-1, Nrf2, HO-1, SOD2, NOX2, Bcl-2/Bax, and caspase-3. RESULTS: The study showed that Tan IIA significantly improved HT22 cell viability under IH conditions. Tan IIA treatment improved mitochondrial membrane potential, decreased cell apoptosis, inhibited oxidative stress, and increased autophagy levels in HT22 cells under IH conditions. Furthermore, Tan IIA increased AMPK phosphorylation and LC3II/I, Beclin-1, Nrf2, HO-1, SOD2, and Bcl-2/Bax expressions, while decreasing mTOR phosphorylation and NOX2 and cleaved caspase-3/caspase-3 expressions. CONCLUSION: The study suggested that Tan IIA significantly ameliorated neuronal injury in HT22 cells exposed to IH. The neuroprotective mechanism of Tan IIA may mainly be related to inhibiting oxidative stress and neuronal apoptosis by activating the AMPK/mTOR autophagy pathway under IH conditions.

Targeting autophagy to discover the Piper wallichii petroleum ether fraction exhibiting antiaging and anti-Alzheimer's disease effects in Caenorhabditis elegans.

BACKGROUND: With population aging, the incidence of aging-related Alzheimer's disease (AD) is increasing, accompanied by decreased autophagy activity. At present, Caenorhabditis elegans (C. elegans) is widely employed to evaluate autophagy and in research on aging and aging-related diseases in vivo. To discover autophagy activators from natural medicines and investigate their therapeutic potential in antiaging and anti-AD effects, multiple C. elegans models related to autophagy, aging, and AD were used. METHOD: In this study, we employed the DA2123 and BC12921 strains to discover potential autophagy inducers using a self-established natural medicine library. The antiaging effect was evaluated by determining the lifespan, motor ability, pumping rate, lipofuscin accumulation of worms, and resistance ability of worms under various stresses. In addition, the anti-AD effect was examined by detecting the paralysis rate, food-sensing behavior, and amyloid-ß and Tau pathology in C. elegans. Moreover, RNAi technology was used to knock down the genes related to autophagy induction. RESULTS: We discovered that Piper wallichii extract (PE) and the petroleum ether fraction (PPF) activated autophagy in C. elegans, as evidenced by increased GFP-tagged LGG-1 foci and decreased GFP-p62 expression. In addition, PPF extended the lifespan and enhanced the healthspan of worms by increasing body bends and pumping rates, decreasing lipofuscin accumulation, and increasing resistance to oxidative, heat, and pathogenic stress. Moreover, PPF exhibited an anti-AD effect by decreasing the paralysis rate, improving the pumping rate and slowing rate, and alleviating Aß and Tau pathology in AD worms. However, the feeding of RNAi bacteria targeting unc-51, bec-1, lgg-1, and vps-34 abolished the antiaging and anti-AD effects of PPF. CONCLUSION: Piper wallichii may be a promising drug for antiaging and anti-AD. More future studies are also needed to identify autophagy inducers in Piper wallichii and clarify their molecular mechanisms.

Systematical characterization of gypenosides in Gynostemma pentaphyllum and the chemical composition variation of different origins.

Gynostemma pentaphyllum (Thunb.) Makino is an herbaceous plant of Cucurbitaceae family, which has been widely used as an herbal tea and traditional Chinese medicine. Since its saponins are similar to ginsenosides and have a wide range of activities, it has attracted wide interest. However, there are still a large number of unknown saponins that have not been isolated, especially some trace gypenosides. In the present study, a HILIC × RP offline two-dimensional liquid separation combined with a multimode data acquisition was developed for the systematical characterization of gypenosides. On top of the negative mode information, considering that saponins are prone to in-source fragmentations in positive ion mode, a precursor ion list data acquisition method was used for the targeted acquisition of multistage positive data. Reference herbal drug was taken as a golden sample to probe the chemical composition of G. pentaphyllum. The mixed sample of commercially available samples were also analyzed in parallel. Furthermore, the chemical compositions of commercially available samples from different sources were compared. In total, 1108 saponins were characterized, among which 588 were accurately characterized, with 574 identified in the reference herbal drug and 700 in the mixed commercially available samples. The commercially available samples showed great composition variation. These findings clarified the material basis and provided clues for quality control of G. pentaphyllum.

Effects of long-term no-tillage on the functional potential of microorganisms involved in the nitrogen, phosphorus and sulfur cycles of black soil.

Understanding the effects of different tillage practices on functional microbial abundance and composition in nitrogen (N), phosphorus (P) and sulfur (S) cycles are essential for the sustainable utilization of black soils. Based on an 8-year field experiment located in Changchun, Jilin Province, we analyzed the abundance and composition of N, P and S cycling microorganisms and their driving factors in different depths of black soil under no til-lage (NT) and conventional tillage (CT). Results showed that compared with CT, NT significantly increased soil water content (WC) and microbial biomass carbon (MBC) at soil depth of 0-20 cm. Compared with CT, NT significantly increased the abundances of functional and encoding genes related to N, P and S cycling, including the nosZ gene encoding N2O reductase, the ureC gene performing organic nitrogen ammoniation, the nifH gene encoding nitrogenase ferritin, the functional genes phnK and phoD driving organic phosphorus mineralization, the encoding pyrroloquinoline quinone synthase ppqC gene and the encoding exopolyphosphate esterase ppX gene, and the soxY and yedZ genes driving sulfur oxidation. The results of variation partitioning analysis and redundancy analysis showed that soil basic properties were the main factors affecting the microbial composition of N, P and S cycle functions (the total interpretation rate was 28.1%), and that MBC and WC were the most important drivers of the functional potential of soil microorganisms in N, P and S cycling. Overall, long-term no tillage could increase the abundance of functional genes of soil microorganisms by affecting soil environment. From the perspective of molecular biology, our results elucidated that no tillage could be used as an effective soil management measure to improve soil health and maintain green agricultural development.

Pan-Cancer Study of the Prognosistic Value of Selenium Phosphate Synthase 1.

Objective: This study sought to determine the mean prognostic usefulness of seleniumphosphate synthase (SEPHS1) by investigating its expression in 33 human malignancies and its relationship to tumor immunity.Methods: The expression of selenophosphate synthase 1 (SEPHS1) in 33 human malignant tumors was examined using the Genotype-Tissue Expression (GTEx), Cancer Genome Atlas (TCGA), and TIMER databases. Furthermore, the TCGA cohort was used to investigate relationships between SEPHS1 and immunological checkpoint genes (ICGs), tumor mutation burden (TMB), microsatellite instability (MSI), and DNA mismatch repair genes (MMRs). To establish independent risk factors and calculate survival probabilities for liver hepatocellular carcinoma (LIHC) and brain lower-grade glioma (LGG), Cox regression models and Kaplan-Meier curves were utilized. Eventually, the Genomics of Cancer Drug Sensitivity (GDSC) database was used to evaluate the drug sensitivity in LGG and LIHC patients with high SEPHS1 expression.Results: Overall, in numerous tumor tissues, SEPHS1 was highly expressed, and it significantly linked with the prognosis of LGG, ACC, and LIHC (P < .05). Furthermore, in numerous cancers, SEPHS1 expression was linked to tumor-infiltrating immune cells (TIICs), TMB, MSI, and MMRs. According to univariate and multivariate Cox analyses, SEPHS1 expression was significant for patients with LGG and LIHC.Conclusion: High SEPHS1 expression has a better prognosis for LGG, while low SEPHS1 expression has a better prognosis for LIHC. Chemotherapy was advised for LGG patients, particularly for those with high SEPHS1 expression because it can predict how responsive patients will be to 5-Fluorouracil and Temozolomide. This interaction between SEPHS1 and chemoradiotherapy has a positive clinical impact and may be used as evidence for chemotherapy for LGG and LIHC patients.

Selenium alleviates endoplasmic reticulum calcium depletion-induced endoplasmic reticulum stress and apoptosis in chicken myocardium after mercuric chloride exposure.

Mercury is a highly toxic heavy metal with definite cardiotoxic properties and can affect the health of humans and animals through diet. Selenium (Se) is a heart-healthy trace element and dietary Se has the potential to attenuate heavy metal-induced myocardial damage in humans and animals. This study was designed to explore antagonistic effect of Se on the cardiotoxicity of mercuric chloride (HgCl2) in chickens. Hyline brown hens received a normal diet, a diet containing 250 mg/L HgCl2, or a diet containing 250 mg/L HgCl2 and 10 mg/kg Na2SeO3 for 7 weeks, respectively. Histopathological observations demonstrated that Se attenuated HgCl2-induced myocardial injury, which was further confirmed by the results of serum creatine kinase and lactate dehydrogenase levels assay and myocardial tissues oxidative stress indexes assessment. The results showed that Se prevented HgCl2-induced cytoplasmic calcium ion (Ca2+) overload and endoplasmic reticulum (ER) Ca2+ depletion mediated by Ca2+-regulatory dysfunction of ER. Importantly, ER Ca2+ depletion led to unfolded protein response and endoplasmic reticulum stress (ERS), resulting in apoptosis of cardiomyocytes via PERK/ATF4/CHOP pathway. In addition, heat shock protein expression was activated by HgCl2 through these stress responses, which was reversed by Se. Moreover, Se supplementation partially eliminated the effects of HgCl2 on the expression of several ER-settled selenoproteins, including selenoprotein K (SELENOK), SELENOM, SELENON, and SELENOS. In conclusion, these results suggested that Se alleviated ER Ca2+ depletion and oxidative stress-induced ERS-dependent apoptosis in chicken myocardium after HgCl2 exposure.

Rational Design of Polymethine Dyes with NIR-II Emission and High Photothermal Conversion Efficiency for Multimodal-Imaging-Guided Photo-Immunotherapy.

Phototheranostics have emerged and flourished as a promising pattern for cancer theranostics owing to their precise photoinduced diagnosis and therapeutic to meet the demands of precision medicine. The diagnosis information and therapeutic effect are directly determined by the fluorescence imaging ability and photothermal conversion efficiency (PCE) of phototheranostic agents. Hence, how to balance the competitive radiative and nonradiative processes of phototheranostic agents is the key factor to evaluate the phototheranostic effect. Herein, molecules named ICRs with high photostaibility  are rationally designed, exhibiting fluorescence emission in the second near-infrared window (NIR-II, 1000-1700 nm) and high PCE, which are related to the strong donor-acceptor (D-A) interaction and high reorganization energy Noteworthily, ICR-Qu with stronger D-A interaction and a large-sized conjugated unit encapsulated in nanoparticles exhibits high PCE (81.1%). In addition, ICR-QuNPs are used for fluorescence imaging (FLI), photoacoustic imaging (PAI), and photothermal imaging (PTI) to guide deep-tissue photonic hyperthermia, achieving precise removal and inhibition of breast cancer. Furthermore, combined with α-PD-1, ICR-QuNPs show huge potential to be a facile and efficient tool for photo-immunotherapy. More importantly, this study not only reports an "all-in-one" polymethine-based phototheranostic agent, but also sheds light on the exploration of versatile organic molecules for future practical applications.