Glucose regulation of adipose tissue browning by CBP/p300- and HDAC3-mediated reversible acetylation of CREBZF.

Glucose is required for generating heat during cold-induced nonshivering thermogenesis in adipose tissue, but the regulatory mechanism is largely unknown. CREBZF has emerged as a critical mechanism for metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD). We investigated the roles of CREBZF in the control of thermogenesis and energy metabolism. Glucose induces CREBZF in human white adipose tissue (WAT) and inguinal WAT (iWAT) in mice. Lys208 acetylation modulated by transacetylase CREB-binding protein/p300 and deacetylase HDAC3 is required for glucose-induced reduction of proteasomal degradation and augmentation of protein stability of CREBZF. Glucose induces rectal temperature and thermogenesis in white adipose of control mice, which is further potentiated in adipose-specific CREBZF knockout (CREBZF FKO) mice. During cold exposure, CREBZF FKO mice display enhanced thermogenic gene expression, browning of iWAT, and adaptive thermogenesis. CREBZF associates with PGC-1α to repress thermogenic gene expression. Expression levels of CREBZF are negatively correlated with UCP1 in human adipose tissues and increased in WAT of obese ob/ob mice, which may underscore the potential role of CREBZF in the development of compromised thermogenic capability under hyperglycemic conditions. Our results reveal an important mechanism of glucose sensing and thermogenic inactivation through reversible acetylation.

PAD4 controls tumor immunity via restraining the MHC class II machinery in macrophages.

Tumor-associated macrophages (TAMs) shape tumor immunity and therapeutic efficacy. However, it is poorly understood whether and how post-translational modifications (PTMs) intrinsically affect the phenotype and function of TAMs. Here, we reveal that peptidylarginine deiminase 4 (PAD4) exhibits the highest expression among common PTM enzymes in TAMs and negatively correlates with the clinical response to immune checkpoint blockade. Genetic and pharmacological inhibition of PAD4 in macrophages prevents tumor progression in tumor-bearing mouse models, accompanied by an increase in macrophage major histocompatibility complex (MHC) class II expression and T cell effector function. Mechanistically, PAD4 citrullinates STAT1 at arginine 121, thereby promoting the interaction between STAT1 and protein inhibitor of activated STAT1 (PIAS1), and the loss of PAD4 abolishes this interaction, ablating the inhibitory role of PIAS1 in the expression of MHC class II machinery in macrophages and enhancing T cell activation. Thus, the PAD4-STAT1-PIAS1 axis is an immune restriction mechanism in macrophages and may serve as a cancer immunotherapy target.

PIKfyve controls dendritic cell function and tumor immunity.

The modern armamentarium for cancer treatment includes immunotherapy and targeted therapy, such as protein kinase inhibitors. However, the mechanisms that allow cancer-targeting drugs to effectively mobilize dendritic cells (DCs) and affect immunotherapy are poorly understood. Here, we report that among shared gene targets of clinically relevant protein kinase inhibitors, high PIKFYVE expression was least predictive of complete response in patients who received immune checkpoint blockade (ICB). In immune cells, high PIKFYVE expression in DCs was associated with worse response to ICB. Genetic and pharmacological studies demonstrated that PIKfyve ablation enhanced DC function via selectively altering the alternate/non-canonical NF-κB pathway. Both loss of Pikfyve in DCs and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively controls DCs, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.

Molecular insights into the catabolism of dibutyl phthalate in Pseudomonas aeruginosa PS1 based on biochemical and multi-omics approaches.

A comprehensive understanding of the molecular mechanisms underlying microbial catabolism of dibutyl phthalate (DBP) is still lacking. Here, we newly isolated a bacterial strain identified as Pseudomonas aeruginosa PS1 with high efficiency of DBP degradation. The degradation ratios of DBP at 100-1000 mg/L by this strain reached 80-99 % within 72 h without a lag phase. A rare DBP-degradation pathway containing two monobutyl phthalate-catabolism steps was proposed based on intermediates identified by HPLC-TOF-MS/MS. In combination with genomic and transcriptomic analyses, we identified 66 key genes involved in DBP biodegradation and revealed the genetic basis for a new complete catabolic pathway from DBP to Succinyl-CoA or Acetyl-CoA in the genus Pseudomonas for the first time. Notably, we found that a series of homologous genes in Pht and Pca clusters were simultaneously activated under DBP exposure and some key intermediate degradation related gene clusters including Pht, Pca, Xyl, Ben, and Cat exhibited a favorable coexisting pattern, which contributed the high-efficient DBP degradation ability and strong adaptability to this strain. Overall, these results broaden the knowledge of the catabolic diversity of DBP in microorganisms and enhance our understanding of the molecular mechanism underlying DBP biodegradation.

Drug conjugates for the treatment of lung cancer: from drug discovery to clinical practice.

A drug conjugate consists of a cytotoxic drug bound via a linker to a targeted ligand, allowing the targeted delivery of the drug to one or more tumor sites. This approach simultaneously reduces drug toxicity and increases efficacy, with a powerful combination of efficient killing and precise targeting. Antibody‒drug conjugates (ADCs) are the best-known type of drug conjugate, combining the specificity of antibodies with the cytotoxicity of chemotherapeutic drugs to reduce adverse reactions by preferentially targeting the payload to the tumor. The structure of ADCs has also provided inspiration for the development of additional drug conjugates. In recent years, drug conjugates such as ADCs, peptide‒drug conjugates (PDCs) and radionuclide drug conjugates (RDCs) have been approved by the Food and Drug Administration (FDA). The scope and application of drug conjugates have been expanding, including combination therapy and precise drug delivery, and a variety of new conjugation technology concepts have emerged. Additionally, new conjugation technology-based drugs have been developed in industry. In addition to chemotherapy, targeted therapy and immunotherapy, drug conjugate therapy has undergone continuous development and made significant progress in treating lung cancer in recent years, offering a promising strategy for the treatment of this disease. In this review, we discuss recent advances in the use of drug conjugates for lung cancer treatment, including structure-based drug design, mechanisms of action, clinical trials, and side effects. Furthermore, challenges, potential approaches and future prospects are presented.

Repurposing plant hormone receptors as chemically-inducible genetic switches for dynamic regulation in yeast.

Precise control of gene expression is critical for optimizing cellular metabolism and improving the production of valuable biochemicals. However, hard-wired approaches to pathway engineering, such as optimizing promoters, can take time and effort. Moreover, limited tools exist for controlling gene regulation in non-conventional hosts. Here, we develop a two-channel chemically-regulated gene expression system for the multi-stress tolerant yeast Kluyveromyces marxianus and use it to tune ethyl acetate production, a native metabolite produced at high titers in this yeast. To achieve this, we repurposed the plant hormone sensing modules (PYR1ABA/HAB1 and PYR1*MANDI/HAB1*) for high dynamic-range gene activation and repression controlled by either abscisic acid (ABA) or mandipropamid (mandi). To redirect metabolic flux towards ethyl acetate biosynthesis, we simultaneously repress pyruvate dehydrogenase (PDA1) and activate pyruvate decarboxylase (PDC1) to enhance ethyl acetate titers. Thus, we have developed new tools for chemically tuning gene expression in K. marxianus and S. cerevisiae that should be deployable across many non-conventional eukaryotic hosts.

Involvement of GSTP1 in low dose radiation-induced apoptosis in GM12878 cells.

BACKGROUND: Low-dose ionizing radiation-induced protection and damage are of great significance among radiation workers. We aimed to study the role of glutathione S-transferase Pi (GSTP1) in low-dose ionizing radiation damage and clarify the impact of ionizing radiation on the biological activities of cells. RESULTS: In this study, we collected peripheral blood samples from healthy adults and workers engaged in radiation and radiotherapy and detected the expression of GSTP1 by qPCR. We utilized γ-rays emitted from uranium tailings as a radiation source, with a dose rate of 14 µGy/h. GM12878 cells subjected to this radiation for 7, 14, 21, and 28 days received total doses of 2.4, 4.7, 7.1, and 9.4 mGy, respectively. Subsequent analyses, including flow cytometry, MTS, and other assays, were performed to assess the ionizing radiation's effects on cellular biological functions. In peripheral blood samples collected from healthy adults and radiologic technologist working in a hospital, we observed a decreased expression of GSTP1 mRNA in radiation personnel compared to the healthy controls. In cultured GM12878 cells exposed to low-dose ionizing radiation from uranium tailings, we noted significant changes in cell morphology, suppression of proliferation, delay in cell cycle progression, and increased apoptosis. These effects were partially reversed by overexpression of GSTP1. Moreover, low-dose ionizing radiation increased GSTP1 gene methylation and downregulated GSTP1 expression. Furthermore, low-dose ionizing radiation affected the expression of GSTP1-related signaling molecules. CONCLUSIONS: This study shows that low-dose ionizing radiation damages GM12878 cells and affects their proliferation, cell cycle progression, and apoptosis. In addition, GSTP1 plays a modulating role under low-dose ionizing radiation damage conditions. Low-dose ionizing radiation affects the expression of Nrf2, JNK, and other signaling molecules through GSTP1.

Prussian Blue Analogue-Derived Co3O4 as Catalysts for Enhanced Selective Oxidation of Cyclohexane Using Molecular Oxygen.

Selective conversion of inert C-H bonds in alkanes into high-value-added functional groups (alcohols, ketones, carboxylic acids, etc.) plays a vital role in establishing a green and sustainable chemical industry. Catalytic selective oxidation of cyclohexane to KA oil (cyclohexanol and cyclohexanone) is a typical representative of alkane functionalization. In this work, hollow cage-like Co3O4 (Co3O4-C) and particle Co3O4 (Co3O4-P) were synthesized by calcining two types of Prussian blue analogues (PBAs), which were used to catalyze the selective oxidation of cyclohexane. The Co3O4-C predominantly exposed (311) crystal plane is easier to adsorb cyclohexane than Co3O4-P, which is beneficial to shorten the induction period, accelerate the reaction rate, and improve the conversion. Consequently, Co3O4-C displayed a 10% conversion of cyclohexane within 1 h, and the KA oil selectivity reached 90%. The Co3O4-P exposed (220) crystal plane has a higher molar percentage of oxygen vacancies and more active oxygen species, as well as a strong cyclohexanone adsorption capacity, which is conducive to the deep oxidation of cyclohexanone to adipic acid and other diacid products. The mechanism analysis of cyclohexane oxidation catalyzed by PBA-based Co3O4 shows that it exemplifies the feasibility to tailor the surface of catalysts by modulating the PBAs, which ultimately influences their reaction performance for accelerating the reaction and maintaining high cyclohexane conversion and KA oil selectivity.

A Novel Sparse Array Configuration for Direction of Arrival Estimation with Increased Uniform Degrees of Freedom and Reduced Mutual Coupling.

Sparse arrays are widely employed in array signal processing due to their obvious advantages in array element distribution and uniform degrees of freedom (uDOFs). In this paper, a generalized augmented multi-subarray nested array (GAMSNA-I) and its variant, GAMSNA-II are proposed, with the objective of increasing uDOFs and reducing mutual coupling. Based on two subarrays of the prototype nested array (NA), GAMSNA-I is constructed by reconfiguring the dense uniform linear array (ULA) and forward-shifting the sparse ULA. GAMSNA-II is obtained by sparsifying the dense part of GAMSNA-I, ensuring constant uDOFs while further reducing mutual coupling. Subsequently, the closed-form expression for the uDOFs of GAMSNA-I with an arbitrary number of sensors is derived, and the proof is provided that the uDOFs of GAMSNA-II remain unchanged relative to that of GAMSNA-I. Compared to some existing array configurations, both GAMSNA-I and GAMSNA-II exhibit improved uDOFs, with GAMSNA-II achieving lower mutual coupling. Simulation results show the superior performance of the proposed GAMSNA-I and GAMSNA-II.

Risk factors for dysphagia in patients with acute and chronic ischemic stroke: A retrospective cohort study.

Background: Dysphagia is a common and clinically significant complication of ischemic stroke. The prevalence and risk factors for dysphagia may vary at different stages following an ischemic stroke. Methods: This study included patients with acute and chronic ischemic stroke who were treated at the Department of Rehabilitation, First Affiliated Hospital, Zhejiang University School of Medicine from 2019 to 2022. Various demographic, clinical, and laboratory parameters were collected, and statistical analyses were performed to investigate their association with dysphagia. Results: Among the 399 ischemic stroke patients included in the study, 165 (41.4 %) experienced dysphagia, with 72 (38.7 %) in the acute phase and 93 (43.7 %) in the chronic phase. Univariate analysis revealed significant associations (p < 0.05) between dysphagia and factors such as pulmonary infection, aphasia, NIHSS score, ADL score, NLR score, lower extremity Brunnstrom's stages, and sit-to-stand balance. Multiple logistic regression analysis, after adjusting for confounding factors, identified the ADL score as an independent predictor of dysphagia. These findings were consistent across three time-windows: the acute phase, the chronic phase, and 180 days after stroke onset. Additionally, the lymphocyte count and pulmonary infection were identified as potential independent indicators. Conclusions: This study investigated the prevalence and risk factors for dysphagia in ischemic stroke patients at different time-windows. A low ADL score (<40) may serve as a valuable and reliable predictor for poststroke dysphagia in clinical settings.

Macrophage CREBZF Orchestrates Inflammatory Response to Potentiate Insulin Resistance and Type 2 Diabetes.

Chronic adipose tissue inflammation accompanied by macrophage accumulation and activation is implicated in the pathogenesis of insulin resistance and type 2 diabetes in humans. The transcriptional coregulator CREBZF is a key factor in hepatic metabolism, yet its role in modulating adipose tissue inflammation and type 2 diabetes remains elusive. The present study demonstrates that overnutrition-induced CREBZF links adipose tissue macrophage (ATM) proinflammatory activation to insulin resistance. CREBZF deficiency in macrophages, not in neutrophils, attenuates macrophage infiltration in adipose, proinflammatory activation, and hyperglycemia in diet-induced insulin-resistant mice. The coculture assays show that macrophage CREBZF deficiency improves insulin sensitivity in primary adipocytes and adipose tissue. Mechanistically, CREBZF competitively inhibits the binding of IκBα to p65, resulting in enhanced NF-κB activity. In addition, bromocriptine is identified as a small molecule inhibitor of CREBZF in macrophages, which suppresses the proinflammatory phenotype and improves metabolic dysfunction. Furthermore, CREBZF is highly expressed in ATM of obese humans and mice, which is positively correlated with proinflammatory genes and insulin resistance in humans. This study identifies a previously unknown role of CREBZF coupling ATM activation to systemic insulin resistance and type 2 diabetes.

A novel incomplete hesitant fuzzy information supplement and clustering method for large-scale group decision-making.

Clustering is an effective means to reduce the scaling of large-scale group decision-making (LSGDM). However, there are many problems with clustering methods, such as incomplete or ambiguous information usually provided by different decision makers. Traditional clustering methods may not be able to handle these situations effectively, resulting in incomplete decision-making information. Calculating the clustering centers may become very complex and time-consuming. Inappropriate distance weights may also lead to incorrect cluster assignments, and these problems will seriously affect the clustering results. This research provides a novel incomplete hesitant fuzzy information supplement and clustering approach for large-scale group decision-making in order to address the aforementioned difficulties. First, the approach takes into account the trust degradation and the inhibition of relationships of distrust in the process of trust propagation, and then it builds a global and local network of trust. A novel supplemental formula is provided that takes into account the decision-preference maker's as well as the trust-neighbor's information, allowing the decision-neighbor maker's recommendation to be realized. Therefore, an improved distance function can be proposed to calculate the weights by combining the relative standard deviation theory and selecting the selected clustering centers by using the density peaks in order to optimize the selection of clustering centers and reduce the complexity and scaling of the decision. Finally, an example is presented to demonstrate how the proposed method can be applied. The consistency index and comparison experiments are used to evaluate if the suggested approach is effective and reliable.

Genome characteristics and the ODV proteome of a second distinct alphabaculovirus from Spodoptera litura.

BACKGROUND: Spodoptera litura is a harmful pest that feeds on more than 80 species of plants, and can be infected and killed by Spodoptera litura nucleopolyhedrovirus (SpltNPV). SpltNPV-C3 is a type C SpltNPV clone, that was observed and collected in Japan. Compared with type A or type B SpltNPVs, SpltNPV-C3 can cause the rapid mortality of S. litura larvae. METHODS: In this study, occlusion bodies (OBs) and occlusion-derived viruses (ODVs) of SpltNPV-C3 were purified, and OBs were observed by scanning electron microscopy (SEM). ODVs were observed under a transmission electron microscope (TEM). RESULTS: Both OBs and ODVs exhibit morphological characteristics typical of nucleopolyhedroviruses (NPVs).The genome of SpltNPV-C3 was sequenced and analyzed; the total length was 148,634 bp (GenBank accession 780,426,which was submitted as SpltNPV-II), with a G + C content of 45%. A total of 149 predicted ORFs were found. A phylogenetic tree of 90 baculoviruses was constructed based on core baculovirus genes. LC‒MS/MS was used to analyze the proteins of SpltNPV-C3; 34 proteins were found in the purified ODVs, 15 of which were core proteins. The structure of the complexes formed by per os infectivity factors 1, 2, 3 and 4 (PIF-1, PIF-2, PIF-3 and PIF-4) was predicted with the help of the AlphaFold multimer tool and predicted conserved sequences in PIF-3. SpltNPV-C3 is a valuable species because of its virulence, and the analysis of its genome and proteins in this research will be beneficial for pest control efforts.

An orthogonalized PYR1-based CID module with reprogrammable ligand-binding specificity.

Plants sense abscisic acid (ABA) using chemical-induced dimerization (CID) modules, including the receptor PYR1 and HAB1, a phosphatase inhibited by ligand-activated PYR1. This system is unique because of the relative ease with which ligand recognition can be reprogrammed. To expand the PYR1 system, we designed an orthogonal '*' module, which harbors a dimer interface salt bridge; X-ray crystallographic, biochemical and in vivo analyses confirm its orthogonality. We used this module to create PYR1*MANDI/HAB1* and PYR1*AZIN/HAB1*, which possess nanomolar sensitivities to their activating ligands mandipropamid and azinphos-ethyl. Experiments in Arabidopsis thaliana and Saccharomyces cerevisiae demonstrate the sensitive detection of banned organophosphate contaminants using living biosensors and the construction of multi-input/output genetic circuits. Our new modules enable ligand-programmable multi-channel CID systems for plant and eukaryotic synthetic biology that can empower new plant-based and microbe-based sensing modalities.

Inundative practice for screening siRNA management candidates against a notorious predatory beetle using olfactory silencing.

Calosoma maximoviczi, a predatory pest beetle, poses a significant threat to wild silk farm production due to its predation on wild silkworms. Given the coexistence of this species with beneficial silkworms in the farm orchards, chemical pesticides are not an ideal solution for controlling its population. In this study, we employed a comprehensive multi-target RNA interference (RNAi) approach to disrupt the olfactory perception of C. maximoviczi through independently silencing 16 odorant receptors (ORs) in the respective genders. Specifically, gene-specific siRNAs were designed to target a panel of ORs, allowing us to investigate the specific interactions between odorant receptors and ligands within this species. Our investigation led to identifying four candidate siOR groups that effectively disrupted the beetle's olfactory tracking of various odorant ligands associated with different trophic levels. Furthermore, we observed sex-specific differences in innate RNAi responses reflected by subsequent gene expression, physiological and behavioral consequences, underscoring the complexity of olfactory signaling and emphasizing the significance of considering species/sex-specific traits when implementing pest control measures. These findings advance our understanding of olfactory coding patterns in C. maximoviczi beetles and establish a foundation for future research in the field of pest management strategies.

MDM2-p53 mediate a miR-181c-3p/LIF axis to regulate low dose-rate radiation-induced DNA damage in human B lymphocytes.

PURPOSE: Prolonged exposure to low dose-rate radiation (LDRR) is of growing concern to public health. Recent evidences indicates that LDRR causes deleterious health effects and is closely related to miRNAs. The aim of our study is to investigate the relationship between miRNAs and DNA damage caused by LDRR. MATERIALS AND METHODS: In this study, we irradiated C57BL/6J mice with 12.5µGy/h dose of γ ray emitted from uranium ore for 8 h a day for 120 days at a total dose of 12 mGy, and identified differentially expressed miRNAs from the mice long-term exposed to LDRR through isolating serum RNAs, constructing small RNA library, Illumina sequencing. To further investigate the role of differential miRNA under LDRR，we first built DNA damage model in Immortal B cells irradiated with 12.5µGy/h dose of γ ray for 28 days at a total dose of 9.4 mGy. Then, we chose the highly conserved miR-181c-3p among 12 miRNA and its mechanism in alleviating DNA damage induced by LDRR was studied by transfection, quantitative PCR, luciferase assay, and Western blot. RESULTS AND CONCLUSIONS: We have found that 12 differentially expressed miRNAs including miR-181c-3p in serum isolated from irradiated mice. Analysis of GO and KEGG indicated that target genes of theses 12 miRNA enriched in pathways related to membrane, protein binding and cancer. Long-term exposure to LDRR induced upregulation of gamma-H2A histone family member X (γ-H2AX) expression, a classical biomarker for DNA damage in B cells. miR-181c-3p inhibited Leukemia inhibitory factor (LIF) expression via combining its 3'UTR. LIF, MDM2, p53, and p-p53-s6 were upregulated after exposure to LDRR. In irradiated B cells, Transfection of miR-181c-3p reduced γ-H2AX expression and suppressed LIF and MDM2 protein levels, whereas p-p53-s6 expression was increased. As expected, the effect of LIF inhibition on irradiated B cells was similar to miR-181c-3p overexpression. Our results suggest that LDRR alters miRNA expression and induces DNA damage. Furthermore, miR-181c-3p can alleviate LDRR-induced DNA damage via the LIF/MDM2/p-p53-s6 pathway in human B lymphocytes. This could provide the basis for prevention and treatment of LDRR injury.

Integrating key generation and distribution with the quantum noise stream cipher system without compromising the transmission performance.

We propose and experimentally demonstrate a secure quantum noise stream cipher transmission system that integrates key generation and distribution. At the stage of carrier phase recovery, the estimated phase noise is used to generate randomness keys without additional equipment. Based on direct sequence spread spectrum technology, we integrate the distributed keys with quantum noise stream cipher signals. The key distribution and encryption transmission can be completed simultaneously without occupying additional bandwidth or time slots. By changing the position of distributed keys in the encryption base, the BER performance of QAM/QNSC signals cannot be affected by the keys. Experimental results demonstrate that the 54.5 Mbps key distribution and 31 Gbps encryption transmission without OSNR penalty can be achieved simultaneously over a 120 km standard single-mode fiber.

The Effects of Visual Cueing on Students with and without Math Learning Difficulties in Online Problem Solving: Evidence from Eye Movement.

This study investigated the impact of visual cueing on attention guidance, deep-thinking promotion, and performance optimization in arithmetic word problem solving for students with mathematical learning difficulties (MLD). The participants included eight students with MLD and twenty students without MLD who attempted to solve mathematical word problems with and without visual cueing. Eye movements were recorded during the tasks. A repeated-measure design and nonparametric tests were applied to enhance the statistical power of the study. The data analysis results indicated that visual cueing effectively guided and sustained the attention of students with MLD, reducing their off-task duration. However, it showed limited influence in facilitating deep thinking and performance improvement for these students. There were no significant attention-guidance or performance-improvement effects observed in the problem-solving processes of students without MLD, who initially demonstrated better concentration levels and performance. The potential explanations for these findings are further discussed in this paper.

Regulating effects of chlorinated drinking water on cecal microbiota of broiler chicks.

In this study, 2 types of drinking water were provided to broiler chicks to evaluate the relationship between the bacterial load of drinking water and cecal microbiota. One type of drinking water was untreated, while the other type was daily treated with sodium dichlorocyanurate (50 mg/L). A total of 240 broiler chicks were divided into 2 groups based on their initial body weight. There were 6 replicates in each group, and each replicate cage contained 20 birds. Each cage was assigned to a different floor of the battery cage. On the final day, water samples were collected from each replicate cage at the opening of the drinking cup height, and one bird was selected from each replicate cage to obtain cecal content samples for measuring microbiota composition using the 16S rRNA technique. We found that drinking water treated with sodium dichlorocyanurate significantly reduced the richness and diversity of microbiota and diminished/disappeared most gram-negative bacteria. Broiler chicks that consumed chlorinated drinking water exhibited changes in the composition of cecal microbiota, with Alistipes serving as the marker species in the cecal content of broiler chicks that consumed untreated water, whereas AF12 served as the marker species in the cecal content of broiler chicks that consumed chlorinated drinking water. Functional prediction using the MetaCyc database and species composition analysis of metabolic pathways showed that changes in 7 metabolic pathways were related to the abundance of Providencia. Therefore, we concluded that chlorinated drinking water reduced the bacterial load in drinking water, thereby altering the cecal microbiota composition and regulating the metabolic activity of broiler chicks.

Resveratrol inhibits TGF-ß1-induced fibrotic effects in human pterygium fibroblasts.

BACKGROUND: Resveratrol is a polyphenolic phytoalexin which has the properties of anti-oxidant, anti-inflammatory and anti-fibrotic effects. The aim of this study was to investigate the anti-fibrotic effects of resveratrol in primary human pterygium fibroblasts (HPFs) and elucidate the underlying mechanisms. METHOD: Profibrotic activation was induced by transforming growth factor-beta1 (TGF-ß1). The expression of profibrotic markers, including type 1 collagen (COL1), α-smooth muscle actin (α-SMA), and fibronectin, were detected by western blot and quantitative real-time-PCR after treatment with various concentrations of resveratrol in HPFs to investigate the anti-fibrotic effects. Relative signaling pathways downstream of TGF-ß1 were detected by Western blot to assess the underlying mechanism. Cell viability and apoptosis were assessed using CCK-8 assay and flow cytometry to evaluate proliferation and drug-induced cytotoxicity. Cell migration and contractile phenotype were detected through wound healing assay and collagen gel contraction assay. RESULTS: The expression of α-SMA, FN and COL1 induced by TGF-ß1 were suppressed by treatment with resveratrol in dose-dependent manner. The Smad3, mitogen-activated protein kinase (p38 MAPK) and phosphatidylinositol-3-kinase (PI3K) / protein kinase B (AKT) pathways were activated by TGF-ß1, while resveratrol attenuated those pathways. Resveratrol also inhibited cellular proliferation, migration and contractile phenotype, and induced apoptosis in HPFs. CONCLUSIONS: Resveratrol inhibit TGF-ß1-induced myofibroblast activation and extra cellular matrix synthesis in HPFs, at least partly, by regulating the TGF-ß/Smad3, p38 MAPK and PI3K/AKT pathways.