Different Short-Chain Fatty Acids Unequally Modulate Intestinal Homeostasis and Reverse Obesity-Related Symptoms in Lead-Exposed High-Fat Diet Mice.

Our previous study showed that heavy metal lead (Pb) exposure exacerbates high-fat-diet (HFD)-induced metabolic damage and significantly depletes the gut microbiota-derived metabolite short-chain fatty acid (SCFA) levels. However, it remains unclear whether SCFA is a key metabolite involved in accelerating adverse consequences after Pb exposure. In this study, we explored the effects of exogenous supplementation of acetate, propionate, and butyrate on a metabolic disorder model in Pb-exposed HFD mice. We found that three SCFA interventions attenuated glycolipid metabolism disorders and liver damage, with butyrate performing the best effects in improving obesity-related symptoms. All three SCFA promoted the abundance of Muribaculaceae and Muribaculum, acetate specifically enriched Christensenellaceae, Blautia, and Ruminococcus, and butyrate specifically enriched Parasutterella, Rikenella, Prevotellaceae_UCG-001, and Bacteroides, which contributed to the positive promotion of SCFA production forming a virtuous cycle. Besides, butyrate inhibited Gram-negative bacteria Escherichia-Shigella. All of these events alleviated the intestinal Th17/Treg imbalance and inflammatory response through crosstalk between the G protein-coupled receptor (GPR)/histone deacetylase 3 (HDAC3) and lipopolysaccharide (LPS)/toll-like receptors 4 (TLR4)/nuclear factor κ-B (NF-κB) pathways and ultimately improved the intestinal barrier function. SCFA further upregulated the monocarboxylate transporter 1 (MCT1) and GPR43/adenosine 5'-monophosphate-activated protein kinase (AMPK) pathways to inhibit hepatic lipid accumulation. Overall, SCFA, especially butyrate, is an effective modulator to improve metabolic disorders in obese individuals exposed to heavy metals by targeting gut microecology.

Vitamin D receptor attenuates carbon tetrachloride-induced liver fibrosis via downregulation of YAP.

Liver fibrosis is characterized by the excessive accumulation of extracellular matrix proteins, which can lead to cirrhosis and liver cancer. Metabolic dysfunction-associated steatosis liver diseases are common causes of liver fibrosis, sharing a similar pathogenesis with carbon tetrachloride (CCl4) exposure. This process involves the activation of hepatic stellate cells (HSCs) into myofibroblasts. However, the detailed mechanism and effective treatment strategies require further investigation. In this study, we uncovered a negative correlation between VDR expression and YAP within HSCs. Subsequently, we demonstrated that VDR exerted a downregulatory influence on YAP transcriptional activity in HSCs. Intriguingly, activation VDR effectively inhibited the culture induced activation of primary HSCs by suppressing the transcriptional activity of early YAP. Furthermore, in vivo results manifested that hepatic-specific deletion of YAP/TAZ ameliorates CCl4-induced liver fibrosis, and nullified the antifibrotic efficacy of VDR. Importantly, a YAP inhibitor rescued the exacerbation of liver fibrosis induced by hepatic-specific VDR knockout. Moreover, the combined pharmacological of VDR agonist and YAP inhibitor demonstrated a synergistic effect in diminishing CCl4-induced liver fibrosis, primary HSCs activation and hepatic injury in vivo. These effects were underpinned by their collective ability to inhibit HSC activation through AMPK activation, consequently curbing ATP synthesis and HSCs proliferation. In conclusion, our results not only revealed the inhibition of VDR on YAP-activated liver stellate cells but also identified a synergistic effect of VDR agonist and YAP inhibitor in an AMPKα-dependent manner, providing a practical foundation for integration of multi-targeted drugs in the therapy of CCl4-induced hepatic fibrosis.

Co-exposure to lead and high-fat diet aggravates systemic inflammation in mice by altering gut microbiota and the LPS/TLR4 pathway.

This study reports the toxicity of Pb exposure on systemic inflammation in high-fat-diet (HFD) mice and the potential mechanisms. Results indicated that Pb exacerbated intestinal barrier damage and increased serum levels of lipopolysaccharide (LPS) and diamine oxidase in HFD mice. Elevated LPS activates the colonic and ileal LPS-TLR4 inflammatory signaling pathway and further induces hepatic and adipose inflammatory expression. The 16S rRNA gene sequencing results showed that Pb promoted the abundance of potentially harmful and LPS-producing bacteria such as Coriobacteriaceae_UCG-002, Alloprevotella, and Oscillibacter in the intestines of HFD mice, and their abundance was positively correlated with LPS levels. Additionally, Pb inhibited the abundance of the beneficial bacteria Akkermansia, resulting in lower levels of the metabolite short-chain fatty acids (SCFAs). Meanwhile, Pb inhibited adenosine 5'-monophosphate-activated protein kinase signaling-mediated lipid metabolism pathways, promoting hepatic lipid accumulation. The above results suggest that Pb exacerbates systemic inflammation and lipid disorders in HFD mice by altering the gut microbiota, intestinal barrier, and the mediation of metabolites LPS and SCFAs. Our study provides potential novel mechanisms of human health related to Pb-induced metabolic damage and offers new evidence for a comprehensive assessment of Pb risk.

GenX caused liver injury and potential hepatocellular carcinoma of mice via drinking water even at environmental concentration.

Hexafluoropropylene oxide dimer acid (GenX) is an alternative to perfluorooctanoic acid (PFOA), whose environmental concentration is close to its maximum allowable value established by the US Environmental Protection Agency, so its effects on human health are of great concern. The liver is one of the most crucial target organ for GenX, but whether GenX exposure induces liver cancer still unclear. In this research project, male C57 mice were disposed to GenX in drinking water at environmental concentrations (0.1 and 10 µg/L) and higher concentrations (1 and 100 mg/L) for 14 weeks to explore its effects on liver injury and potential carcinogenicity in mice. GenX was found to cause a dose-dependent increase in the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), and triglyceride (TG). As the content of GenX in drinking water increased, so did the concentrations of Glypican-3 (GPC-3) and detachment gamma-carboxyprothrombin (DCP), indicators of early hepatocellular cancer. GenX destroyed the boundaries and arrangements of hepatocytes, in which monocyte infiltration, balloon-like transformation, and obvious lipid vacuoles were observed between cells. Following exposure to GenX, Masson sections revealed a significant quantity of collagen deposition in the liver. Alpha-feto protein (AFP), vascular endothelial growth factor (VEGF), Ki67, matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) gene expression increased in a dose-dependent manner in the treatment group relative to the control group. In general, drinking water GenX exposure induced liver function impairment, elevated blood lipid level, caused liver pathological structure damage and liver fibrosis lesions, changed the liver inflammatory microenvironment, and increased the concentration of liver-related tumor indicator even in the environmental concentration, suggesting GenX is a potential carcinogen.

Lead exposure exacerbates liver injury in high-fat diet-fed mice by disrupting the gut microbiota and related metabolites.

Lead (Pb) is a widespread toxic endocrine disruptor that could cause liver damage and gut microbiota dysbiosis. However, the causal relationship and underlying mechanisms between the gut microbiota and Pb-induced liver injury are unclear. In this study, we investigated the metabolic toxicity caused by Pb exposure in normal chow (Chow) and high-fat diet (HFD) mice and confirmed the causal relationship by fecal microbial transplantation (FMT) and antibiotic cocktail experiments. The results showed that Pb exposure exacerbated HFD-induced hepatic lipid deposition, fibrosis, and inflammation, but it had no significant effect on Chow mice. Pb increased serum lipopolysaccharide (LPS) levels and induced intestinal inflammation and barrier damage by activating TLR4/NFκB/MLCK in HFD mice. Furthermore, Pb exposure disrupted the gut microbiota, reduced short-chain fatty acid (SCFA) concentrations and the colonic SCFA receptors, G protein-coupled receptor (GPR) 41/43/109A, in HFD mice. Additionally, Pb significantly inhibited the hepatic GPR109A-mediated adenosine 5'-monophosphate-activated protein kinase (AMPK) pathway, resulting in hepatic lipid accumulation. FMT from Pb-exposed HFD mice exacerbated liver damage, disturbed lipid metabolic pathways, impaired intestinal barriers, and altered the gut microbiota and metabolites in recipient mice. However, mice exposed to HFD + Pb and HFD mice had similar levels of these biomarkers in microbiota depleted by antibiotics. In conclusion, our study provides new insights into gut microbiota dysbiosis as a potential novel mechanism for human health related to liver function impairment caused by Pb exposure.

VDRA downregulate ß-catenin/Smad3 and DNA damage and repair associated with improved prognosis in ccRCC patients.

The clear cell renal cell carcinoma (ccRCC) spotlighted the poorest survival, while chromophobe renal cell carcinoma (chRCC) was associated with the best survival. Earlier studies corroborated vitamin D receptor (VDR) was a promising molecular for improving the prognosis of RCC. In contrast to VDRA, the one of VDR isoforms, VDRB1 (VDR isoform B1) has an N-terminal extension of 50 amino acids and is less ligand-dependent. However, the functional differences between VDRA and VDRB1, and their roles in the prognosis of ccRCC and chRCC, have not been investigated. In the present study, we uncovered that the transcripts related to vitamin D pathway and cellular calcium signaling were effectively decreased in the context of ccRCC, yet failed to exert a comparable effect within chRCC. Specially, minimally levels of VDRA wherein kidneys of patients suffering from ccRCC predict shorter survival time. In addition, the protein expressions for ß-catenin/Smad3 pathway and DNA damage and repair pathways were obviously impeded in VDRA-overexpressed ccRCC cells, yet this inhibitory effect was conspicuously absent in enable VDRB1 cells. Our results provide a new idea to improve the prognosis of ccRCC via VDRA upregulation.

Genome-Wide Identification and Expression Profiling of Potato (Solanum tuberosum L.) Universal Stress Proteins Reveal Essential Roles in Mechanical Damage and Deoxynivalenol Stress.

Universal stress proteins (USPs) play an important regulatory role in responses to abiotic stress. Most of the research related to USPs so far has been conducted on plant models such as Arabidopsis (Arabidopsis thaliana), rice (Oryza sativa L.), and cotton (Gossypium hirsutum L.). The potato (Solanum tuberosum L.) is one of the four major food crops in the world. The potato is susceptible to mechanical damage and infection by pathogenic fungi during transport and storage. Deoxynivalenol (DON) released by Fusarium can seriously degrade the quality of potatoes. As a result, it is of great significance to study the expression pattern of the potato StUSP gene family under abiotic stress conditions. In this study, a total of 108 USP genes were identified from the genome of the Atlantic potato, divided into four subgroups. Based on their genetic structure, the physical and chemical properties of their proteins and other aspects of their biological characteristics are comprehensively analyzed. Collinear analysis showed that the homologous genes of StUSPs and four other representative species (Solanum lycopersicum, Arabidopsis, Oryza sativa L., and Nicotiana attenuata) were highly conserved. The cis-regulatory elements of the StUSPs promoter are involved in plant hormones, environmental stress, mechanical damage, and light response. RNA-seq analysis showed that there are differences in the expression patterns of members of each subgroup under different abiotic stresses. A Weighted Gene Coexpression Network Analysis (WGCNA) of the central gene showed that the differential coexpression gene is mainly involved in the plant-pathogen response process, plant hormone signal transduction, and the biosynthesis process of secondary metabolites. Through qRT-PCR analysis, it was confirmed that StUSP13, StUSP14, StUSP15, and StUSP41 may be important candidate genes involved in the response to adversity stress in potatoes. The results of this study provide a basis for further research on the functional analysis of StUSPs in the response of potatoes to adversity stress.

Oxidative stress and pro-inflammatory cytokines following perchloroethylene exposure in young female dry-cleaning workers.

BACKGROUND: The involvement of Perchloroethylene (PCE) in the development of autoimmune diseases has been reported. However, few studies investigated immunotoxicity in PCE-exposed workers. OBJECTIVE: To study changes in the oxidative stress and cytokine profile of young female dry-cleaning workers exposed to PCE. METHODS: Thirty-eight exposed workers and 38 unexposed controls were recruited. All the participants were young nonsmoker females. Individual interviews were conducted by a physician. Blood samples were collected and hematological tests were performed by an automated Coulter Counter. Plasma PCE levels were determined using gas chromatography/flame ionization detection. Plasma total antioxidant capacity (TAC), Catalase (CAT), Superoxide dismutase (SOD), and Malondialdehyde (MDA) levels were measured using the colorimetric method. The levels of plasma cytokines interleukin-1ß (IL-1ß), IL-2, IL-4, IL-6, IL-8, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) were measured by commercially kits. RESULTS: The levels of plasma PCE averaged 561±96 ng/ml in the exposed group compared with 1.3±0.5 ng/ml in the controls. The hematological tests failed to find abnormalities in the exposed workers. Exposed workers presented significantly increased plasma levels of MDA, SOD and CAT. There were no significant differences between the two groups for level of plasma TAC. Significantly increased plasma IL-1ß and TNF-α and decreased IL-2 and IL-8 levels were seen in the exposed workers. There were no significant differences between the two groups for IL-4, IL-6, and IFN-γ. CONCLUSION: PCE exposure resulted in changed cytokine profile in dry-cleaning workers, suggesting the potential immunotoxicity of PCE at low exposure levels.

GenX Disturbs the Indicators of Hepatic Lipid Metabolism Even at Environmental Concentration in Drinking Water via PPARα Signaling Pathways.

Hexafluoropropylene oxide dimer acid (HFPO-DA; trade name GenX), as a substitute for perfluorooctanoic acid (PFOA), has been attracting increasing attention. However, its impact and corresponding mechanism on hepatic lipid metabolism are less understood. To investigate the possible mechanisms of GenX for hepatotoxicity, a series of in vivo and in vitro experiments were conducted. In in vivo experiment, male mice were exposed to GenX in drinking water at environmental concentrations (0.1 and 10 µg/L) and high concentrations (1 and 100 mg/L) for 14 weeks. In in vitro experiments, human hepatocellular carcinoma cells (HepG2) were exposed to GenX at 10, 160, and 640 µM for 24 and 48 h. GenX exposure via drinking water resulted in liver damage and disruption of lipid metabolism even at environmental concentrations. The results of triglycerides (TG) and total cholesterol (TC) in this study converged with the results of the population study, for which TG increased in the liver but unchanged in the serum, whereas TC increased in both liver and serum concentrations. KEGG and GO analyses revealed that the hepatotoxicity of GenX was associated with fatty acid transport, synthesis, and oxidation pathways and that Peroxisome Proliferator-Activated Receptor (PPARα) contributed significantly to this process. PPARα inhibitors significantly reduced the expression of CD36, CPT1ß, PPARα, SLC27A1, ACOX1, lipid droplets, and TC, suggesting that GenX exerts its toxic effects through PPARα signaling pathway. In general, GenX at environmental concentrations in drinking water causes abnormal lipid metabolism via PPARα signaling pathway.

Environmental Cadmium Exposure Exacerbated Bone Loss in NAFLD Mice.

Due to rapid urbanization and industrialization, Cadmium (Cd) contamination is widespread. Meanwhile, the prevalence of nonalcoholic fatty liver disease (NAFLD) has been increasing. Cd is linked to bone damage. However, the osteotoxicity of environmental Cd exposure in NAFLD remains unclear. Therefore, this study aimed to investigate the effects and potential mechanisms of Cd on bone metabolism in NAFLD mice. NAFLD mice were treated with 50 mg/L cadmium chloride in drinking water for 12 weeks. Bone microstructures were scanned by Micro-CT. Liver lipid droplets and fibrosis were measured by histopathological staining. Insulin tolerance tests were performed in mice. RT-PCR and Western blot were performed to analyse hepatic inflammation factors. Results show no damage in healthy mice exposed to Cd. However, Cd exacerbated liver fibrosis and significantly reduced cancellous bone mineral density and decreased the number and thickness of trabecular bone in NAFLD mice. Additionally, the morphology of trabecular bone transformed from a plate structure to a rod structure in NAFLD mice after Cd exposure. The underlying mechanism appears to be related to the Cd-induced direct or indirect toxicity. Exacerbated liver fibrosis, increased inflammatory factors (TGF-ß and IL-1ß), and reduced lecithin-cholesterol acyltransferase (LCAT) and insulin-like growth factor-1 (IGF-1) might contribute to bone damages. Collectively, our study illustrates that despite lower dosing Cd exposure did not induce bone damages in healthy mice, Cd caused bone loss in NAFLD mice. Therefore, it is recommended that individuals with metabolic disorders should avoid working in Cd pollution environment and consuming cadmium-contaminated food and water.

Dietary fats and serum lipids in relation to the risk of ovarian cancer: a meta-analysis of observational studies.

Although numerous epidemiological studies investigated the association between dietary fat intakes or serum lipid levels and ovarian cancer risk, a consistent and explicit conclusion for specific dietary fats or serum lipids that increase the risk of ovarian cancer is not available. In this study, a systematic review and meta-analysis were conducted to assess the key dietary fats and serum lipids that increased the risk of ovarian cancer. Databases such as PubMed, Web of Science, and EMBASE were searched for observational studies. A total of 41 studies met the inclusion criteria, including 18 cohort and 23 case-control studies (109,507 patients with ovarian cancer and 2,558,182 control/non-ovarian cancer participants). Higher dietary intakes of total fat (RR = 1.19, 95% CI = 1.06-1.33, I2 = 60.3%), cholesterol (RR = 1.14, 95% CI = 1.03-1.26, I2 = 19.4%), saturated fat (RR = 1.13, 95% CI = 1.04-1.22, I2 = 13.4%), and animal fat (RR = 1.21, 95% CI = 1.01-1.43, I2 = 70.5%) were significantly associated with a higher risk of ovarian cancer. A higher level of serum triglycerides was accompanied by a higher risk of ovarian cancer (RR = 1.33, 95% CI = 1.02-1.72, I2 = 89.3%). This meta-analysis indicated that a higher daily intake of total fat, saturated fat, animal fat, and cholesterol and higher levels of serum triglycerides were significantly associated with an increased risk of ovarian cancer.

Early surgical treatment of closed reduction and internal fixation for a 30-day old intertrochanteric fracture with hemiplegia after acute stroke: A case report.

RATIONALE: Currently, there are no clear guidelines to determine whether and when to perform surgical hip repair in patients with acute stroke and hip fracture. PATIENT CONCERNS: In this case report, we report a case of 75-year-old woman admitted with left hip pain and limited mobility for 1 month. DIAGNOSES: Patient had a history of acute cerebral infarction 42 days ago, and diagnosed with a left intertrochanteric fracture at another hospital 30 days ago. INTERVENTION: Patient was treated with closed reduction and internal fixation with proximal femoral nail anti-rotation. OUTCOMES: At 2-year follow-up, the patient's basic function was restored. The fracture healed well, and the Harris hip score was 75. LESSONS: Without consistent guidelines, individualized treatment strategies including surgical methods and timing of surgery should be made to weigh the risks and benefits for patients with acute stroke and intertrochanteric fractures.

A Review of Traditional and Emerging Residual Chlorine Quenchers on Disinfection By-Products: Impact and Mechanisms.

Disinfection by-products (DBPs) are the most common organic contaminants in tap water and are of wide concern because of their highly developmental toxic, cytotoxic, and carcinogenic properties. Typically, to control the proliferation of pathogenic microorganisms, a certain concentration of residual chlorine is retained in the factory water, which reacts with the natural organic matter and the disinfection by-products that have been formed, thus affecting the determination of DBPs. Therefore, to obtain an accurate concentration, residual chlorine in tap water needs to be quenched prior to treatment. Currently, the most commonly used quenching agents are ascorbic acid, sodium thiosulfate, ammonium chloride, sodium sulfite, and sodium arsenite, but these quenching agents can cause varying degrees of DBPs degradation. Therefore, in recent years, researchers have attempted to find emerging chlorine quenchers. However, no studies have been conducted to systematically review the effects of traditional quenchers and new ones on DBPs, as well as their advantages, disadvantages, and scope of application. For inorganic DBPs (bromate, chlorate, and chlorite), sodium sulfite has been proven to be the ideal chlorine quencher. For organic DBPs, although ascorbic acid caused the degradation of some DBPs, it remains the ideal quenching agent for most known DBPs. Among the studied emerging chlorine quenchers, n-acetylcysteine (NAC), glutathione (GSH), and 1,3,5-trimethoxybenzene are promising for their application as the ideal chlorine quencher of organic DBPs. The dehalogenation of trichloronitromethane, trichloroacetonitrile, trichloroacetamide, and bromochlorophenol by sodium sulfite is caused by nucleophilic substitution reaction. This paper takes the understanding of DBPs and traditional and emerging chlorine quenchers as a starting point to comprehensively summarize their effects on different types of DBPs, and to provide assistance in understanding and selecting the most suitable residual chlorine quenchers during DBPs research.

Overlooked inorganic DBPs in trichloroisocyanuric acid (TCCA) disinfected indoor swimming pool: Evidences from concentration, cytotoxicity, and human health risk.

Trichloroisocyanuric acid (TCCA) is a popular disinfectant for swimming pools in China. However, the occurrence and importance of regulated disinfection byproducts (DBPs) in TCCA-disinfected swimming pools are less understood. This study analyzed 12 regulated DBPs (4 trihalomethanes (THMs), 5 haloacetic acid (HAAs), bromate, chlorate, and chlorite) in 85 swimming pool water samples and 17 input tap water samples from one swimming pool for 17 days continuously. Considering water temperature, pH, free chlorine, total chlorine, and urea, most of swimming pool water samples were within the water quality limits for China. Total concentrations of THMs, HAAs, and inorganic DBPs of 20.4-42.2, 82.0-229, and 100-729 µg/L in the swimming pool, and 16.6-28.3, 8.2-12.8, and 64.4-95.6 µg/L in the tap water, indicating inorganic DBPs are the dominant swimming pool and drinking water pollutants. Cancer risk values of regulated DBPs in swimming pools and input tap water are 2.7E-05 and 8.1E-05, respectively, and exceed the US EPA's threshold (1.0E-06). The non-cancer risk is below the US EPA's threshold. Following TCCA disinfection, the concentration and calculated cytotoxicity of regulated DBPs had a 3.6-fold and 1.9-fold increase, respectively. Inorganic DBPs contribute to the calculated concentration and cancer risks of DBPs in swimming pools and tap water at sufficient concentrations warranting regulation. This study provides data on 12 regulated DBPs in TCCA-disinfected indoor swimming pools, highlighting the importance of inorganic DBPs from evidences of concentration, cytotoxicity, and cancer risk for the first time.

Ultrasmall iron-quercetin metal natural product nanocomplex with antioxidant and macrophage regulation in rheumatoid arthritis.

Oxidative stress, due to the disruption of the balance between reactive oxygen species (ROS) generation and the antioxidant defense system, plays an important role in the pathogenesis of rheumatoid arthritis (RA). Excessive ROS leads to the loss of biological molecules and cellular functions, release of many inflammatory mediators, stimulate the polarization of macrophages, and aggravate the inflammatory response, thus promoting osteoclasts and bone damage. Therefore, foreign antioxidants would effectively treat RA. Herein, ultrasmall iron-quercetin natural coordination nanoparticles (Fe-Qur NCNs) with excellent anti-inflammatory and antioxidant properties were constructed to effectively treat RA. Fe-Qur NCNs obtained by simple mixing retain the inherent ability to remove ROS of quercetin and have a better water-solubility and biocompatibility. In vitro experiments showed that Fe-Qur NCNs could effectively remove excess ROS, avoid cell apoptosis, and inhibit the polarization of inflammatory macrophages by reducing the activation of the nuclear factor-κ-gene binding (NF-κB) pathways. In vivo experiments showed that the swollen joints of mice with rheumatoid arthritis treated with Fe-Qur NCNs significantly improved, with Fe-Qur NCNs largely reducing inflammatory cell infiltration, increasing anti-inflammatory macrophage phenotypes, and thus inhibiting osteoclasts, which led to bone erosion. This study demonstrated that the new metal-natural coordination nanoparticles could be an effective therapeutic agent for the prevention of RA and other diseases associated with oxidative stress.

Trimethylamine N-oxide aggravated cognitive impairment from APP/PS1 mice and protective roles of voluntary exercise.

To determine whether trimethylamine N-oxide (TMAO) would aggravate cognitive dysfunction from APP/PS1 mice and the potential protective effects of voluntary wheel running (VWR). TMAO impaired learning and memory abilities, and exercise reversed TMAO induced cognitive impairment. Serum TMAO, choline, betaine and TMA were significantly elevated from TMAO group, while exercise group had decreased TMAO, betaine and TMA level. TMAO group has significantly upregulated BACE1 from both hippocampus and cortex, also increased cathepsin B, p-Tau at Ser396&Ser404, GFAP, p-NF-κB p65 in cortex, while reduced BDNF, synaptophysin and PSD95 in hippocampus, also reduced occludin and ZO-1 from cortex, and reduced occludin from colon. In contrast, BACE1 from both hippocampus and cortex, also cathepsin B and p-Tauser396 from cortex were reduced, BDNF, snaptophysin, and PSD95 from hippocampus, ZO-1 from cortex, and occludin from colon were elevated post exercise compared to TMAO group. Exercise elevated α diversity index of cecal content, and TMAO and exercise affected gut microbiota profiles differentially. In conclusion, TMAO led to gut microbiota dysbiosis, impaired gut-brain integrity, elevated neuroinflammation, Aß pathology and tau phosphorylation, disordered synaptic function; and exercise could reverse TMAO induced cognitive dysfunction via improving the above markers. The potential deleterious effects of TMAO on cognitive function need to be validated in humans, also dosages of exercise for exerting neuroprotective effects against TMAO induced cognitive impairment.

Nano-enabled photosynthesis in tumours to activate lipid peroxidation for overcoming cancer resistances.

Apoptosis dysregulation is an important mechanism responsible for the intrinsic and acquired resistance of melanoma, which necessitates the exploration of oncological treatments to activate nonapoptotic cell death. Herein, we developed nano-enabled photosynthesis in tumours to activate lipid peroxidation and ferroptosis to overcome melanoma resistance. Controlled photosynthesis was conducted in tumours to construct a hyperoxic microenvironment with photosynthetic microcapsules (PMCs), which were prepared by encapsulating cyanobacteria and upconversion nanoparticles in alginate microcapsules and driven by external near infrared photons. The combination of PMCs and X-rays evoked lipid peroxidation, Fe2+ release, glutathione peroxidase 4 suppression, glutathione reduction and ferroptosis in melanoma cells and xenografts. Consequently, the intrinsic and acquired resistance in melanoma could be overcome by the combined treatment, which further inhibited tumour metastases and improved the survival rate of melanoma-bearing mice. Overall, the development of nano-enabled photosynthesis in tumours will inspire the exploration of oncological treatments.

Cadmium exposure decreases fasting blood glucose levels and exacerbates type-2 diabetes in a mouse model.

PURPOSE: Although the effects of cadmium (Cd) on the development of diabetes have been extensively investigated, the relationship between Cd exposure and the severity of established diabetes is unclear. Herein, we investigate the effects of long-term exposure to Cd in a streptozotocin-induced mouse model of type-2 diabetes mellitus (T2DM) and the underlying mechanism. METHODS: C57BL/6 Mice were divided into the following four groups: (1) control group; (2) Cd-exposed group; (3) diabetic group; (4) Cd-exposed diabetic group. Cd exposure was established by the administration of 155 ppm CdCl2 in drinking water. After 25 weeks of treatment, serum fasting glucose and insulin were measured. Meanwhile, the liver and pancreas specimens were sectioned and stained with Hematoxylin and eosin. Gluconeogenesis, glycolysis, lactate concentration, and fibrosis in liver were evaluated. RESULTS: Clinical signs attributable to diabetes were more apparent in Cd-exposed diabetic mice, while no effects of Cd exposure were found on non-diabetic mice. Cd exposure significantly decreased fasting blood glucose (FBG) levels in diabetic group. We further demonstrated that the glycolysis related hepatic enzymes, pyruvate kinase M2 (PKM-2) and lactic dehydrogenase A (LDHA) were both increased, while the gluconeogenesis related hepatic enzymes, phosphoenolpyruvate-1 (PCK-1) and glucose-6-phosphatase (G6Pase) were both decreased in Cd exposed diabetic mice, indicating that Cd increased glycolysis and inhibited gluconeogenesis in diabetic model. Moreover, lactate accumulation was noted accompanied by the increased inflammation and fibrosis in the livers of diabetic mice following Cd exposure. CONCLUSIONS: Cd exposure disturbed glucose metabolism and exacerbated diabetes, providing a biological relevance that DM patients are at greater risk when exposed to Cd.

Effect of 1α,25(OH)2D3-Treated M1 and M2 Macrophages on Cell Proliferation and Migration Ability in Ovarian Cancer.

The biological active form of vitamin D3, 1α,25-dehydroxyvitamin D3 [1α,25(OH)2D3], exerts pleiotropic effects including bone mineralization, anti-tumor, as well as immunomodulator. This study aimed to explore the potential impact of 1α,25(OH)2D3 on tumor-associated macrophages (TAMs) infiltration in ovarian cancer. Firstly, human monocytic THP-1 cells were differentiated into macrophages (M0) in the presence of phorbol 12-myristate 13-acetate (PMA). In Vivo, 1α,25(OH)2D3 not only reversed the polarization of M2 macrophages, but also decreased the proliferation and migration abilities of ovarian cancer cells induced by M2 macrophages supernatant. Furthermore, 1α,25(OH)2D3 dramatically decreased the secretion of TGF-ß1 and MMP-9 in M2 macrophages. However, no significant effect was observed in 1α,25(OH)2D3 treated M1 macrophages. In Vivo, vitamin D3 had an inhibitive effect of 1α,25(OH)2D3-treated M2 macrophages on tumorigenesis. In addition, we conducted the association of TAMs with the poor prognosis of patients with ovarian cancer by meta-analysis, which suggested the higher proportion of M2 macrophages was related to the poorer prognosis in ovarian cancer. Collectively, these results identified distinct roles of 1α,25(OH)2D3 treated M1 and M2 macrophages on cell proliferation and migration abilities in ovarian cancer.

Gefitinib facilitates PINK1/Parkin-mediated mitophagy by enhancing mitochondrial recruitment of OPTN.

Gefitinib, a well-known epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for the targeted therapy of lung cancer, induces autophagy in association with drug resistance. However, it remains unclear whether gefitinib treatment can affect the selective form of autophagy (i.e., mitophagy) and be beneficial for the treatment of human diseases with decreased autophagy, such as neurodegenerative diseases. Here, we show that gefitinib treatment promotes PINK1/Parkin-mediated mitophagy in both nonneuronal and neuronal cells, and this effect is independent of EGFR. Moreover, we found that gefitinib treatment increases the recruitment of the autophagy receptor optineurin (OPTN) to damaged mitochondria, which is a downstream signaling event in PINK1/Parkin-mediated mitophagy. In addition, gefitinib treatment significantly alleviated neuronal damage in TBK1-deficient neurons, resulting in impeded mitophagy. In conclusion, our study suggests that gefitinib promotes PINK1/Parkin-mediated mitophagy via OPTN and may be beneficial for the treatment of neurodegenerative diseases that are associated with defective mitophagy.