Effects of Bacillus thuringiensis Treatment on Expression of Detoxification Genes in Chlorantraniliprole-Resistant Plutella xylostella.

Detoxification genes are crucial to insect resistance against chemical pesticides, yet their expression may be altered by exposure to biopesticides such as spores and insecticidal proteins of Bacillus thuringiensis (Bt). Increased enzymatic levels of selected detoxification genes, including glutathione S-transferase (GST), cytochrome P450 (CYP450), and carboxylesterase (CarE), were detected in chlorantraniliprole (CAP)-resistant strains of the diamondback moth (DBM, Plutella xylostella) from China when compared to a reference susceptible strain. These CAP-resistant DBM strains displayed distinct expression patterns of GST 1, CYP6B7, and CarE-6 after treatment with CAP and a Bt pesticide (Bt-G033). In particular, the gene expression analysis demonstrated significant upregulation of the CYP6B7 gene in response to the CAP treatment, while the same gene was downregulated following the Bt-G033 treatment. Downregulation of CYP6B7 using RNAi resulted in increased susceptibility to CAP in resistant DBM strains, suggesting a role of this gene in the resistant phenotype. However, pretreatment with a sublethal dose of Bt-G033 inducing the downregulation of CYP6B7 did not significantly increase CAP potency against the resistant DBM strains. These results identify the DBM genes involved in the metabolic resistance to CAP and demonstrate how their expression is affected by exposure to Bt-G033.

An Engineered Imine Reductase for Highly Diastereo- and Enantioselective Synthesis of ß-Branched Amines with Contiguous Stereocenters.

ß-Branched chiral amines with contiguous stereocenters are valuable building blocks for preparing various biologically active molecules. However, their asymmetric synthesis remains challenging. Herein, we report a highly diastereo- and enantioselective biocatalytic approach for preparing a broad range of ß-branched chiral amines starting from their corresponding racemic ketones. This involves a dynamic kinetic resolution-asymmetric reductive amination process catalyzed using only an imine reductase. Four rounds of protein engineering endowed wild-type PocIRED with higher reactivity, better stereoselectivity, and a broader substrate scope. Using the engineered enzyme, various chiral amine products were synthesized with up to >99.9% ee, >99:1 dr, and >99% conversion. The practicability of the developed biocatalytic method was confirmed by producing a key intermediate of tofacitinib in 74% yield, >99.9% ee, and 98:2 dr at a challenging substrate loading of 110 g L-1. Our study provides a highly capable imine reductase and a protocol for developing an efficient biocatalytic dynamic kinetic resolution-asymmetric reductive amination reaction system.

[Research progress of traditional Chinese medicine in regulating autophagy for intervening in diabetic cardiomyopathy].

Diabetic cardiomyopathy(DCM) is a chronic complication of diabetes mellitus that leads to cardiac damage in the later stages of the disease, and its pathogenesis is complex, involving metabolic disorders brought about by a variety of aberrant alterations such as endoplasmic reticulum stress, oxidative stress, inflammation, and apoptosis, defects in cardiomyocyte Ca~(2+) transporter, and myocardial fibrosis. Currently, there is a lack of specific diagnosis and treatment in the clinic. Autophagy is a highly conserved scavenging mechanism that removes proteins, damaged organelles or foreign contaminants and converts them into energy and amino acids to maintain the stability of the intracellular environment. Inhibition of autophagy can cause harmful metabolites to accumulate in the cell, while over-activation of autophagy can disrupt normal cellular structures and cause cell death. Prolonged high glucose levels disrupt cardiomyocyte autophagy levels and exacerbate the development of DCM. The protective or detrimental effects of autophagy on cells ring true with the traditional Chinese medicine theory of healthy Qi and pathogenic Qi. Autophagy in the physiological state of the removal of intracellular substances and the generation of substances beneficial to the survival of cells is the inhibition of pathogenic Qi to help the performance of healthy Qi, so the organism is healthy. In the early stages of the disease, when autophagy is impaired and incapable of removing waste substances, pathogenic Qi is prevalent; In the later stages of the disease, excessive activation of autophagy can destroy normal cells, leading to a weakening of healthy Qi. Traditional Chinese medicine has the advantage of targeting multiple sites and pathways. Studies in recent years have confirmed that traditional Chinese medicine monomers or formulas can target autophagy, promote the restoration of autophagy levels, maintain mitochondrial and endoplasmic reticulum homeostasis, and reduce oxidative stress, endoplasmic reticulum stress, inflammation, and apoptosis in order to prevent and control DCM. This study provides a review of the relationship between autophagy and DCM and the intervention of traditional Chinese medicine in autophagy for the treatment of DCM, with a view to providing new clinical ideas and methods for the treatment of DCM with traditional Chinese medicine.

Enhancing therapeutic potential: Human adipose-derived mesenchymal stem cells modified with recombinant adeno-associated virus expressing VEGF165 gene for peripheral nerve injury.

This study aimed to investigate the therapeutic potential of human adipose-derived mesenchymal stem cells (hADSCs) modified with recombinant adeno-associated virus (rAAV) carrying the vascular endothelial growth factor 165 (VEGF165) gene in peripheral nerve injury (PNI). The hADSCs were categorized into blank, control (transduced with rAAV control vector), and VEGF165 (transduced with rAAV VEGF165 vector) groups. Subsequently, Schwann cell differentiation was induced, and Schwann cell markers were assessed. The sciatic nerve injury mouse model received injections of phosphate-buffered saline (PBS group), PBS containing hADSCs (hADSCs group), rAAV control vector (control-hADSCs group), or rAAV VEGF165 vector (VEGF165-hADSCs group) into the nerve defect site. Motor function recovery, evaluated through the sciatic function index (SFI), and nerve regeneration, assessed via toluidine blue staining along with scrutiny of Schwann cell markers and neurotrophic factors, were conducted. Modified hADSCs exhibited enhanced Schwann cell differentiation and elevated expression of Schwann cell markers [S100 calcium-binding protein B (S100B), NGF receptor (NGFR), and glial fibrillary acidic protein (GFAP)]. Mice in the VEGF165-hADSCs group demonstrated improved motor function recovery compared to those in the other three groups, accompanied by increased fiber diameter, axon diameter, and myelin thickness, as well as elevated expression of Schwann cell markers (S100B, NGFR, and GFAP) and neurotrophic factors [mature brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF)] in the distal nerve segment. rAAV-VEGF165 modification enhances hADSC potential in PNI, promoting motor recovery and nerve regeneration. Elevated Schwann cell markers and neurotrophic factors underscore therapy benefits, providing insights for nerve injury strategies.

In situ DRIFTs-based comprehensive reaction mechanism of photo-thermal synergetic catalysis for dry reforming of methane over Ru-CeO2 catalyst.

Solar-driven photo-thermal dry reforming of methane (DRM) is an environmentally friendly production route for high-value-added chemicals. However, the lack of thorough understanding of the mechanism for photo-thermal reaction has limited its further development. Here, we systematically investigated the mechanism of photo-thermal DRM reaction with the representative of Ru/CeO2 catalyst. Through in situ DRIFTs and transient experiments, comprehensive investigation into the reaction steps and their reactive sites in the process of DRM reaction were conducted. Besides, the excitation and migration direction of photo-electron was determined by ISI-XPS experiments, and the change of surface defect structure induced by light was characterized by ISI-EPR experiments. Based on the above results, the photo-enhancement effect on each micro-reaction step was determined. This study provides a theoretical basis for the industrialization of photo-thermal DRM reaction and its development of catalysts.

The first high-altitude autotetraploid haplotype-resolved genome assembled (Rhododendron nivale subsp. boreale) provides new insights into mountaintop adaptation.

BACKGROUND: Rhododendron nivale subsp. boreale Philipson et M. N. Philipson is an alpine woody species with ornamental qualities that serve as the predominant species in mountainous scrub habitats found at an altitude of ∼4,200 m. As a high-altitude woody polyploid, this species may serve as a model to understand how plants adapt to alpine environments. Despite its ecological significance, the lack of genomic resources has hindered a comprehensive understanding of its evolutionary and adaptive characteristics in high-altitude mountainous environments. FINDINGS: We sequenced and assembled the genome of R. nivale subsp. boreale, an assembly of the first subgenus Rhododendron and the first high-altitude woody flowering tetraploid, contributing an important genomic resource for alpine woody flora. The assembly included 52 pseudochromosomes (scaffold N50 = 42.93 Mb; BUSCO = 98.8%; QV = 45.51; S-AQI = 98.69), which belonged to 4 haplotypes, harboring 127,810 predicted protein-coding genes. Conjoint k-mer analysis, collinearity assessment, and phylogenetic investigation corroborated autotetraploid identity. Comparative genomic analysis revealed that R. nivale subsp. boreale originated as a neopolyploid of R. nivale and underwent 2 rounds of ancient polyploidy events. Transcriptional expression analysis showed that differences in expression between alleles were common and randomly distributed in the genome. We identified extended gene families and signatures of positive selection that are involved not only in adaptation to the mountaintop ecosystem (response to stress and developmental regulation) but also in autotetraploid reproduction (meiotic stabilization). Additionally, the expression levels of the (group VII ethylene response factor transcription factors) ERF VIIs were significantly higher than the mean global gene expression. We suspect that these changes have enabled the success of this species at high altitudes. CONCLUSIONS: We assembled the first high-altitude autopolyploid genome and achieved chromosome-level assembly within the subgenus Rhododendron. In addition, a high-altitude adaptation strategy of R. nivale subsp. boreale was reasonably speculated. This study provides valuable data for the exploration of alpine mountaintop adaptations and the correlation between extreme environments and species polyploidization.

Decoding the RNA viromes in shrew lungs along the eastern coast of China.

Shrews being insectivores, serve as natural reservoirs for a wide array of zoonotic viruses, including the recently discovered Langya henipavirus (LayV) in China in 2018. It is crucial to understand the shrew-associated virome, viral diversity, and new viruses. In the current study, we conducted high-throughput sequencing on lung samples obtained from 398 shrews captured along the eastern coast of China, and characterized the high-depth virome of 6 common shrew species (Anourosorex squamipes, Crocidura lasiura, Crocidura shantungensis, Crocidura tanakae, Sorex caecutiens, and Suncus murinus). Our analysis revealed numerous shrew-associated viruses comprising 54 known viruses and 72 new viruses that significantly enhance our understanding of mammalian viruses. Notably, 34 identified viruses possess spillover-risk potential and six were human pathogenic viruses: LayV, influenza A virus (H5N6), rotavirus A, rabies virus, avian paramyxovirus 1, and rat hepatitis E virus. Moreover, ten previously unreported viruses in China were discovered, six among them have spillover-risk potential. Additionally, all 54 known viruses and 12 new viruses had the ability to cross species boundaries. Our data underscore the diversity of shrew-associated viruses and provide a foundation for further studies into tracing and predicting emerging infectious diseases originated from shrews.

ADH4-a potential prognostic marker for hepatocellular carcinoma with possible immune-related implications.

OBJECTIVE: This study aims to explore ADH4 expression in hepatocellular carcinoma (HCC), its prognostic impact, and its immune correlation to provide novel insights into HCC prognostication and treatment. METHODS: HCC prognostic marker genes were rigorously selected using GEO database, Lasso regression, GEPIA, Kaplan-Meier and pROC analyses. The expression of interested markers (ADH4, DNASE1L3, RDH16, LCAT, HGFAC) in HCC and adjacent tissues was assessed by Immunohistochemistry (IHC). We observed that ADH4 exhibited low expression levels in liver cancer tissues and high expression levels in normal liver tissues. However, the remaining four genes did not manifest any statistically significant differences between hepatocellular carcinoma (HCC) tissue and adjacent non-cancerous tissue. Consequently, ADH4 became the primary focus of our research. ADH4 expression was validated by signed-rank tests and unpaired Wilcoxon rank sum tests across pan-cancer and HCC datasets. Clinical significance and associations with clinicopathological variables were determined using Kaplan-Meier, logistic regression and Cox analyses on TCGA data. The ADH4-related immune responses were explored by Spearman correlation analysis using TIMER2 data. CD68, CD4, and CD19 protein levels were confirmed by IHC in HCC and non-cancerous tissues. RESULTS: ADH4 showed significant downregulation in various cancers, particularly in HCC. Moreover, low ADH4 expression was associated with clinicopathological variables and served as an independent prognostic marker for HCC patients. Additionally, ADH4 affects a variety of biochemical functions and may influence cancer development, prognosis, and treatment by binding to immune cells. Furthermore, at the immune level, the low expression pattern of ADH4 is TME-specific, indicating that ADH4 has the potential to be used as a target for cancer immunotherapy. CONCLUSION: This study highlights the diagnostic, prognostic and immunomodulatory roles of ADH4 in HCC. ADH4 could serve as a valuable biomarker for HCC diagnosis and prognosis, as well as a potential target for immunotherapeutic interventions.

Correction: Qi et al. Melatonin Alleviates High Temperature-Induced Pollen Abortion in Solanum lycopersicum. Molecules 2018, 23, 386.

In the original publication [...].

Semiconductive Potassium Hydroxamate Coordination Polymers with Dual Charge Transport Paths Originating from the π-π Stacking Columns.

Semiconductive coordination polymers (CPs) have recently garnered a significant amount of attention due to their widespread application in many areas. The "through-space" approach has emerged as the most versatile strategy for constructing semiconductive CPs. However, this approach often leads to the formation of unidirectional charge transport paths, resulting in anisotropic electrically conductive performance and low average conductivities in pressed pellets, thus presenting significant challenges for the practical application of semiconductive CPs. Consequently, there is a strong desire to explore simpler and more versatile strategies for designing semiconductive CPs with dual or multiple charge transport paths. Herein, we report on two semiconductive potassium hydroxamate coordination polymers, denoted as [K(HONDI)(H2O)2]n (1) and [K(HONDI)]n (2). Both compounds theoretically possess dual charge transport paths, occurring internally and externally within the π-π stacking columns of the ligands. Conductivity measurements revealed that compounds 1 and 2 both exhibit semiconductive properties, with their electrical conductivities reaching 2.3 × 10-6 and 1.9 × 10-7 S/cm, respectively, at 30 °C. Their electrically conductive performance could be attributed to theoretically biaxial "band-like" charge transport inside crystals and "hopping" charge transport between grain boundaries.

[Effects of Landscape Pattern on Water Quality at Different Spatial and Temporal Scales in Wuding River Basin and Yanhe River Basin].

To explore the relationship between land use and water quality in basins with different land use patterns at different spatial and temporal scales, the Wuding River Basin and Yanhe River Basin were taken as research objects. Based on land use data in 2020 and water quality monitoring data during two periods, the redundancy analysis method was adopted to quantitatively explore the impact of land use on water quality at multiple scales. The results showed that： ① The main land use types in the two basins were cultivated land and grassland, and the difference was mainly in the proportion of bare land and forest land. ② The water quality in spring was better than that in autumn, and the water quality in the middle and lower reaches was worse. ③ The interpretation rate of land use on the riparian scale was the highest in the two basins. ④ The effect of land use on water quality was more significant in the Wuding River Basin in autumn than in spring, whereas the Yanhe River Basin showed the opposite trend. ⑤ Different land uses had different impacts on water quality. Bare land, cultivated land, and Shannon diversity index （SHDI） in the Wuding River Basin had significant impacts on water quality, whereas grassland, cultivated land, artificial surface, patch density （PD）, and SHDI were significant in the Yanhe River Basin. Cultivated land and artificial surfaces in the Wuding River Basin had a negative impact on water quality. Grassland and bare land had a negative correlation with most chemical indicators. Artificial surfaces and grasslands in the Yanhe River Basin had a negative impact on water quality, whereas forest land had a significant purification effect. The research results provide important information for sustainable land use and multi-scale landscape planning, which can be used to improve water quality.

Clinical efficacy and immune response of neoadjuvant camrelizumab plus chemotherapy in resectable locally advanced oesophageal squamous cell carcinoma: a phase 2 trial.

BACKGROUND: Neoadjuvant immunotherapy is under intensive investigation for esophageal squamous cell carcinoma (ESCC). This study assesses the efficacy and immune response of neoadjuvant immunochemotherapy (nICT) in ESCC. METHODS: In this phase II trial (ChiCTR2100045722), locally advanced ESCC patients receiving nICT were enrolled. The primary endpoint was the pathological complete response (pCR) rate. Multiplexed immunofluorescence, RNA-seq and TCR-seq were conducted to explore the immune response underlying nICT. RESULTS: Totally 42 patients were enrolled, achieving a 27.0% pCR rate. The 1-year, 2-year DFS and OS rates were 89.2%, 64.4% and 97.3%, 89.2%, respectively. RNA-seq analysis highlighted T-cell activation as the most significantly enriched pathway. The tumour immune microenvironment (TIME) was characterised by high CD4, CD8, Foxp3, and PD-L1 levels, associating with better pathological regression (TRS0/1). TIME was categorised into immune-infiltrating, immune-tolerant, and immune-desert types. Notably, the immune-infiltrating type and tertiary lymphoid structures correlated with improved outcomes. In the context of nICT, TIM-3 negatively influenced treatment efficacy, while elevated TIGIT/PD-1 expression post-nICT correlated positively with CD8+ T cell levels. TCR-seq identified three TCR rearrangements, underscoring the specificity of T-cell responses. CONCLUSIONS: Neoadjuvant camrelizumab plus chemotherapy is effective for locally advanced, resectable ESCC, eliciting profound immune response that closely associated with clinical outcomes.

[Clinical Significance of the Levels of Peripheral Blood Tregs and Cytokines IL-35, TGF-ß and IL-10 in Hemophilia A Patients with Fâ § Inhibitor].

OBJECTIVE: To explore the levels of regulatory T cells (Tregs) and cytokines IL-35, TGF-ß and IL-10 in peripheral blood of hemophilia A(HA) patients with FⅧ inhibitor and their clinical significance. METHODS: 43 HA patients admitted to the Hematology Department of the Affiliated Hospital of North China University of Science and Technology from October 2019 to December 2020 were selected, including 6 cases with FⅧ inhibitor and 37 cases without FⅧ inhibitor. In addition, 20 healthy males who underwent physical examinations were selected as healthy controls. Flow cytometry was used to detect the levels of CD4 + CD25 + CD127 - Tregs in peripheral blood of the HA patients and healthy controls, and ELISA assay was used to detect the expression levels of IL-35, TGF-ß and IL-10 in serum, and their differences between different groups were compared. RESULTS: Compared with the healthy control group, the level of Tregs in HA patients was decreased, and the level of Tregs in the FⅧ inhibitor positive group was the lowest, the difference was statistically significant (P <0.05). There was no significant difference in the expression level of Tregs in HA patients of different severity levels. The serum IL-35, TGF-ß, and IL-10 levels in both FⅧ inhibitor negative and positive groups were significantly lower than those in healthy control group, and those in FⅧ inhibitor positive group were significantly lower than those in FⅧ inhibitor negative group (all P <0.05). CONCLUSION: The decrease of Tregs, IL-35, TGF-ß, and IL-10 levels in HA patients may be related to the formation of FⅧ inhibitors.

Fish gut-derived probiotic Pediococcus pentosaceus alleviates gossypol-induced intestinal inflammation by inhibiting NLRC3/NF-κB/IL-1ß signal pathway in Nile tilapia.

Cottonseed meal (CSM) and cottonseed protein concentrate (CPC) serve as protein alternatives to fish meal and soybean meal in the feed industry. However, the presence of gossypol residue in CSM and CPC can potentially trigger severe intestinal inflammation, thereby restricting the widespread utilization of these two protein sources. Probiotics are widely used to prevent or alleviate intestinal inflammation, but their efficacy in protecting fish against gossypol-induced enteritis remains uncertain. Here, the protective effect of Pediococcus pentosaceus, a strain isolated from the gut of Nile tilapia (Oreochromis niloticus), was evaluated. Three diets, control diet (CON), gossypol diet (GOS) and GOS supplemented with P. pentosaceus YC diet (GP), were used to feed Nile tilapia for 10 weeks. After the feeding trial, P. pentosaceus YC reduced the activity of myeloperoxidase (MPO) in the proximal intestine (PI) and distal intestine (DI). Following a 7-day exposure to Aeromonas hydrophila, the addition of P. pentosaceus YC was found to increase the survival rate of the fish. P. pentosaceus YC significantly inhibited the oxidative stress caused by gossypol, which was evidenced by lower reactive oxygen species (ROS) and malondialdehyde (MDA), as well as higher activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in PI and DI. Addition of P. pentosaceus YC significantly inhibited enteritis, with the lower expression of pro-inflammatory cytokines (il-1ß, il-6, il-8) and higher expression of anti-inflammatory cytokines tgf-ß. RNA-seq analysis indicated that P. pentosaceus YC supplementation significantly inhibited nlrc3 and promoted nf-κb expression in PI and DI, and the siRNA interference experiment in vivo demonstrated that intestinal inflammation was mediated by NLRC3/NF-κB/IL-1ß signaling pathway. Fecal bacteria transplantation experiment demonstrated that gut microbiota mediated the protective effect of P. pentosaceus YC. These findings offer valuable insights into the application of P. pentosaceus YC for alleviating gossypol-induced intestinal inflammation in fish.

Preparation of micron-sized benzamidine-modified magnetic agarose beads for trypsin purification from fish viscera.

The effective method for trypsin purification should be established because trypsin has important economic value. In this work, a novel and simple strategy was proposed for fabricating micron-sized magnetic Fe3O4@agarose-benzamidine beads (MABB) with benzamidine as a ligand, which can efficiently and selectively capture trypsin. The micro-sized MABB, with clear spherical core-shell structure and average particle size of 6.6 µm, showed excellent suspension ability and magnetic responsiveness in aqueous solution. The adsorption capacity and selectivity of MABB towards target trypsin were significantly better than those of non-target lysozyme. According to the Langmuir equation, the maximum adsorption capacity of MABB for trypsin was 1946 mg g-1 at 25 °C, and the adsorption should be a physical sorption process. Furthermore, the initial adsorption rate and half equilibrium time of MABB toward trypsin were 787.4 mg g-1 min-1 and 0.71 min, respectively. To prove the practicability, MABB-based magnetic solid-phase extraction (MSPE) was proposed, and the related parameters were optimized in detail to improve the purification efficiency. With Tris-HCl buffer (50 mM, 10 mM CaCl2, pH 8.0) as extraction buffer, Tris-HCl buffer (50 mM, 100 mM CaCl2, pH 8.0) as rinsing buffer, acidic eluent (0.01 M HCl, 0.5 M NaCl, pH 2.0) as eluent buffer and alkaline buffer (1 M Tris-HCl buffer, pH 10.0) as neutralization solution, the MABB-based MSPE was successfully used for trypsin purification from the viscera of grass carp (Ctenopharyngodon idella). The molecular weight of purified trypsin was determined as approximate 23 kDa through sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The purified trypsin was highly active from 30 °C to 60 °C, with an optimum temperature of 50 °C, and was tolerant to pH variation, exhibiting 85 % of maximum enzyme activity from pH 7.0 to 10.0. The results demonstrated that the proposed MABB-based MSPE could effectively purify trypsin and ensure the biological activity of purified trypsin. Therefore, we believe that the novel MABB could be applicable for efficient purification of trypsin from complex biological systems.

Synergistic Sr Activation and Cr Buffering Effect on RuO2 Electronic Structures for Enhancing the Acidic Oxygen Evolution Reaction.

The oxygen evolution reaction (OER) performance of ruthenium-based oxides strongly correlates with the electronic structures of Ru. However, the widely adopted monometal doping method unidirectionally regulates only the electronic structures, often failing to balance the activity and stability. Here, we propose an "elastic electron transfer" strategy to achieve bidirectional optimization of the electronic structures of Sr, Cr codoped RuO2 catalysts for acidic OER. The introduction of electron-withdrawing Sr intrinsically activates the Ru sites by increasing the oxidation state of Ru. Simultaneously, Cr acts as an electron buffer, donating electrons to Ru in the presence of Sr in the as-prepared catalysts and absorbing excess electrons from Sr leaching during the OER. Such a bidirectional regulation feature of Cr prevents overoxidation of Ru and maintains its high oxidation state during the OER. The optimal Ru3Cr1Sr0.175 catalyst exhibits a low overpotential (214 mV @ 10 mA cm-2) and excellent stability (over 300 h).

Synthesis of cholesterol analogues and comparison on their effect on plasma cholesterol with ß-Sitosterol.

The application of plant sterols in the treatment of hypercholesterolemia is promising. We hypothesize that plant sterols can reduce blood cholesterol because they have a side chain of at least three branches. Three cholesterol analogues were synthesized: CA0 (no side chain), CA3 (a 3­carbon chain with one branch), and CA14 (a 14­carbon side chain with two branches), and then compared their effect on blood cholesterol with that of ß-sitosterol. Structurally, ß-sitosterol has a 10­carbon side chain with three branches. Results demonstrated that ß-sitosterol could effectively reduce plasma total cholesterol (TC) by 20.3%, whereas CA0, CA3 and CA14 did not affect plasma TC in hypercholesterolemia hamsters. ß-Sitosterol was absent in the plasma and liver, indicating it was not absorbed. We concluded that ß-sitosterol with three branches had plasma TC-lowering activity. In contrast, cholesterol analogues with a side chain of two or fewer branches did not affect plasma cholesterol.

Dietary supplementation with capsaicinoids alleviates obesity in mice fed a high-fat-high-fructose diet.

Capsaicinoids are the pungent compounds in chili peppers. The present study investigated the effect of capsaicinoids on obesity in mice induced by a high-fat-high-fructose diet. Thirty-two male C57BL/6J mice were randomly divided into four groups (n = 8) and fed one of the following diets, namely, a low-fat diet (LFD), a high-fat-high-fructose diet (HFF), an HFF + 0.015% capsaicinoids (LCP), and an HFF + 0.045% capsaicinoids (HCP), for 12 weeks. Results showed that capsaicinoids significantly reversed HFF-induced obesity. Supplementation with capsaicinoids improved glucose tolerance, reduced plasma lipids, and attenuated inflammation. Capsaicinoids also reduced hepatic lipid accumulation by upregulating the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). In addition, capsaicinoids enhanced the production of fecal short-chain fatty acids (SCFAs) and increased the fecal excretion of lipids. Gut microbiota analysis revealed that capsaicinoids decreased the Firmicutes/Bacteroidetes ratio and beneficially reconstructed the microbial community. However, the effects of capsaicinoids on intestinal villus length and lipid tolerance were negligible. In conclusion, capsaicinoids effectively attenuated HFF-induced obesity and metabolic syndrome by favorably modulating lipid metabolism, improving SCFA production, and reshaping gut microbial structure.

Distribution and spread of tigecycline resistance gene tet(X4) in Escherichia coli from different sources.

Tigecycline serves as a last-resort antimicrobial agent against severe infections caused by multidrug-resistant bacteria. Tet(X) and its numerous variants encoding flavin-dependent monooxygenase can confer resistance to tigecycline, with tet(X4) being the most prevalent variant. This study aims to investigate the prevalence and characterize tigecycline resistance gene tet(X) in E. coli isolates from various origins in Yangzhou, China, to provide insights into tet(X) dissemination in this region. In 2022, we tested the presence of tet(X) in 618 E. coli isolates collected from diverse sources, including patients, pig-related samples, chicken-related samples, and vegetables in Yangzhou, China. The antimicrobial susceptibility of tet(X)-positive E. coli isolates was conducted using the agar dilution method or the broth microdilution method. Whole genome sequencing was performed on tet(X)-positive strains using Illumina and Oxford Nanopore platforms. Four isolates from pig or pork samples carried tet(X4) and exhibited resistance to multiple antimicrobial agents, including tigecycline. They were classified as ST542, ST10, ST761, and ST48, respectively. The tet(X4) gene was located on IncFIA8-IncHI1/ST17 (n=2), IncFIA18-IncFIB(K)-IncX1 (n=1), and IncX1 (n=1) plasmids, respectively. These tet(X4)-carrying plasmids exhibited high similarity to other tet(X4)-bearing plasmids with the same incompatible types found in diverse sources in China. They shared related genetic environments of tet(X4) associated with ISCR2, as observed in the first identified tet(X4)-bearing plasmid p47EC. In conclusion, although a low prevalence (0.65%) of tet(X) in E. coli strains was observed in this study, the horizontal transfer of tet(X4) among E. coli isolates mediated by pandemic plasmids and the mobile element ISCR2 raises great concerns. Thus, heightened surveillance and immediate action are imperative to curb this clinically significant resistance gene and preserve the efficacy of tigecycline.

Spautin-1 promotes PINK1-PRKN-dependent mitophagy and improves associative learning capability in an alzheimer disease animal model.

Spautin-1 is a well-known macroautophagy/autophagy inhibitor via suppressing the deubiquitinases USP10 and USP13 and promoting the degradation of the PIK3C3/VPS34-BECN1 complex, while its effect on selective autophagy remains poorly understood. Mitophagy is a selective form of autophagy for removal of damaged and superfluous mitochondria via the autophagy-lysosome pathway. Here, we report a surprising discovery that, while spautin-1 remains as an effective autophagy inhibitor, it promotes PINK1-PRKN-dependent mitophagy induced by mitochondrial damage agents. Mechanistically, spautin-1 facilitates the stabilization and activation of the full-length PINK1 at the outer mitochondrial membrane (OMM) via binding to components of the TOMM complex (TOMM70 and TOMM20), leading to the disruption of the mitochondrial import of PINK1 and prevention of PARL-mediated PINK1 cleavage. Moreover, spautin-1 induces neuronal mitophagy in Caenorhabditis elegans (C. elegans) in a PINK-1-PDR-1-dependent manner. Functionally, spautin-1 is capable of improving associative learning capability in an Alzheimer disease (AD) C. elegans model. In summary, we report a novel function of spautin-1 in promoting mitophagy via the PINK1-PRKN pathway. As deficiency of mitophagy is closely implicated in the pathogenesis of neurodegenerative disorders, the pro-mitophagy function of spautin-1 might suggest its therapeutic potential in neurodegenerative disorders such as AD.Abbreviations: AD, Alzheimer disease; ATG, autophagy related; BafA1, bafilomycin A1; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; CCCP, carbonyl cyanide m-chlorophenyl hydrazone; COX4/COX IV, cytochrome c oxidase subunit 4; EBSS, Earle's balanced salt; ECAR, extracellular acidification rate; GFP, green fluorescent protein; IA, isoamyl alcohol; IMM, inner mitochondrial membrane; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MMP, mitochondrial membrane potential; mtDNA, mitochondrial DNA; nDNA, nuclear DNA; O/A, oligomycin-antimycin; OCR, oxygen consumption rate; OMM, outer mitochondrial membrane; OPTN, optineurin; PARL, presenilin associated rhomboid like; PINK1, PTEN induced kinase 1; PRKN, parkin RBR E3 ubiquitin protein ligase; p-Ser65-Ub, phosphorylation of Ub at Ser65; TIMM23, translocase of inner mitochondrial membrane 23; TOMM, translocase of outer mitochondrial membrane; USP10, ubiquitin specific peptidase 10; USP13, ubiquitin specific peptidase 13; VAL, valinomycin; YFP, yellow fluorescent protein.