Effects of dietary selenized glucose on intestinal microbiota and tryptophan metabolism in rats: Assessing skatole reduction potential.

3-Methylindole (Skatole), a degradation product of tryptophan produced by intestinal microbial activity, significantly contributes to odor nuisance. Its adverse effects on animal welfare, human health, and environmental pollution have been noted. However, it is still unclear whether the intestinal microbiota mediates the impact of selenium (Se) on skatole production and what the underlying mechanisms remain elusive. A selenized glucose (SeGlu) derivative is a novel organic selenium compound. In this study, a diverse range of dietary SeGlu-treated levels, including SeGlu-deficient (CK), SeGlu-adequate (0.15 mg Se per L), and SeGlu-supranutritional (0.4 mg Se per L) conditions, were used to investigate the complex interaction of SeGlu on intestinal microbiome and serum metabolome changes in male Sprague-Dawley (SD) rats. The study showed that SeGlu supplementation enhanced the antioxidant ability in rats, significantly manifested in the increases of the activity of catalase (CAT) and glutathione peroxidase (GSH-Px), while no change in the level of malonaldehyde (MDA). Metagenomic sequencing analysis verified that the SeGlu treatment group significantly increased the abundance of beneficial microorganisms such as Clostridium, Ruminococcus, Faecalibacterium, Lactobacillus, and Alloprevotella while reducing the abundance of opportunistic pathogens such as Bacteroides and Alistipes significantly. Further metabolomic analysis revealed phenylalanine, tyrosine, and tryptophan biosynthesis changes in the SeGlu treatment group. Notably, the biosynthesis of indole, a critical pathway, was affected by SeGlu treatment, with several crucial enzymes implicated. Correlation analysis demonstrated strong associations between specific bacterial species - Treponema, Bacteroides, and Ruminococcus, and changes in indole and derivative concentrations. Moreover, the efficacy of SeGlu-treated fecal microbiota was confirmed through fecal microbiota transplantation, leading to a decrease in the concentration of skatole in rats. Collectively, the analysis of microbiota and metabolome response to diverse SeGlu levels suggests that SeGlu is a promising dietary additive in modulating intestinal microbiota and reducing odor nuisance in the livestock and poultry industry.

Prevention and treatment strategies for kidney transplant recipients in the context of long-term existence of COVID-19.

The sudden outbreak of coronavirus disease 2019 (COVID-19) in early 2020 posed a massive threat to human life and caused an economic upheaval worldwide. Kidney transplant recipients (KTRs) became susceptible to infection during the COVID-19 pandemic owing to their use of immunosuppressants, resulting in increased hospitalization and mortality rates. Although the current epidemic situation is alleviated, the long-term existence of COVID-19 still seriously threatens the life and health of KTRs with low immunity. The Omicron variant, a highly infectious but less-pathogenic strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has raised concerns among transplant physicians regarding managing KTRs diagnosed with this variant. However, currently, there are no clear and unified guidelines for caring for KTRs infected with this variant. Therefore, we aimed to summarize the ongoing research on drugs that can treat Omicron variant infections in KTRs and explore the potential of adjusting immunotherapy strategies to enhance their responsiveness to vaccines. Herein, we discuss the situation of KTRs since the emergence of COVID-19 and focus on various prevention and treatment strategies for KTRs since the Omicron variant outbreak. We hope to assist physicians in managing KTRs in the presence of long-term COVID-19 variants.

Long-term dietary exposure to 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) reduced feeding in common carp (Cyprinus carpio): Via the JAK-STAT signaling pathway.

Polybrominated diphenyl ethers (PBDEs) are widely present in water ecosystems where they pose a significant threat to aquatic life, but our knowledge about how PBDEs affect feeding is limited. Therefore, this study explored the effects of continuous dietary exposure to 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) (40 and 4000 ng/g) on the feeding in common carp (Cyprinus carpio) and the underlying mechanism. BDE-47 significantly decreased the food intake of carp. Transcriptome analysis of brain tissue showed that BDE-47 mainly affected the nervous, immune, and endocrine systems. Further examination of the expression levels of appetite factors in the brain revealed that BDE-47 caused dysregulation of appetite factors expressions such as agrp, pomc, cart, etc. In addition, the JAK-STAT signaling pathway was activated under BDE-47 exposure. It can be concluded from these findings that BDE-47 activated the JAK-STAT signaling pathway, causing imbalanced expression of appetite factors, leading to disordered feeding behavior and decreased food intake in carp. These results provide an important reference for a more comprehensive understanding of the hazards posed by BDE-47 on animal feeding and the associated mechanisms.

Transport of polyethylene and polypropylene microplastics under the action of agricultural chemicals: Role of pesticide adjuvants and neonicotinoid active ingredients.

Understanding the impact of various agricultural chemical components on the fate and transport of microplastics (MPs) in the subsurface is essential. In this study, column experiments on saturated porous media were conducted to explore the influence of the coexistence environment of pesticide adjuvants (surfactants) and active ingredients (neonicotinoids) on the transport of polyethylene (PE) and polypropylene (PP) MPs. An anionic surfactant (sodium dodecyl sulfate (SDS)), a nonionic surfactant (nonylphenol ethoxylate (NP-40)), and three neonicotinoid insecticides (acetamiprid, dinotefuran, and nitenpyram) could independently increase MP migration by 8.90%-60.75% by improving the hydrophilicity. Acetamiprid or dinotefuran reduced the adhesion work of the binary system by competing with SDS for adsorption sites, thereby inhibiting PE mobility. However, nitenpyram in the mixture was not easily adsorbed on the surface of PE MPs together with SDS because of nitenpyram's high hydrophilicity. Neonicotinoid molecules could not reduce the hydrophilic modification of SDS on PP MPs by competing for adsorption sites. Owing to their weak charge and adhesion work of nonionic surfactants (-4.80 mV and 28.45 kT for PE and -8.21 mV and 17.64 kT for PP), neonicotinoids tended to occupy the adsorption sites originally belonging to NP-40. The long molecular chain of NP-40 made it difficult for high-concentration neonicotinoids to affect the adhesion on MPs. In addition, NP-40 was harder to peel off from the MP surface than SDS, leading to a larger MP transport ability in the sand column.

Altered perivascular spaces in subcortical white matter in Parkinson's disease patients with levodopa-induced dyskinesia.

Dilated perivascular spaces (PVS) have emerged as a pathological hallmark in various neurological conditions, including Parkinson's disease (PD). Levodopa-induced dyskinesia (LID), an intractable motor complication of PD, remains enigmatic regarding the distribution patterns of PVS. Our objective was to scrutinize the percent PVS (pPVS) changes within PD patients with LID (PD-LID). In total, 132 individuals were enrolled, including PD-LID (n = 42), PD patients without LID (PD-nLID, n = 45), and healthy controls (HCs, n = 45). Employing an automated approach for PVS quantification based on structural magnetic resonance imaging, we comprehensively evaluated total pPVS in subcortical white matter globally and regionally. A significant increase in global pPVS was observed in PD patients versus HCs, particularly evident in PD-LID relative to HCs. Within the PD-LID group, elevated pPVS was discerned in the right inferior frontal gyrus region (rIFG) (pars opercularis), contrasting with PD-nLID and HCs. Moreover, PD patients exhibited increased pPVS in bilateral superior temporal regions compared to HCs. Notably, pPVS in the rIFG positively correlated with dyskinetic symptoms and could well identify LID. Our findings unveiled PVS alternations in subcortical white matter in PD-LID at both global and regional levels, highlighting the increased pPVS in rIFG as a prospective imaging marker for LID.

Lipid droplet accumulation in Wdr45-deficient cells caused by impairment of chaperone-mediated autophagic degradation of Fasn.

BACKGROUND: ß-Propeller protein-associated neurodegeneration (BPAN) is a genetic neurodegenerative disease caused by mutations in WDR45. The impairment of autophagy caused by WDR45 deficiency contributes to the pathogenesis of BPAN; however, the pathomechanism of this disease is largely unknown. Lipid dyshomeostasis is involved in neurogenerative diseases, but whether lipid metabolism is affected by Wdr45 deficiency and whether lipid dyshomeostasis contributes to the progression of BPAN are unclear. METHODS: We generated Wdr45 knockout SN4741 cell lines using CRISPR‒Cas9-mediated genome editing, then lipid droplets (LDs) were stained using BODIPY 493/503. Chaperone-mediated autophagy was determined by RT-qPCR and western blotting. The expression of fatty acid synthase (Fasn) was detected by western blot in the presence or absence of the lysosomal inhibitor NH4Cl and the CMA activator AR7. The interaction between Fasn and HSC70 was analyzed using coimmunoprecipitation (Co-IP) assay. Cell viability was measured by a CCK-8 kit after treatment with the Fasn inhibitor C75 or the CMA activator AR7. RESULTS: Deletion of Wdr45 impaired chaperone-mediated autophagy (CMA), thus leading to lipid droplet (LD) accumulation. Moreover, Fasn can be degraded via CMA, and that defective CMA leads to elevated Fasn, which promotes LD formation. LD accumulation is toxic to cells; however, cell viability was not rescued by Fasn inhibition or CMA activation. Inhibition of Fasn with a low concentration of C75 did not affect cell viability but decreases LD density. CONCLUSIONS: These results suggested that Fasn is essential for cell survival but that excessive Fasn leads to LD accumulation in Wdr45 knockout cells.

Liproxstatin-1 Alleviated Ischemia/Reperfusion-Induced Acute Kidney Injury via Inhibiting Ferroptosis.

Ferroptosis, as a novel regulable cell death, is characterized by iron overload, glutathione depletion, and an accumulation of lipid peroxides. Recently, it has been discovered that ferroptosis is involved in ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) and plays a crucial role in renal tubular cell death. In this study, we tried to investigate the effect and mechanism of liproxstatin-1 (Lip-1) in I/R-induced AKI and seek the key regulator of ferroptosis in I/R-induced AKI. Mice were administrated with clamping bilateral renal pedicles for 30 min. We found that early growth response 1 (EGR1) might be a key regulator of ferroptosis, and Lip-1 could suppress ferroptosis via EGR1. Meanwhile, Lip-1 could reduce macrophage recruitment and the release of inflammatory cytokines. These findings indicated that Lip-1 alleviated I/R-induced AKI via regulating EGR1, and it might pave the theoretical basis of a new therapeutic strategy for I/R-induced AKI.

Discovery of a small-molecule NDR1 agonist for prostate cancer therapy.

Prostatic cancer (PCa) is a common malignant neoplasm in men worldwide. Most patients develop castration-resistant prostate cancer (CRPC) after treatment with androgen deprivation therapy (ADT), usually resulting in death. Therefore, investigating new therapeutic targets and drugs for PCa patients is urgently needed. Nuclear Dbf2-related kinase 1 (NDR1), also known as STK38, is a serine/threonine kinase in the NDR/LATS kinase family that plays a critical role in cellular processes, including immunity, inflammation, metastasis, and tumorigenesis. It was reported that NDR1 inhibited the metastasis of prostate cancer cells by suppressing epithelial-mesenchymal transition (EMT), and decreased NDR1 expression might lead to a poorer prognosis, suggesting the enormous potential of NDR1 in antitumorigenesis. In this study, we characterized a small-molecule agonist named aNDR1, which specifically bound to NDR1 and potently promoted NDR1 expression, enzymatic activity and phosphorylation. aNDR1 exhibited drug-like properties, such as favorable stability, plasma protein binding capacity, cell membrane permeability, and PCa cell-specific inhibition, while having no obvious effect on normal prostate cells. Meanwhile, aNDR1 exhibited good antitumor activity both in vitro and in vivo. aNDR1 inhibited proliferation and migration of PCa cells and promoted apoptosis of PCa cells in vitro. We further found that aNDR1 inhibited subcutaneous tumors and lung metastatic nodules in vivo, with no obvious toxicity to the body. In summary, our study presents a potential small-molecule lead compound that targets NDR1 for clinical therapy of PCa patients.

Stereoselective transport of 2-aryl propionic acid enantiomers in porous media subjected to chiral organic acids.

The study examined the transport behavior of the 2-aryl propionic acid (2-APA) chiral pharmaceutical enantiomers by means of a laboratory-scale saturated quartz sand column experiment. Four typical of 2-APA and their enantiomers were selected for the study under different types of chiral organic acids (COAs)-mediated effects. Differences in the transport of the 2-APA enantiomeric pairs have been identified in response to various pH, types of COAs, and enantiomeric structures of COAs. Redundancy analysis identified the factors responsible for the largest differences in transport of 2-APA enantiomeric pairs, while spectroscopic characterization and density function theory (DFT) studies elucidated the underlying mechanisms contributing to the differences in transport of enantiomeric pairs. Obvious correlations among homochirality or heterochirality between COAs and 2-APA enantiomeric pairs were observed for changes in the mobility of 2-APA. The results indicate widespread COAs significantly affect the transport behavior of chiral man-made chemicals, suggesting more attention is needed to fill the gap in the perception of the transport behavior of chiral compounds.

The FTO Mediated N6-Methyladenosine Modification of DDIT4 Regulation with Tumorigenesis and Metastasis in Prostate Cancer.

The progression of numerous malignancies has been linked to N6-methyladenosine (m6A) alteration. However, the opposite trend of m6A levels in the development and metastasis of cancer has not been reported. This study aimed to evaluate the biological function and mechanism of fat mass and obesity-associated protein (FTO) in regulating m6A modification in prostate cancer development and epithelial-mesenchymal transition (EMT). An EMT model of LNCaP and PC-3 cells was established with transforming growth factor-ß treatment, and FTO knockout cell line was established in prostate cancer cells using the CRISPR/Cas9 gene editing technology. The level of m6A modification in tumor tissues was higher than that in normal prostate tissues; m6A levels were decreased after EMT. FTO deletion increased m6A expression and enhanced PC-3 cell motility, invasion, and EMT both in vitro and in vivo. RNA sequencing and functional investigations suggested that DDIT4, a novel EMT target gene, plays a role in m6A-regulated EMT, which was recognized and stabilized by the m6A effector IGF2BP2/3. Decreased FTO expression was an independent indicator of worse survival, and the level of DDIT4 was considerably elevated in patients with bone metastasis. Thus, this study revealed that the m6A demethylase FTO can play different roles in prostate cancer as a regulator of EMT and an inhibitor of m6A modification. Moreover, DDIT4 can be suggested as a possible biomarker for prostate cancer metastasis prediction.

Dynamic ion exchange engineering bismuth ferrite-derived Bi2O2CO3 for rapid piezo-photocatalytic degradation of tetracycline.

Piezoelectric materials can generate the built-in electric field under ultrasound assistance, which is beneficial to the separation of the photogenerated electron-hole pairs in photocatalysis. Meanwhile, the ultrasound stress usually leads to accelerate electron transfer and enhance catalytic activity. Thus, piezo-photocatalysis technique is believed to be one of the effective techniques for organic pollutant degradation. In this work, a binary piezoelectric integrated piezo-photocatalytic Z-Scheme heterojunction with bismuth ferrite (BFO) and bismuth oxycarbonate (Bi2O2CO3, BOC) based on the in situ production of Bi2O2CO3 on Bi25FeO40 surface in dichloromethane, where Bi25FeO40 was employed as piezoelectric materials and Bi source, CO2 dissolved in dichloromethane was used as carbon source. Under 60 min ultrasound and visible light irradiation, the optimal BFO/BOC presented a higher piezo-photocatalytic tetracycline (TC) degradation rate (95 %) than Bi25FeO40 (30 %) and Bi2O2CO3 (17 %). Moreover, the optimal BFO/BOC illustrated higher piezo-photocatalytic TC degradation rate under ultrasound and visible light irradiation than that under visible light condition and ultrasound condition, respectively. These results strongly demonstrated the synergistically piezo-photocatalytic degradation of TC by BFO and BOC. This work not only provides a novel piezo-photocatalyst for pollutant degradation, but also provides a novel method to prepare Bi2O2CO3-based piezo-photocatalytic composite catalyst.

Promoting microbial fermentation in lignocellulosic hydrolysates by removal of inhibitors using MTES and PEI-modified chitosan-chitin nanofiber hybrid aerogel.

To further enhance the removal efficiency for furanic and phenolic compounds in lignocellulosic hydrolysates, a new detoxification strategy was proposed, which retained fermentable sugars and promoted the growth and metabolism of subsequent bacteria. The best adsorbent (P/M-CCA) was prepared by hybrid chitosan-chitin nanofiber, graft modification with polyethylenimine, and silanization with methyl triethoxylsilane in order. Taken corn cob hydrolysate as object, the removal rates of HMF and furfural were 85.1 % and 99.0 %, respectively. The removal rates of six out of nine phenolic inhibitors were 100 %, and the other three were more than 65 %. Even better, the retention rates of glucose and xylose were both 100 %. In contrast to no growth in undetoxified hydrolysates, Bacillus coagulans grew normally in detoxified hydrolysates, and lactic acid reached 19.1 g/L after 12 h fermentation. P/M-CCA achieves both removal of multiple inhibitors and retain sugars, which would promote the valorization of highly toxic lignocellulosic hydrolysates.

Decoding Cosmetic Complexities: A Comprehensive Guide to Matrix Composition and Pretreatment Technology.

Despite advancements in analytical technologies, the complex nature of cosmetic matrices, coupled with the presence of diverse and trace unauthorized additives, hinders the application of these technologies in cosmetics analysis. This not only impedes effective regulation of cosmetics but also leads to the continual infiltration of illegal products into the market, posing serious health risks to consumers. The establishment of cosmetic regulations is often based on extensive scientific experiments, resulting in a certain degree of latency. Therefore, timely advancement in laboratory research is crucial to ensure the timely update and adaptability of regulations. A comprehensive understanding of the composition of cosmetic matrices and their pretreatment technologies is vital for enhancing the efficiency and accuracy of cosmetic detection. Drawing upon the China National Medical Products Administration's 2021 Cosmetic Classification Rules and Classification Catalogue, we streamline the wide array of cosmetics into four principal categories based on the following compositions: emulsified, liquid, powdered, and wax-based cosmetics. In this review, the characteristics, compositional elements, and physicochemical properties inherent to each category, as well as an extensive overview of the evolution of pretreatment methods for different categories, will be explored. Our objective is to provide a clear and comprehensive guide, equipping researchers with profound insights into the core compositions and pretreatment methods of cosmetics, which will in turn advance cosmetic analysis and improve detection and regulatory approaches in the industry.

The impact of long-term PM1 exposure on all-cause mortality and its interaction with BMI: A nationwide prospective cohort study in China.

BACKGROUND: China has a serious air pollution problem and a high prevalence of obesity. The interaction between the two and its impact on all-cause mortality is a public health issue of great concern. OBJECTIVES: This study aimed to investigate the association between long-term exposure to particulate matter with aerodynamic diameter ≤ 1 µm (PM1) and all-cause mortality, as well as the interaction effect of body mass index (BMI) in the association. METHODS: A total of 33,087 participants from 162 counties in 25 provinces in China were included, with annual average PM1 exposure being estimated based on the county address. The PM1-mortality relation was evaluated using the time-varying Cox proportional hazards models, with the dose-response relationship being fitted using the penalized splines. Besides, the potential interaction effect of BMI in the PM1-mortality relation was evaluated. RESULTS: The incidence of all-cause deaths was 76.99 per 10,000 person-years over a median of 8.2 years of follow-up. After controlling for potential confounders, the PM1-mortality relation was approximately J-shaped. The full-adjustment analysis observed the hazard ratio (HR) of all-cause mortality was 1.114 [95 % confidence interval (CI): 1.017-1.220] corresponding to a 10 µg/m3 rise in PM1 concentration. Further stratified analyses suggested the adverse effects of PM1 might be more pronounced among the underweight. DISCUSSION: Higher PM1 concentrations were associated with an increase in all-cause mortality. The BMI might further alter the relation, and the underweight population was the sensitive subgroup of the population that needed to be protected.

Evolution characteristics of micromechanics provides insights into the microstructure of pharmaceutical tablets fabricated by bimodal mixtures.

This research focuses on the evolution of mechanical behavior of bimodal mixtures undergoing compaction and diametrical compression. The clusters were built and discrete element method (DEM) was used to investigate the densification process and micromechanics of bimodal mixtures. Additionally, a more comprehensive investigate of the respective breakage of the bimodal mixtures has been carried out. On this basis, qualitative and quantitative analysis of the compressive force, force chain, contact bonds and density field evolution characteristics of the clusters are investigated during the compression process. The entire loading process of the clusters is divided into three stages: rearrangement, breakage and elastic-plastic deformation. Additionally, there are differences in the evolution of micromechanics behavior of different particles in the bimodal mixture, with pregelatinized starch breakage and deformation occurring before microcrystalline cellulose. With the tablet deformation, the fragmentation process of the tablet started at the point of contact and extended toward the center, and the curvature of the force chain increased. This approach may potentially hold a valuable new information relevant to important transformation forms batch manufacturing to advanced manufacturing for the oral solid dosage form.

Effects of Lianhuaqingwen Capsules in adults with mild-to-moderate coronavirus disease 2019: an international, multicenter, double-blind, randomized controlled trial.

BACKGROUND: In a randomized trial, Lianhuaqingwen (LHQW) capsule was effective for accelerating symptom recovery among patients with coronavirus disease 2019 (COVID-19). However, the lack of blinding and limited sample sizes decreased the level of clinical evidence. OBJECTIVES: To evaluate the efficacy and safety of LHQW capsule in adults with mild-to-moderate COVID-19. METHODS: We conducted a double-blind randomized controlled trial in adults with mild-to-moderate COVID-19 (17 sites from China, Thailand, Philippine and Vietnam). Patients received standard-of-care alone or plus LHQW capsules (4 capsules, thrice daily) for 14 days. The primary endpoint was the median time to sustained clinical improvement or resolution of nine major symptoms. RESULTS: The full-analysis set consisted of 410 patients in LHQW capsules and 405 in placebo group. LHQW significantly shortened the primary endpoint in the full-analysis set (4.0 vs. 6.7 days, hazards ratio: 1.63, 95% confidence interval: 1.39-1.90). LHQW capsules shortened the median time to sustained clinical improvement or resolution of stuffy or runny nose (2.8 vs. 3.7 days), sore throat (2.0 vs. 2.6 days), cough (3.2 vs. 4.9 days), feeling hot or feverish (1.0 vs. 1.3 days), low energy or tiredness (1.3 vs. 1.9 days), and myalgia (1.5 vs. 2.0 days). The duration to sustained clinical improvement or resolution of shortness of breath, headache, and chills or shivering did not differ significantly between the two groups. Safety was comparable between the two groups. No serious adverse events were reported. INTERPRETATION: LHQW capsules promote recovery of mild-to-moderate COVID-19 via accelerating symptom resolution and were well tolerated. Trial registration ChiCTR2200056727 .

Targeting the hedgehog pathway in MET mutation cancers and its effects on cells associated with cancer development.

The mutation of MET plays a crucial role in the initiation of cancer, while the Hedgehog (Hh) pathway also plays a significant role in cell differentiation and the maintenance of tumor stem cells. Conventional chemotherapy drugs are primarily designed to target the majority of cell populations within tumors rather than tumor stem cells. Consequently, after a brief period of remission, tumors often relapse. Moreover, the exclusive targeting of tumor stemness cell disregards the potential for other tumor cells to regain stemness and acquire drug resistance. As a result, current drugs that solely target the HGF/c-MET axis and the Hh pathway demonstrate only moderate efficacy in specific types of cancer. Mounting evidence indicates that these two pathways not only play important roles in cancer but also exert significant influence on the development of resistance to single-target therapies through the secretion of their own ligands. In this comprehensive review, we analyze and compare the potential impact of the Hh pathway on the tumor microenvironment (TME) in HGF/c-MET-driven tumor models, as well as the interplay between different cell types. Additionally, we further substantiate the potential and necessity of dual-pathway combination therapy as a critical target in MET addicted cancer treatment. Video Abstract.

Melatonin protects HT-22 cells against palmitic acid-induced glucolipid metabolic dysfunction and cell injuries: Involved in the regulation of synaptic plasticity and circadian rhythms.

Melatonin (MLT) is ahormonal substance reported with various pharmacological activities.Based on its effects of neuroprotection and metabolic regulation, the aim of the present study is to investigate its potential effect on palmitic acid (PA)-induced cell injuries and glucolipid metabolic dysfunction and explore the possible mechanism. Briefly, HT-22 cells were challenged with PA (0.1 mM, 24 h) and treated with MLT (10-6-10-8 mol/L). Cell proliferation, lipid accumulation and glucose consumption were detected. The protein expression of key molecular involved with the function of synaptic plasticity and circadian rhythms were measured via western blotting, and the expression of Map-2, MT1A, MT1B and Bmal1 were measured via immunofluorescence staining. The results showed that MLT could alleviate the neurotoxicity induced by PA, as indicated by the increased cell proliferation, enhanced fluorescence intensity of Map-2, and decreased lipid deposition and insulin resistance. Moreover, treatment of MLT could reverse the imbalanced expression of p-Akt, p-ERK, Synapsin I, Synaptotagmin I, BDNF, MT1B, Bmal1, and Clock in PA-induced HT-22 cells. These results suggested a remarkably neuroprotective effect of MLT against PA-induced cell injury and glucolipid metabolic dysfunction, the mechanism of which might be involved in the regulation of synaptic plasticity and circadian rhythms.

Inhibitory effects of hinokitiol on the development and pathogenicity of Colletotrichum gloeosporioides.

Postharvest anthracnose of mango fruit caused by Colletotrichum gloeosporioides is a devastating fungal disease, which causes tremendous quality deterioration and economic losses. Hinokitiol, an environmentally friendly natural compound, is effective in controlling a variety of postharvest fungal diseases. However, there is still a lack of research on the inhibitory effect of hinokitiol on C. gloeosporioides and its possible modes of action. In the present study, the activity of hinokitiol against C. gloeosporioides and its potential mechanisms involved have been investigated. We found that hinokitiol treatment could effectively inhibit the virulence of C. gloeosporioides to harvested mango fruit. After treatment with 8 mg/L hinokitiol, the mycelial growth of C. gloeosporioides was completely inhibited. When the concentration of hinokitiol reached 9 mg/L, the spore germination rate of C. gloeosporioides decreased to 2.43% after 9 h of cultivation. The inhibitory effect is mainly due to the attenuation in cell viability, and impairment in plasma membrane followed by leakage of cytoplasmic contents such as nucleic acids, proteins, and soluble carbohydrates, which ultimately leads to the destruction of cell structure. Furthermore, hinokitiol suppressed the expression of pathogenicity-related genes, leading to reduced infection activity. Collectively, these results suggest that hinokitiol may be an excellent bio-fungicides for the management of mango anthracnose.

CD137L Inhibition Ameliorates Hippocampal Neuroinflammation and Behavioral Deficits in a Mouse Model of Sepsis-Associated Encephalopathy.

Anxiety manifestations and cognitive dysfunction are common sequelae in patients with sepsis-associated encephalopathy (SAE). Microglia-mediated inflammatory signaling is involved in anxiety, depression, and cognitive dysfunction during acute infection with bacterial lipopolysaccharide (LPS). However, the molecular mechanisms underlying microglia activation and behavioral and cognitive deficits in sepsis have not been in fully elucidated. Based on previous research, we speculated that the CD137 receptor/ligand system modulates microglia function during sepsis to mediate classical neurological SAE symptoms. A murine model of SAE was established by injecting male C57BL/6 mice with LPS, and cultured mouse BV2 microglia were used for in vitro assays. RT-qPCR, immunofluorescence staining, flow cytometry, and ELISA were used to assess microglial activation and the expression of CD137L and inflammation-related cytokines in the mouse hippocampus and in cultured BV2 cells. In addition, behavioral tests were conducted in assess cognitive performance and behavioral distress. Immunofluorescence and RT-qPCR analyses showed that hippocampal expression of CD137L was upregulated in activated microglia following LPS treatment. Pre-treatment with the CD137L neutralizing antibody TKS-1 significantly reduced CD137L levels, attenuated the expression of M1 polarization markers in microglia, and inhibited the production of TNF-α, IL-1ß, and IL-6 in both LPS-treated mice and BV2 cells. Conversely, stimulation of CD137L signaling by recombinant CD137-Fc fusion protein activated the synthesis and release of pro-inflammatory cytokines in cultures BV2 microglia. Importantly, open field, elevated plus maze, and Y-maze spontaneous alternation test results indicated that TKS-1 administration alleviated anxiety-like behavior and spatial memory decline in mice with LPS-induced SAE. These findings suggest that CD137L upregulation in activated microglia critically contributes to neuroinflammation, anxiety-like behavior, and cognitive dysfunction in the mouse model of LPS-induced sepsis. Therefore, therapeutic modulation of the CD137L/CD137 signaling pathway may represent an effective way to minimize brain damage and prevent cognitive and emotional deficits associated with SAE.