Inulin Reduces Kidney Damage in Type 2 Diabetic Mice by Decreasing Inflammation and Serum Metabolomics.

This study is aimed at assessing the impact of soluble dietary fiber inulin on the treatment of diabetes-related chronic inflammation and kidney injury in mice with type 2 diabetes (T2DM). The T2DM model was created by feeding the Institute of Cancer Research (ICR) mice a high-fat diet and intraperitoneally injecting them with streptozotocin (50 mg/kg for 5 consecutive days). The thirty-six ICR mice were divided into three dietary groups: the normal control (NC) group, the T2DM (DM) group, and the DM + inulin diet (INU) group. The INU group mice were given inulin at the dose of 500 mg/kg gavage daily until the end of the 12th week. After 12 weeks, the administration of inulin resulted in decreased serum levels of fasting blood glucose (FBG), low-density lipoprotein cholesterol (LDL-C), blood urea nitrogen (BUN), and creatinine (CRE). The administration of inulin not only ameliorated renal injury but also resulted in a reduction in the mRNA expressions of inflammatory factors in the spleen and serum oxidative stress levels, when compared to the DM group. Additionally, inulin treatment in mice with a T2DM model led to a significant increase in the concentrations of three primary short-chain fatty acids (SCFAs) (acetic acid, propionic acid, and butyric acid), while the concentration of advanced glycation end products (AGEs), a prominent inflammatory factor in diabetes, exhibited a significant decrease. The results of untargeted metabolomics indicate that inulin has the potential to alleviate inflammatory response and kidney damage in diabetic mice. This beneficial effect is attributed to its impact on various metabolic pathways, including glycerophospholipid metabolism, taurine and hypotaurine metabolism, arginine biosynthesis, and tryptophan metabolism. Consequently, oral inulin emerges as a promising treatment option for diabetes and kidney injury.

MITF regulates the subcellular location of HIF1α through SUMOylation to promote the invasion and metastasis of daughter cells derived from polyploid giant cancer cells.

High concentrations of cobalt chloride (CoCl2) can induce the formation of polyploid giant cancer cells (PGCCs) in various tumors, which can produce daughter cells with strong proliferative, migratory and invasive abilities via asymmetric division. To study the role of hypoxia­inducible factor (HIF) 1α in the formation of PGCCs, colon cancer cell lines Hct116 and LoVo were used as experimental subjects. Western blotting, nuclear and cytoplasmic protein extraction and immunocytochemical experiments were used to compare the changes in the expression and subcellular localization of HIF1α, microphthalmia­associated transcription factor (MITF), protein inhibitor of activated STAT protein 4 (PIAS4) and von Hippel­Lindau disease tumor suppressor (VHL) after treatment with CoCl2. The SUMOylation of HIFα was verified by co­immunoprecipitation assay. After inhibiting HIF1α SUMOylation, the changes in proliferation, migration and invasion abilities of Hct116 and LoVo were compared by plate colony formation, wound healing and Transwell migration and invasion. In addition, lysine sites that led to SUMOylation of HIF1α were identified through site mutation experiments. The results showed that CoCl2 can induce the formation of PGCCs with the expression level of HIF1α higher in treated cells than in control cells. HIF1α was primarily located in the cytoplasm of control cell. Following CoCl2 treatment, the subcellular localization of HIF1α was primarily in the nuclei of PGCCs with daughter cells (PDCs). After treatment with SUMOylation inhibitors, the nuclear HIF1α expression in PDCs decreased. Furthermore, their proliferation, migration and invasion abilities also decreased. After inhibiting the expression of MITF, the expression of HIF1α decreased. MITF can regulate HIF1α SUMOylation. Expression and subcellular localization of VHL and HIF1α did not change following PIAS4 knockdown. SUMOylation of HIF1α occurs at the amino acid sites K391 and K477 in PDCs. After mutation of the two sites, nuclear expression of HIF1α in PDCs was reduced, along with a significant reduction in the proliferation, migration and invasion abilities. In conclusion, the post­translation modification regulated the subcellular location of HIF1α and the nuclear expression of HIF1α promoted the proliferation, migration and invasion abilities of PDCs. MITF could regulate the transcription and protein levels of HIF1α and participate in the regulation of HIF1α SUMOylation.

Dormant cancer cells and polyploid giant cancer cells: The roots of cancer recurrence and metastasis.

Tumour cell dormancy is critical for metastasis and resistance to chemoradiotherapy. Polyploid giant cancer cells (PGCCs) with giant or multiple nuclei and high DNA content have the properties of cancer stem cell and single PGCCs can individually generate tumours in immunodeficient mice. PGCCs represent a dormant form of cancer cells that survive harsh tumour conditions and contribute to tumour recurrence. Hypoxic mimics, chemotherapeutics, radiation and cytotoxic traditional Chinese medicines can induce PGCCs formation through endoreduplication and/or cell fusion. After incubation, dormant PGCCs can recover from the treatment and produce daughter cells with strong proliferative, migratory and invasive abilities via asymmetric cell division. Additionally, PGCCs can resist hypoxia or chemical stress and have a distinct protein signature that involves chromatin remodelling and cell cycle regulation. Dormant PGCCs form the cellular basis for therapeutic resistance, metastatic cascade and disease recurrence. This review summarises regulatory mechanisms governing dormant cancer cells entry and exit of dormancy, which may be used by PGCCs, and potential therapeutic strategies for targeting PGCCs.

Hemoglobin is associated with BMDs and risk of the 10-year probability of fractures in patients with type 2 diabetes mellitus.

Purpose: This study aimed to investigate the associations between hemoglobin (HGB) levels and bone mineral density (BMD) and fracture risk in type 2 diabetes mellitus(T2DM) population of different ages. Method: This cross-sectional study included 641 patients with T2DM (57.9% males). BMD of the femoral neck (FN), total hip (TH), and lumbar spine (LS) were measured using dual-energy X-ray absorptiometry. The 10-year probability of fracture was assessed using a fracture risk assessment tool (FRAX). HGB and other biochemical indices were measured in a certified laboratory at our hospital. Statistical analysis was performed using SPSS 26.0 and R language (R version 4.1.0). Generalized additive models (GAMs) were used to identify the associations between HGB and BMD and fracture risk. Results: Patients with osteoporosis have lower HGB levels than the non-osteoporotic population and lower FN BMD in patients with anemia than in the non-anemic population. In patients with T2DM, there was sex- and age-related variability in the correlation between HGB levels and BMDs and fracture risk. In older men, HGB level was an independent determinant of BMD and was positively correlated with FN and TH BMD. In non-older women, HGB level was an independent determinant of BMD and fracture risk, positively associated with BMDs and negatively associated with 10-year probability of fracture risk. GAMs revealed a positive linear association between HGB level and BMDs in non-older female patients but not in older male patients. Conclusion: Our study provides a new perspective on the association of HGB level and BMDs with fracture risk. Relatively high HGB levels are a protective factor for bone quality in patients with T2DM. However, the bone-protective effect of HGB is influenced by age and sex and persists only in older men and non-older women with T2DM.

14-3-3ε: a protein with complex physiology function but promising therapeutic potential in cancer.

Over the past decade, the role of the 14-3-3 protein has received increasing interest. Seven subtypes of 14-3-3 proteins exhibit high homology; however, each subtype maintains its specificity. The 14-3-3ε protein is involved in various physiological processes, including signal transduction, cell proliferation, apoptosis, autophagy, cell cycle regulation, repolarization of cardiac action, cardiac development, intracellular electrolyte homeostasis, neurodevelopment, and innate immunity. It also plays a significant role in the development and progression of various diseases, such as cardiovascular diseases, inflammatory diseases, neurodegenerative disorders, and cancer. These immense and various involvements of 14-3-3ε in diverse processes makes it a promising target for drug development. Although extensive research has been conducted on 14-3-3 dimers, studies on 14-3-3 monomers are limited. This review aimed to provide an overview of recent reports on the molecular mechanisms involved in the regulation of binding partners by 14-3-3ε, focusing on issues that could help advance the frontiers of this field. Video Abstract.

Medication Bias During the Hospital-to-Family Transition Among Young and Middle-Aged Chinese Patients with Type 2 Diabetes: A Qualitative Study.

Objective: This study aimed to examine the prevalence of medication non-adherence among young and middle-aged Chinese individuals diagnosed with type 2 diabetes, and to explore the underlying causes of such deviations. Methods: The Medication Discrepancy Tool (MDT) was used to assess medication deviations in a cohort of 100 patients who had been discharged from the hospital. Furthermore, 15 subjects were interviewed to gain a better understanding of their medication non-adherence experiences. Results: The rate of medication deviation in the studied cohort was 79.5%, with the most frequent deviation being a reduction in the types of drugs taken. The primary cause of this deviation was found to be patient-derived, with the most common reason being symptom improvement. Iatrogenic medication deviation was most often caused by incomplete or inaccurate medication education for medical staff at discharge, resulting in patients having to guess their own medication. Internal and extrinsic motivating factors were identified as the primary causes of medication deviation behavior. Conclusion: This study has demonstrated that medication non-adherence is a major issue among young and middle-aged Chinese individuals diagnosed with type 2 diabetes. Therefore, it is essential for nurses to be aware of the importance of medication adherence management and working.

Lactiplantibacillus plantarum NKK20 Alleviates High-Fat-Diet-Induced Nonalcoholic Fatty Liver Disease in Mice through Regulating Bile Acid Anabolism.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic disease in modern society. It is characterized by an accumulation of lipids in the liver and an excessive inflammatory response. Clinical trials have provided evidence that probiotics may prevent the onset and relapse of NAFLD. The aim of this study was to explore the effect of Lactiplantibacillus plantarum NKK20 strain (NKK20) on high-fat-diet-induced NAFLD in an ICR murine model and propose the underlying mechanism whereby NKK20 protects against NAFLD. The results showed that the administration of NKK20 ameliorated hepatocyte fatty degeneration, reduced total cholesterol and triglyceride concentrations, and alleviated inflammatory reactions in NAFLD mice. In addition, the 16S rRNA sequencing results indicated that NKK20 could decrease the abundance of Pseudomonas and Turicibacter and increase the abundance of Akkermansia in NAFLD mice. LC-MS/MS analysis showed that NKK20 could significantly increase the concentration of short-chain fatty acids (SCFAs) in the colon contents of mice. The obtained non-targeted metabolomics results revealed a significant difference between the metabolites in the colon contents of the NKK20 administration group and those in the high-fat diet group, in which a total of 11 different metabolites that were significantly affected by NKK20 were observed, and these metabolites were mainly involved in bile acid anabolism. UPLC-MS technical analysis revealed that NKK20 could change the concentrations of six conjugated and free bile acids in mouse liver. After being treated with NKK20, the concentrations of cholic acid, glycinocholic acid, and glycinodeoxycholic acid in livers of the NAFLD mice were significantly decreased, while the concentration of aminodeoxycholic acid was significantly increased. Thus, our findings indicate that NKK20 can regulate bile acid anabolism and promote the production of SCFA, which can inhibit inflammation and liver damage and thus prevent the development of NAFLD.

Berberine-Based Carbon Quantum Dots Improve Intestinal Barrier Injury and Alleviate Oxidative Stress in C57BL/6 Mice with 5-Fluorouracil-Induced Intestinal Mucositis by Enhancing Gut-Derived Short-Chain Fatty Acids Contents.

This study aims to evaluate the effect of berberine-based carbon quantum dots (Ber-CDs) on improving 5-fluorouracil (5-FU)-induced intestinal mucositis in C57BL/6 mice, and explored the mechanisms behind this effect. Thirty-two C57BL/6 mice were divided into four groups: normal control (NC), 5-FU-induced intestinal mucositis model (5-FU), 5-FU + Ber-CDs intervention (Ber-CDs), and 5-FU + native berberine intervention (Con-CDs). The Ber-CDs improved body weight loss in 5-FU-induced mice with intestinal mucositis compared to the 5-FU group. The expressions of IL-1ß and NLRP3 in spleen and serum in Ber-CDs and Con-Ber groups were significantly lower than those in the 5-FU group, and the decrease was more significant in the Ber-CDs group. The expressions of IgA and IL-10 in the Ber-CDs and Con-Ber groups were higher than those in the 5-FU group, but the up-regulation was more significant in the Ber-CDs group. Compared with the 5-FU group, the relative contents of Bifidobacterium, Lactobacillus and the three main SCFAs in the colon contents were significantly increased the Ber-CDs and Con-Ber groups. Compared with the Con-Ber group, the concentrations of the three main short-chain fatty acids in the Ber-CDs group were significantly increased. The expressions of Occludin and ZO-1 in intestinal mucosa in the Ber-CDs and Con-Ber groups were higher than those in the 5-FU group, and the expressions of Occludin and ZO-1 in the Ber-CDs group were more higher than that in the Con-Ber group. In addition, compared with the 5-FU group, the damage of intestinal mucosa tissue in the Ber-CDs and Con-Ber groups were recovered. In conclusion, berberine can attenuate intestinal barrier injury and oxidative stress in mice to mitigate 5-fluorouracil-induced intestinal mucositis, moreover, the above effects of Ber-CDs were more significant than those of native berberine. These results suggest that Ber-CDs may be a highly effective substitute for natural berberine.

The associations between uric acid with BMDs and risk of the 10-year probability of fractures in Chinese patients with T2DM stratified by age and gender.

PURPOSE: Accumulating evidence suggests that serum uric acid (SUA) plays a beneficial role in bone health in the general population through antioxidant mechanisms. However, there is controversy over the association between SUA and bone in patients with type 2 diabetes mellitus (T2DM). We aimed to investigate the association of serum UA with BMDs and future fracture risks and its potential influencing factors in those patients. METHOD: This was a cross-sectional study of 485 patients. BMDs at femoral neck (FN), Troch and the lumbar spine (LS) were measured by DXA. The 10-year probability of fracture risk was assessed using the fracture risk assessment tool (FRAX). SUA level and other biochemical indexes were measured. RESULTS: There were lower SUA concentrations in patients with osteoporosis/osteopenia compared with those in the normal group, which only existed in non-elderly men and elderly women with T2DM. After adjustment for potential confounders, SUA was positively associated with BMD and negatively with 10-year probability of fracture risk only in non-elderly men and elderly women with T2DM. Multiple stepwise regression analysis showed that SUA was an independent determinant of BMD and 10-year probability of fracture risk, which also occurred in the above patients. CONCLUSION: These results implied that relatively high SUA is a protective factor for bone in T2DM patients, but the osteoprotective effect of SUA was mediated by age and gender, and persisted only in non-elderly men and elderly women. Large intervention studies are needed to further confirm the outcomes and provide possible explanations.

The negative effect of G1958A polymorphism on MTHFD1 protein stability and HCC growth.

PURPOSE: Methylenetetrahydrofolate dehydrogenase (MTHFD1), a key enzyme on the folate pathway, has been implicated in the tumor development of distinct types of cancers. The single nucleotide polymorphism (SNP) of 1958G > A mutation in the coding region of MTHFD1 (arginine 653 is mutated into glutamine) has been detected in a significant proportion of clinical samples of hepatocellular carcinoma (HCC). METHODS : Hepatoma cell lines, 97H and Hep3B were used. The expression of MTHFD1 and SNP mutation protein was determined by immunoblotting analysis. The protein ubiquitination of MTHFD1 was detected by immunoprecipitation analysis. The post-translational modification sites and interacting proteins of MTHFD1 in the presence of G1958A SNP were identified by mass spectrometry. Metabolic flux analysis was used to detect the synthesis of relevant metabolites sourced from serine isotope. RESULTS: The present study showed G1958A SNP of MTHFD1, encoding MTHFD1 R653Q, was associated with the attenuated protein stability caused by ubiquitination-mediated protein degradation. Mechanistically, MTHFD1 R653Q displayed an enhanced binding to the E3 ligase TRIM21, which was responsible for the augmented ubiquitination, and MTHFD1 K504 was identified to be the primary ubiquitination site. The subsequent metabolite analysis revealed MTHFD1 R653Q resulted in the repressed flux of serine-derived methyl group into metabolite precursors for purine synthesis, and the compromised purine synthesis was demonstrated to be responsible for the impeded growth capability in MTHFD1 R653Q-expressing cells. Moreover, the suppressive effect of MTHFD1 R653Q expression in tumorigenesis was verified by xenograft analysis, and the relationship between MTHFD1 G1958A SNP and its protein levels was revealed in clinical human liver cancer specimens. CONCLUSION: Our results uncovered an unidentified mechanism underlying of the impact of G1958A SNP on MTHFD1 protein stability and tumor metabolism in HCC. which provides a molecular basis for the according clinical management when considering MTHFD1 as a therapeutic target.

A combination of FDM, EWM, and GRA to measure performance in higher vocational college: An empirical case from China.

Given the problems of unclear division of evaluation factors, inadequate utilization of objective data and unreasonable distribution of weight in college performance measurement, this study extracts relevant indicators and quantitative data from the survey report of administrational institutions, and constructs a comprehensive performance measurement model based on the integration of fuzzy Delphi method (FDM), Entropy weight method (EWM), and grey relational analysis (GRA). The study seeks to identify differences in measurement analysis by comparing the weights, the performance and the rankings of the alternatives about higher vocational colleges in Zhejiang province. Finally, the results show the following: (1) by FDM, 33 indicators about colleges' performance are selected to form the evaluation system of the college's performance, (2) the indicators' weights are obtained through EWM and GRA, and a nonparametric test shows that there is no significant difference between the two types of weights, (3) the grey relational degrees of the alternatives are obtained and ranked on the basis of comprehensive evaluation model. By nonparametric test, there is a significant difference between the two types of relational degrees. On the contrary, no significant difference is found in the ranking of relational degrees, (4) based on the analysis results, this study further compares the performance of alternatives in different forms. There are significant differences between the performance of public colleges and private colleges, while no significant differences are observed between the performance of vocational colleges in Hangzhou and non-Hangzhou. Given the reliability and validity of the model, the comprehensive measurement model provides a relatively objective reference for college governance and administrational institutions, and also becomes an effective tool of colleges' evaluation to assist and improve the management practice in educational institutions.

Sodium butyrate attenuate hyperglycemia-induced inflammatory response and renal injury in diabetic mice.

The activation of the monocyte-macrophage system and the damage to the renal and pancreatic tissue are common complications in patients with diabetes induced by hyper-glycemia. This study aimed to evaluate the effect and mechanism of butyrate (NaB), a metabolite of intestinal flora, on inhibiting the inflammatory response of human monocyte-macrophages (THP-1 cells) induced by high glucose and the damage of pancreatic and renal tissue in diabetic mice. The results showed that high concentration glucose significantly up-regulated the expressions of IL-1ß, TNF-α, and NLRP3 in THP-1 cells and mouse spleen, and that NaB could inhibit the overexpression of those genes. The abundance of Beclin-1, LC3B and reactive oxygen species (ROS) in THP-1 cells is increased due to the high glucose concentration, and NaB can inhibit the genes responsible for upregulating the expression. In diabetic mice, vacuolar degeneration of renal tubules was observed. Then we observed that some of the epithelial cells of the renal tubules were exfoliated and some formed tubules. NaB could alleviate these pathological lesions, but NaB cannot alleviate pancreatic injury. Our results indicated that NaB could be used for the prevention and adjuvant treatment of diabetic kidney injury.

KOtBu-Promoted, Three-Component Domino Reaction of Arenes(indoles/phenols), C60, and (Per/poly)fluoroarenes: Achieving Direct C-C Cross-Coupling of Fullerene with (Per/poly)fluoroarenes.

A KOtBu-promoted, three-component cross-coupling of arenes(indoles/phenols), C60, and (per/poly)fluoroarenes has been established for the one-pot efficient synthesis of various 1,4-arene-bridged bis(polyfluoroaryl)-functionalized [60]fullerenes. This developed reaction system demonstrates good functional group compatibilities with broad substrate scope, which exhibits high regio- and chemoselectivities. Further control experiment succeeded in providing a one-pot protocol for the synthesis of various 1,2-N-(per/poly)fluoroarene-substituted 1,2-(3-indole)(hydro)fullerenes.

Expression and Prognostic Value of Cytokines in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma / 中国实验血液学杂志

OBJECTIVE@#To investigate the expression and prognostic value of cytokines in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL).@*METHODS@#Clinical data of 62 patients diagnosed with DLBCL in the First People's Hospital of Yunnan Province from June 2017 to November 2018 were collected. The differences in expression levels of 14 serum cytokines [interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-17F, IL-22, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, TNF-β] in patients with different survival outcomes, and the impact of the cytokines on 3-year progression-free survival (PFS) and 3-year overall survival (OS) of patients with DLBCL were analyzed retrospectively.@*RESULTS@#Among the 14 cytokines, only the expression of IL-10 was significantly different in patients with different survival outcomes (P =0.007). According to the receiver operating characteristic (ROC) curve, the optimal cut-off value for IL-10 was 11.74 pg/ml. Serum IL-10 was positively correlated with infection markers procalcitonin (PCT) (r =0.321, P =0.029), C-reactive protein (CRP) (r =0.320, P =0.013) and tumor burden index lactate dehydrogenase (LDH) (r =0.439, P <0.001) in newly diagnosed DLBCL patients. The level of IL-10 in patients with pulmonary infection was significantly higher than that in patients without pulmonary infection (P =0.012). However, there was no statistically significant difference on the 3-year survival outcomes between patients with or without pulmonary infection. There was no significant difference in IL-10 level in patients with different Ann Arbor stages (P >0.05). Patients with high IL-10 level (IL-10>11.74 pg/ml) had significantly higher LDH level than those with low IL-10 level (IL-10≤11.74 pg/ml) (P <0.001). The 3-year PFS rate and 3-year OS rate of DLBCL patients with high IL-10 level were significantly lower than those of low IL-10 level group [(44.4±11.7)% vs (81.8±5.8)%, P <0.001; (61.6±11.5)% vs (93.2±3.8)%, P =0.001].@*CONCLUSION@#Serum IL-10 level in newly diagnosed DLBCL patients can reflect the inflammatory state of the body, which may be related to tumor load. Newly diagnosed DLBCL patients with serum IL-10>11.74 pg/ml have higher early mortality and worse prognosis.

Lactiplantibacillus plantarum NKK20 Increases Intestinal Butyrate Production and Inhibits Type 2 Diabetic Kidney Injury through PI3K/Akt Pathway.

Nephropathy injury is a prevalent complication observed in individuals with diabetes, serving as a prominent contributor to end-stage renal disease, and the advanced glycation products (AGEs) are important factors that induce kidney injury in patients with diabetes. Addressing this condition remains a challenging aspect in clinical practice. The aim of this study was to explore the effects of Lactiplantibacillus plantarum NKK20 strain (NKK20) which protects against diabetic kidney disease (DKD) based on animal and cell models. The results showed that the NKK20 can significantly reduce renal inflammatory response, serum oxidative stress response, and AGE concentration in diabetic mice. After treatment with NKK20, the kidney damage of diabetic mice was significantly improved, and more importantly, the concentration of butyrate, a specific anti-inflammatory metabolite of intestinal flora in the stool of diabetic mice, was significantly increased. In addition, nontargeted metabolomics analysis showed a significant difference between the metabolites in the mouse serum contents of the NKK20 administration group and those in the nephropathy injury group, in which a total of 24 different metabolites that were significantly affected by NKK20 were observed, and these metabolites were mainly involved in glycerophospholipid metabolism and arachidonic acid metabolism. Also, the administration of butyrate to human kidney- (HK-) 2 cells that were stimulated by AGEs resulted in a significant upregulation of ZO-1, Occludin, and E-cadherin gene expressions and downregulation of α-SMA gene expression. This means that butyrate can maintain the tight junction structure of HK-2 cells and inhibit fibrosis. Butyrate also significantly inhibited the activation of PI3K/Akt pathway. These results indicate that NKK20 can treat kidney injury in diabetic mice by reducing blood glucose and AGE concentration and increasing butyrate production in the intestine. By inhibiting PI3K pathway activation in HK-2 cells, butyrate maintains a tight junction structure of renal tubule epithelial cells and inhibits renal tissue fibrosis. These results suggest that NKK20 is helpful to prevent and treat the occurrence and aggravation of diabetic kidney injury.

Sodium Butyrate Attenuates AGEs-Induced Oxidative Stress and Inflammation by Inhibiting Autophagy and Affecting Cellular Metabolism in THP-1 Cells.

In recent years, sodium butyrate has gained increased attention for its numerous beneficial properties. However, whether sodium butyrate could alleviate inflammatory damage by macrophage activation and its underlying mechanism remains unclear. The present study used an advanced glycosylation products- (AGEs-) induced inflammatory damage model to study whether sodium butyrate could alleviate oxidative stress, inflammation, and metabolic dysfunction of human monocyte-macrophage originated THP-1 cells in a PI3K-dependent autophagy pathway. The results indicated that sodium butyrate alleviated the AGEs-induced oxidative stress, decreased the level of reactive oxygen species (ROS), increased malondialdehyde (MDA) and mRNA expression of pro-inflammatory cytokines of interleukin (IL)-1ß and tumor necrosis factor (TNF)-α, and increased the content of superoxide dismutase (SOD). Sodium butyrate reduced the protein expression of the NLR family, pyrin domain-containing protein 3 (NLRP3) and Caspase-1, and decreased the nucleus expression of nuclear factor-kappaB (NF-κB). Sodium butyrate decreased the expression of light-chain-associated protein B (LC3B) and Beclin-1, and inhibited autophagy. Moreover, sodium butyrate inhibited the activation of the PI3K/Akt pathway in AGEs-induced THP-1 cells. In addition, the metabolomics analysis showed that sodium butyrate could affect the production of phosphatidylcholine, L-glutamic acid, UDP-N-acetylmuraminate, biotinyl-5'-AMP, and other metabolites. In summary, these results revealed that sodium butyrate inhibited autophagy and NLRP3 inflammasome activation by blocking the PI3K/Akt/NF-κB pathway, thereby alleviating oxidative stress, inflammation, and metabolic disorder induced by AGEs.

Short-Chain Fatty Acids Weaken Ox-LDL-Induced Cell Inflammatory Injury by Inhibiting the NLRP3/Caspase-1 Pathway and Affecting Cellular Metabolism in THP-1 Cells.

Short-chain fatty acids (SCFAs) are important anti-inflammatory metabolites of intestinal flora. Oxidized low-density lipoprotein (ox-LDL)-induced macrophage activation is critical for the formation of atherosclerosis plaque. However, the association between SCFAs and ox-LDL-induced macrophage activation with respect to the formation of atherosclerosis plaque has not yet been elucidated. The present study investigated whether SCFAs (sodium acetate, sodium propionate, and sodium butyrate) can affect ox-LDL-induced macrophage activation and potential signaling pathways via regulation of the expression of the NLRP3/Caspase-1 pathway. Using human monocyte-macrophage (THP-1) cells as a model system, it was observed that ox-LDL not only induced cell inflammatory injury but also activated the NLRP3/Caspase-1 pathway. The exogenous supplementation of three SCFAs could significantly inhibit cell inflammatory injury induced by ox-LDL. Moreover, three SCFAs decreased the expression of IL-1ß and TNF-α via the inactivation of the NLRP3/Caspase-1 pathway induced by ox-LDL. Furthermore, three SCFAs affected cellular metabolism in ox-LDL-induced macrophages, as detected by untargeted metabolomics analysis. The results of the present study indicated that three SCFAs inhibited ox-LDL-induced cell inflammatory injury by blocking the NLRP3/Caspase-1 pathway, thereby improving cellular metabolism. These findings may provide novel insights into the role of SCFA intervention in the progression of atherosclerotic plaque formation.

Correlation of Serum M-CSF, CER, and TIMP-1 Levels with Liver Fibrosis in Viral Hepatitis.

Objective: This research is aimed at investigating the relationship between liver fibrosis in viral hepatitis and macrophage colony-stimulating factor (M-CSF), tissue inhibitor of matrix metalloproteinase (TIMP-1), and ceruloplasmin (CER) in serum level. Methods: Patients were randomly selected among those admitted to our hospital, and 60 healthy volunteers were chosen to serve as control participants. The levels of serum M-CSF, CER, and TIMP-1 were compared. According to the severity of their liver fibrosis, patients with CHB were separated into four groups: S1, S2, S3, and S4. Serum levels of M-CSF, CER, and TIMP-1 were correlated with liver fibrosis and hepatitis markers, and the diagnostic usefulness of the three indices was assessed with liver cirrhosis patients. Results: Increases in M-CSF and TIMP-1 in the CHB group but decreases in CER were statistically significant (P < 0.05). Serum levels of M-CSF, CER, TIMP-1, HA, PC-III, C-IV, and LN differed significantly across the four study groups (P < 0.05). Over time, as liver fibrosis worsened, we observed a progressive uptick in M-CSF, TIMP-1, LN, HA, C-IV, and PC-III levels and a progressive downtick in CER levels, with significant (P < 0.05) differences between the groups. There was a significant positive correlation between liver fibrosis and serum M-CSF, PC-III, TIMP-1, HA, LN, and C-IV levels in the CHB group (P < 0.05) and a significant negative correlation between serum CER and these same factors (P < 0.05). The AUC of 0.956 for diagnosing the S4 stage was greater than that of 0.857, 0.851, and 0.817 for M-CSF, CER, and TIMP-1, respectively. Conclusions: In CHB patients, the liver fibrosis degree is associated with the M-CSF, CER, and TIMP-1 levels, and the combined clinical detection of these three markers has better diagnostic significance.

IL-17D-induced inhibition of DDX5 expression in keratinocytes amplifies IL-36R-mediated skin inflammation.

Aberrant RNA splicing in keratinocytes drives inflammatory skin disorders. In the present study, we found that the RNA helicase DDX5 was downregulated in keratinocytes from the inflammatory skin lesions in patients with atopic dermatitis and psoriasis, and that mice with keratinocyte-specific deletion of Ddx5 (Ddx5∆KC) were more susceptible to cutaneous inflammation. Inhibition of DDX5 expression in keratinocytes was induced by the cytokine interleukin (IL)-17D through activation of the CD93-p38 MAPK-AKT-SMAD2/3 signaling pathway and led to pre-messenger RNA splicing events that favored the production of membrane-bound, intact IL-36 receptor (IL-36R) at the expense of soluble IL-36R (sIL-36R) and to the selective amplification of IL-36R-mediated inflammatory responses and cutaneous inflammation. Restoration of sIL-36R in Ddx5∆KC mice with experimental atopic dermatitis or psoriasis suppressed skin inflammation and alleviated the disease phenotypes. These findings indicate that IL-17D modulation of DDX5 expression controls inflammation in keratinocytes during inflammatory skin diseases.