The dePARylase NUDT16 promotes radiation resistance of cancer cells by blocking SETD3 for degradation via reversing its ADP-ribosylation.

Poly(ADP-ribosyl)ation (PARylation) is a critical posttranslational modification that plays a vital role in maintaining genomic stability via a variety of molecular mechanisms, including activation of replication stress and the DNA damage response. The nudix hydrolase NUDT16 was recently identified as a phosphodiesterase that is responsible for removing ADP-ribose units and that plays an important role in DNA repair. However, the roles of NUDT16 in coordinating replication stress and cell cycle progression remain elusive. Here, we report that SETD3, which is a member of the SET-domain containing protein (SETD) family, is a novel substrate for NUDT16, that its protein levels fluctuate during cell cycle progression, and that its stability is strictly regulated by NUDT16-mediated dePARylation. Moreover, our data indicated that the E3 ligase CHFR is responsible for the recognition and degradation of endogenous SETD3 in a PARP1-mediated PARylation-dependent manner. Mechanistically, we revealed that SETD3 associates with BRCA2 and promotes its recruitment to stalled replication fork and DNA damage sites upon replication stress or DNA double-strand breaks, respectively. Importantly, depletion of SETD3 in NUDT16-deficient cells did not further exacerbate DNA breaks or enhance the sensitivity of cancer cells to IR exposure, suggesting that the NUDT16-SETD3 pathway may play critical roles in the induction of tolerance to radiotherapy. Collectively, these data showed that NUDT16 functions as a key upstream regulator of SETD3 protein stability by reversing the ADP-ribosylation of SETD3, and NUDT16 participates in the resolution of replication stress and facilitates HR repair.

MXenes as emerging adsorbents for removal of environmental pollutants.

MXenes are a recently emerging class of two-dimensional nanomaterials that have gained considerable interest in the field of environmental protection. Owing to their high surface area, abundant terminal groups, and unique two-dimensional layered structures, MXenes have demonstrated high efficacy as adsorbents for various pollutants. Here we focused on the latest developments in the field of MXene-based adsorbents, including the structure and properties of MXenes, their synthesis and modification methods, and their adsorption performance and mechanisms for various pollutants. Among the pollutants that have been reported to be adsorbed by MXenes are radionuclides (U(VI), Sr(II), Cs(I), Eu(III), Ba(II), Th(IV), and Tc(VII)/Re(VII)), heavy metals (Hg(II), Cu(II), Cr(VI), and Pb(II)), dyes, per- and polyfluoroalkyl substances (PFAS), antibiotics (tetracycline, ciprofloxacin, and sulfonamides), antibiotic resistance genes (ARGs), and other contaminates. Moreover, future directions in MXene research are also suggested in this review.

Identification and Validation of the Pyroptosis-Related Hub Gene Signature and the Associated Regulation Axis in Diabetic Keratopathy.

Background: Diabetic keratopathy (DK) poses a significant challenge in diabetes mellitus, yet its molecular pathways and effective treatments remain elusive. The aim of our research was to explore the pyroptosis-related genes in the corneal epithelium of the streptozocin-induced diabetic rats. Methods: After sixteen weeks of streptozocin intraperitoneal injection, corneal epithelium from three diabetic rats and three normal groups underwent whole-transcriptome sequencing. An integrated bioinformatics pipeline, including differentially expressed gene (DEG) identification, enrichment analysis, protein-protein interaction (PPI) network, coexpression, drug prediction, and immune deconvolution analyses, identified hub genes and key drivers in DK pathogenesis. These hub genes were subsequently validated in vivo through RT-qPCR. Results: A total of 459 DEGs were screened out from the diabetic group and nondiabetic controls. Gene Set Enrichment Analysis highlighted significant enrichment of the NOD-like receptor, Toll-like receptor, and NF-kappa B signaling pathways. Intersection of DEGs and pyroptosis-related datasets showed 33 differentially expressed pyroptosis-related genes (DEPRGs) associated with pathways such as IL-17, NOD-like receptor, TNF, and Toll-like receptor signaling. A competing endogenous RNA network comprising 16 DEPRGs, 22 lncRNAs, 13 miRNAs, and 3 circRNAs was constructed. After PPI network, five hub genes (Nfkb1, Casp8, Traf6, Ptgs2, and Il18) were identified as upregulated in the diabetic group, and their expression was validated by RT-qPCR in streptozocin-induced rats. Immune infiltration characterization showed that diabetic corneas owned a higher proportion of resting mast cells, activated NK cells, and memory-resting CD4 T cells. Finally, several small compounds including all-trans-retinoic acid, Chaihu Shugan San, dexamethasone, and resveratrol were suggested as potential therapies targeting these hub genes for DK. Conclusions: The identified and validated hub genes, Nfkb1, Casp8, Traf6, Ptgs2, and Il18, may play crucial roles in DK pathogenesis and serve as therapeutic targets.

Strategy for treating MAFLD: Electroacupuncture alleviates hepatic steatosis and fibrosis by enhancing AMPK mediated glycolipid metabolism and autophagy in T2DM rats.

BACKGROUND: Recent studies have highlighted type 2 diabetes (T2DM) as a significant risk factor for the development of metabolic dysfunction-associated fatty liver disease (MAFLD). This investigation aimed to assess electroacupuncture's (EA) impact on liver morphology and function in T2DM rats, furnishing experimental substantiation for its potential to stall MAFLD progression in T2DM. METHODS: T2DM rats were induced by a high-fat diet and a single intraperitoneal injection of streptozotocin, and then randomly assigned to five groups: the T2DM group, the electroacupuncture group, the metformin group, combination group of electroacupuncture and metformin, combination group of electroacupuncture and Compound C. The control group received a standard diet alongside intraperitoneal citric acid - sodium citrate solution injections. After a 6-week intervention, the effects of each group on fasting blood glucose, lipids, liver function, morphology, lipid droplet infiltration, and fibrosis were evaluated. Techniques including Western blotting, qPCR, immunohistochemistry, and immunofluorescence were employed to gauge the expression of key molecules in AMPK-associated glycolipid metabolism, insulin signaling, autophagy, and fibrosis pathways. Additionally, transmission electron microscopy facilitated the observation of liver autophagy, lipid droplets, and fibrosis. RESULTS: Our studies indicated that hyperglycemia, hyperlipidemia and IR promoted lipid accumulation, pathological and functional damage, and resulting in hepatic steatosis and fibrosis. Meanwhile, EA enhanced the activation of AMPK, which in turn improved glycolipid metabolism and autophagy through promoting the expression of PPARα/CPT1A and AMPK/mTOR pathway, inhibiting the expression of SREBP1c, PGC-1α/PCK2 and TGFß1/Smad2/3 signaling pathway, ultimately exerting its effect on ameliorating hepatic steatosis and fibrosis in T2DM rats. The above effects of EA were consistent with metformin. The combination of EA and metformin had significant advantages in increasing hepatic AMPK expression, improving liver morphology, lipid droplet infiltration, fibrosis, and reducing serum ALT levels. In addition, the ameliorating effects of EA on the progression of MAFLD in T2DM rats were partly disrupted by Compound C, an inhibitor of AMPK. CONCLUSIONS: EA upregulated hepatic AMPK expression, curtailing gluconeogenesis and lipogenesis while boosting fatty acid oxidation and autophagy levels. Consequently, it mitigated blood glucose, lipids, and insulin resistance in T2DM rats, thus impeding liver steatosis and fibrosis progression and retarding MAFLD advancement.

[Mechanism of electroacupuncture regulating nuclear factor-κB pathway to improve the dedifferentiation of pancreatic ß-cells in rats with T2DM].

OBJECTIVE: To observe the effects of electroacupuncture (EA) on the expression of serum interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and the pancreatic nuclear factor-κB (NF-κB) pathway in type 2 diabetes mellitus (T2DM) rats, and to explore the possible mechanism by which EA improving the dedifferentiation of pancreatic ß-cells in the treatment of T2DM. METHODS: Among 18 SPF-grade male Wistar rats, 6 rats were randomly selected as the control group, and the remaining 12 rats were fed with high-sugar and high-fat diet combined with intraperitoneal injection of 2% streptozotocin solution (35 mg/kg) to establish T2DM model. After successful modeling, the 12 rats were randomly divided into a model group and an EA group, with 6 rats in each group. The EA group received EA at bilateral "Zusanli" (ST 36), "Sanyinjiao" (SP 6), "Weiwanxiashu" (EX-B 3), and "Pishu" (BL 20), with continuous wave, frequency of 15 Hz, current intensity of 2 mA, for 20 min each time, once a day, 6 times a week, for a total of 6 weeks. Fasting blood glucose (FBG) levels were measured before modeling and before and after intervention. After intervention, ELISA was used to detect the serum fasting insulin (FINS), IL-1ß and TNF-α levels, and the ß-cell function index (HOMA-ß) and insulin resistance index (HOMA-IR) were calculated; HE staining was used to observe the morphology of the pancreatic islets; Western blot was used to detect the protein expression of pancreatic forkhead box protein O1 (FoxO1), pancreatic and duodenal homeobox 1 (PDX-1), neurogenin 3 (NGN3), and NF-κB p65. RESULTS: After intervention, the FBG in the model group was higher than that in the control group (P<0.01), and the FBG in the EA group was lower than that in the model group (P<0.01). Compared with the control group, the model group had increased levels of serum FINS, IL-1ß, TNF-α, and HOMA-IR (P<0.01), and decreased HOMA-ß (P<0.01), reduced protein expression of pancreatic FoxO1 and PDX-1 (P<0.01), and increased protein expression of pancreatic NGN3 and NF-κB p65 (P<0.01, P<0.05). Compared with the model group, the EA group had lower serum FINS, IL-1ß, TNF-α levels, and HOMA-IR (P<0.01), higher HOMA-ß (P<0.05), increased protein expression of pancreatic FoxO1 and PDX-1 (P<0.01, P<0.05), and decreased protein expression of pancreatic NGN3 and NF-κB p65 (P<0.01, P<0.05). The control group's pancreatic islets showed no obvious abnormalities; the model group's pancreatic islets were irregular in shape and had unclear boundaries with the surrounding area, with immune cell infiltration, reduced ß-cell nuclei, disordered arrangement of islet cells, and increased intercellular spaces; the EA group showed improvements in islet morphology, immune cell infiltration, ß-cell nuclei count, and the arrangement and spacing of islet cells approaching normal. CONCLUSION: EA could lower the blood glucose levels in T2DM rats, alleviate chronic inflammatory responses in the islets, and improve the dedifferentiation of pancreatic ß-cells, which may be related to the inhibition of pancreatic NF-κB pathway expression.

Deubiquitinating Enzyme USP19 Regulates Ferroptosis and Mitochondrial Damage in SH-SY5Y Cells by Targeting the NOX4 Protein.

Background: Ferroptosis is extremely relevant to the progression of neurodegenerative pathologies such as Alzheimer's disease (AD). Ubiquitin-specific proteases (USP) can affect the NADPH oxidase family. Objective: Our study aimed to elucidate the potential role and molecular basis of a certain USP19 in reducing ferroptosis and mitochondrial injury in AD cells by targeting NOX4 stability. Methods: The deubiquitinase USP family gene USP19, which affects the stability of NOX4 protein, was first screened. The cell model of AD was constructed after interfering with SH-SY5Y cells by Aß1-40, and then SH-SY5Y cells were infected with lentiviral vectors to knock down USP19 and overexpress NOX4, respectively. Finally, the groups were tested for cell viability, changes in cellular mitochondrial membrane potential, lipid reactive oxygen species, intracellular iron metabolism, and NOX4, Mf1, Mf2, and Drp1 protein expression. Results: 5 µmol/L Aß1-40 intervened in SH-SY5Y cells for 24 h to construct a cell model of AD. Knockdown of USP19 decreased the expression of NOX4 protein, promoted the expression of mitochondrial fusion proteins Mnf1 and Mnf2, and inhibited the expression of the splitting protein Drp1. Furthermore, USP19 knockdown decreased mitochondrial membrane potential, SOD, MDA, intracellular iron content and increased GSH/GSSG ratio in SH-SY5Y cells. Our study revealed that NOX4 protein interacts with USP19 and knockdown of USP19 enhanced ubiquitination to maintain NOX4 protein stability. Conclusions: USP19 attenuates mitochondrial damage in SH-SY5Y cells by targeting NOX4 protein with Aß1-40.

Structural insights into the catalytic mechanism of the AP endonuclease AtARP.

Base excision repair (BER) is a critical genome defense pathway that copes with a broad range of DNA lesions induced by endogenous or exogenous genotoxic agents. AP endonucleases in the BER pathway are responsible for removing the damaged bases and nicking the abasic sites. In plants, the BER pathway plays a critical role in the active demethylation of 5-methylcytosine (5mC) DNA modification. Here, we have determined the crystal structures of Arabidopsis AP endonuclease AtARP in complex with the double-stranded DNA containing tetrahydrofuran (THF) that mimics the abasic site. We identified the critical residues in AtARP for binding and removing the abasic site and the unique residues for interacting with the orphan base. Additionally, we investigated the differences among the three plant AP endonucleases and evaluated the general DNA repair capacity of AtARP in a mammalian cell line. Our studies provide further mechanistic insights into the BER pathway in plants.

Case report: Abscesses in children caused by invasive group A Streptococcus.

Streptococcus is one of the common pathogens of suppurative infections. Invasive group A Streptococcus (iGAS) infections often develop from skin or soft tissue infections, and streptococcal toxic shock syndrome is considered the main cause of death in Chinese children with iGAS infectious disease. However, soft tissue infections caused by iGAS infections, especially the formation of abscesses, are relatively rare. A retrospective study was conducted, and pediatric in-patients who were diagnosed with an iGAS infection identified by cultures from normally sterile sites and treated in a tertiary hospital during 2016-2018 were included. A total of 14 patients were identified, which included 10 boys and four girls. The patients had an age range from 3 months to 10 years and were diagnosed with soft tissue infections and a formation of abscesses caused by iGAS infections. The most common sites of infections were the lower limbs. In five patients, the abscess was accompanied by fever, and the local soft tissue showed redness, swelling, tenderness, and an elevated skin temperature. Laboratory findings included an increased white blood cell (WBC) count in 12 patients, an increased C reactive protein (CRP) level in seven patients, and an increased erythrocyte sedimentation rate (ESR) in 10 patients. No patients had an elevated procalcitonin level. For all 14 patients, we performed puncture and drainage of abscesses, and cultured GAS from the drainage fluid. All children also received antibiotic treatment. During 2 months of follow-up, the patients' condition remained stable and no evidence of kidney or heart damage was observed. For pediatric patients with abscesses, early diagnosis, prompt treatment with incision and drainage, and immediate culture of the drainage fluid are important. Upon confirmation of an iGAS infection, ß-lactam antibiotics should be given to provide effective treatment, and in some patients with poor therapeutic outcomes, the use of vancomycin as an alternative can achieve the desired results.

Interaction between antibiotics and microplastics: Recent advances and perspective.

Both microplastics and antibiotics are emerging pollutants, which are ubiquitous in aquatic environments. With small size, high specific surface area, and attached biofilm, microplastics are capable of adsorbing or biodegrading antibiotic pollutants across aquatic environments. However, the interactions between them are poorly understood, especially factors that affect microplastics' chemical vector effects and the mechanisms driving these interactions. In this review, the properties of microplastics and their interaction behavior and mechanisms towards antibiotics were comprehensively summarized. Particularly, the impact of weathering properties of microplastics and the growth of attached biofilm was highlighted. We concluded that compared with virgin microplastics, aged microplastics usually adsorb more types and quantities of antibiotics from aquatic environments, whilst the attached biofilm could further enhance the adsorption capacities and biodegrade some antibiotics. This review can answer the knowledge gaps of the interaction between microplastics and antibiotics (or other pollutants), offer basic information for evaluating their combined toxicity, provide insights into the distribution of both emerging pollutants in the global water chemical cycle, and inform measures to remove microplastic-antibiotic pollution.

Efficient adsorptive removal of Co2+ from aqueous solution using graphene oxide.

This study aimed to utilize synthesized graphene oxide (GO) for adsorptive removal of cobalt ions and investigate the adsorption mechanism using advanced techniques such as X-ray absorption spectra (XAFS). The GO was synthesized via an improved Hummers method, resulting in high surface area (93.7 m2/g) and abundant oxygen-containing functional groups. Various characterizations, including SEM, TEM, Raman, FT-IR, TG, potentiometric titrations, and N2 sorption-desorption measurements, were employed to characterize the GO. The adsorption behavior of GO towards Co2+ was investigated, and the results showed that the adsorption process followed a pseudo-second-order kinetic model and the Langmuir model, with a maximum sorption capacity of 93.7 mg/g. The adsorption process was chemisorption and endothermic, with GO showing adsorption selectivity order of Co2+ > Sr2+ > Cs+. Based on various characterizations such as X-ray absorption near-edge spectroscopy (XANES), extended X-ray absorption fine structure (EXAFS), FT-IR, and XPS, the sorption mechanism of Co2+ onto GO was discussed, with the results indicating that coordination and electrostatic interaction were the primary adsorption mechanisms, with oxygen-containing functional groups playing a vital role. The first coordinating atom for Co2+ was O, and the coordination environment was similar to that of cobalt acetate and CoO. Overall, this study provides comprehensive understanding of the adsorption behavior and mechanism of Co2+ onto GO, highlighting its potential as an effective adsorbent for removing nuclides from aqueous solution.

Dendrobium mixture ameliorates type 2 diabetes mellitus with non-alcoholic fatty liver disease through PPAR gamma: An integrated study of bioinformatics analysis and experimental verification.

Dendrobium mixture (DM) is a patented Chinese herbal medicine indicated which has anti-inflammatory and improved glycolipid metabolism. However, its active ingredients, targets of action, and potential mechanisms are still uncertain. Here, we investigate the role of DM as a prospective modulator of protection against non-alcoholic fatty liver disease (NAFLD) induced by type 2 diabetes mellitus (T2DM) and illustrate the molecular mechanisms potentially involved. The network pharmacology and TMT-based quantitative protomics analysis were conducted to identify potential gene targets of the active ingredients in DM against NAFLD and T2DM. DM was administered to the mice of DM group for 4 weeks, and db/m mice (control group) and db/db mice (model group) were gavaged by normal saline. DM was also given to Sprague-Dawley (SD) rats, and the serum was subjected to the palmitic acid-induced HepG2 cells with abnormal lipid metabolism. The mechanism of DM protection against T2DM-NAFLD is to improve liver function and pathological morphology by promoting peroxisome proliferator-activated receptor γ (PPARγ) activation, lowering blood glucose, improving insulin resistance (IR), and reducing inflammatory factors. In db/db mice, DM reduced RBG, body weight, and serum lipids levels, and significantly alleviated histological damage of liver steatosis and inflammation. It upregulated the PPARγ corresponding to the prediction from the bioinformatics analysis. DM significantly reduced inflammation by activating PPARγ in both db/db mice and palmitic acid-induced HepG2 cells.

Effects of electroacupuncture on the glucose-lipid metabolism and the expression of ZAG and GLUT4 in the femoral quadriceps and adipose tissue in the rats with type 2 diabetes mellitus. / 电针对2åž‹ç³–å°¿ç— å¤§é¼ ç³–è„‚ä»£è°¢åŠè‚¡å››å¤´è‚Œå’Œè„‚è‚ªç»„ç»‡ZAG、GLUT4表达的影响.

OBJECTIVES: To observe the effects on the glucose-lipid metabolism and the expression of zinc-α2-glycoprotein (ZAG) and glucose transporter 4 (GLUT4) in the femoral quadriceps and adipose tissue after electroacupuncture (EA) at "Pishu" (BL 20), "Weiwanxiashu" (EX-B 3), "Zusanli" (ST 36) and "Sanyinjiao" (SP 6) in the rats with diabetes mellitus type 2 (T2DM), so as to explore the effect mechanism of EA in treatment of T2DM. METHODS: Twelve ZDF male rats were fed with high-sugar and high-fat fodder, Purina #5008 for 4 weeks to induce T2DM model. After successfully modeled, the rats were randomly divided into a model group and an EA group, with 6 rats in each one. Additionally, 6 ZL male rats of the same months age were collected as the blank group. The rats in the EA group were treated with EA at bilateral "Pishu" (BL 20), "Weiwanxiashu" (EX-B 3), "Zusanli" (ST 36) and "Sanyinjiao" (SP 6), with continuous wave, 15 Hz in frequency, and 2 mA in intensity. The electric stimulation lasted 20 min each time. EA was delivered once daily, 6 times a week for 4 weeks. Separately, the levels of fasting blood glucose (FBG) was measured before modeling, before and after intervention, and the body mass of each rat was weighted before and after intervention. After intervention, the levels of the total cholesterol (TC), triacylglycerol (TG) and free fatty acid (FFA) in serum were detected using enzyme colorimetric method; and the levels of the serum insulin (INS) and ZAG were detected by ELISA. Besides, the insulin sensitivity index (HOMA-ISI) was calculated. With Western blot technique adopted, the protein expressions of ZAG and GLUT4 in the femoral quadriceps and adipose tissue were determined. RESULTS: After intervention, compared with the blank group, the levels of FBG and body mass, and the levels of serum TC, TG, FFA and INS increased (P<0.01), while HOMA-ISI decreased (P<0.01); the level of ZAG in the serum and the protein expressions of ZAG and GLUT4 in the femoral quadriceps and adipose tissue dropped (P<0.01) in the model group. In the EA group, compared with the model group, the levels of FBG and body mass, and the levels of serum TC, TG, FFA and INS were reduced (P<0.01), and HOMA-ISI increased (P<0.01); the level of ZAG in the serum and the protein expressions of ZAG and GLUT4 in the femoral quadriceps and adipose tissue increased (P<0.01, P<0.05). CONCLUSIONS: Electroacupuncture can effectively regulate glucose-lipid metabolism, improve insulin resistance and sensitivity in the rats with T2DM, which is associated with the modulation of ZAG and GLUT4 expression in the skeletal muscle and adipose tissue.

[Effect of electroacupuncture on liver Akt/FoxO1 signaling pathway in rats with diabetic fatty].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on liver protein kinase B (Akt)/forkhead box transcription factor 1 (FoxO1) signaling pathway in Zucker diabetic fatty (ZDF) rats, and to explore the possible mechanism of EA on improving liver insulin resistance of type 2 diabetes mellitus. METHODS: Twelve male 2-month-old ZDF rats were fed with high-fat diet for 4 weeks to establish diabetes model. After modeling, the rats were randomly divided into a model group and an EA group, with 6 rats in each group. In addition, six male Zucker lean (ZL) rats were used as the blank group. The rats in the EA group were treated with EA at bilateral "Zusanli" (ST 36), "Sanyinjiao" (SP 6), "Weiwanxiashu" (EX-B 3), and "Pishu" (BL 20). The ipsilateral "Zusanli" (ST 36) and "Weiwanxiashu" (EX-B 3) were connected to EA device, continuous wave, frequency of 15 Hz, 20 min each time, once a day, six times a week, for a total of 4 weeks. The fasting blood glucose (FBG) in each group was compared before modeling, before intervention and after intervention; the serum levels of insulin (INS) and C-peptide were measured by radioimmunoassay method, and the insulin resistance index (HOMA-IR) was calculated; HE staining method was used to observe the liver tissue morphology; Western blot method was used to detect the protein expression of Akt, FoxO1 and phosphoenolpyruvate carboxykinase (PEPCK) in the liver. RESULTS: Before intervention, compared with the blank group, FBG was increased in the model group and the EA group (P<0.01); after intervention, compared with the model group, FBG in the EA group was decreased (P<0.01). Compared with the blank group, the serum levels of INS and C-peptide, HOMA-IR, and the protein expression of hepatic FoxO1 and PEPCK were increased (P<0.01), while the protein expression of hepatic Akt was decreased (P<0.01) in the model group. Compared with the model group, the serum levels of INS and C-peptide, HOMA-IR, and the protein expression of hepatic FoxO1 and PEPCK were decreased (P<0.01), while the protein expression of hepatic Akt was increased (P<0.01) in the EA group. In the model group, the hepatocytes were structurally disordered and randomly arranged, with a large number of lipid vacuoles in the cytoplasm. In the EA group, the morphology of hepatocytes tended to be normal and lipid vacuoles were decreased. CONCLUSION: EA could reduce FBG and HOMA-IR in ZDF rats, improve liver insulin resistance, which may be related to regulating Akt/FoxO1 signaling pathway.

Dendrobium mixture ameliorates hepatic injury induced by insulin resistance in vitro and in vivo through the downregulation of AGE/RAGE/Akt signaling pathway.

Dendrobium mixture (DM) is a patented Chinese herbal medicine which has been shown to ameliorate type 2 diabetes mellitus (T2DM) with non-alcoholic fatty liver disease (NAFLD) in vivo and in vitro. We aimed to investigate the underlying mechanism of DM as a therapeutic agent in attenuating liver steatosis in relation to type 2 diabetes mellitus (T2DM). DM (16.2 g/kg/d) was administered to db/db mice for 4 weeks. The db/m mice and db/db mice in the control and model groups were given normal saline. Additionally, DM (11.25 g/kg/d) was administered to Sprague-Dawley (SD) rats, and the serum was collected and used in an experiment involving palmitic acid (PA)-induced human liver HepG2 cells with abnormal lipid and glucose metabolism. In db/db mice, the administration of DM significantly alleviated liver steatosis, including histological damage and cell apoptosis. DM was found to prevent the upregulation of the RAGE and AKT1 proteins in liver tissues. The underlying mechanism of DM was further studied in PA-induced HepG2 cells. Post-DM administration serum from SD rats reduced lipid accumulation and regulated glucose metabolism in HepG2 cells. Consequently, it inhibited RAGE/AKT signaling and restored autophagy activity. The upregulated autophagy was associated with the mTOR-AMPK signaling pathway. Furthermore, post-DM administration serum reduced apoptosis of hepatocytes in PA-induced HepG2 cells. Our study supports the potential use of DM as a therapeutic agent for the treatment of NAFLD in T2DM. The mechanism underlying this therapeutic potential is associated with the downregulation of the AGE/RAGE/Akt signaling pathway.

A protocol for a single center, randomized, controlled trial comparing the clinical efficacy of 3% diquafosol and 0.1% hyaluronic acid in diabetic patients with dry eye disease.

BACKGROUND: The global prevalence of diabetes mellitus (DM) continues to rise and 70% of diabetic individuals have dry eye disease (DED) that leads to subsequent abnormalities of the corneal epithelium, corneal nerves, tear film, or corneal endothelium. In addition, persons with diabetes produce fewer tear secretions than healthy individuals. While several anti-inflammatory drug-based therapies for dry eye in diabetic individuals are currently being administered, their efficacy has not been studied in detail. Therefore, the aim of this study was to compare the effectiveness of 3% diquafosol (DQS) vs 0.1% hyaluronic acid (HA) eye drops in diabetic dry eye patients. METHODS: This triple-blind randomized, control trial will include 202 diabetic-related DED and will be assigned to DQS (n = 101) and HA (n = 101) one drop, six times per day for 8 weeks. Tear film lipid layer, non-invasive breakup time, conjunctivocorneal staining score, corneal sensitivity, tear MMP-9 levels, meibomian gland expression and quality, tear meniscus height, corneal nerves, immune/inflammatory cell change, conjunctival hyperemia, and ocular surface disease index questionnaire score will be assessed and compared at baseline, week 4, and week 8. DISCUSSION: This study will be a standardized, scientific, clinical trial designed to evaluate the therapeutic effects and safety of DQS and HA for diabetic dry eye treatment. TRIAL REGISTRATION: ClinicalTrials.govNCT05682547. Registered on December 05, 2022.

Selective and effective adsorption of cesium ions by metal hexacyanoferrates (MHCF, M = Cu, Co, Ni) modified chitosan fibrous biosorbent.

Selective and effective adsorptive removal of radiocesium is of great importance in terms of nuclear waste management and environmental remediation, but is still challenging because of its radioactive and non-complexing nature. Herein, metal hexacyanoferrates (MHCF, M = Cu, Co, or Ni) modified fibrous chitosan was prepared by multiple sequential adsorption and self-assembly approach, and applied for the selective and effective adsorption of Cs+. The physically supported MHCF in chitosan fibers showed good crystallinity and stability, and the obtained fibrous composite has high specific surface area (18.2-29.4 m2 g-1). Moreover, MHCF crystals endowed the fibrous chitosan-based adsorbent with a high adsorption capacity and selectivity towards Cs+. Its adsorption kinetic and isotherm performance followed the pseudo second-order model and the Sips model. The qm value of three fibrous MHCF/chitosan (M = Cu, Co, or Ni) composites was 24.9-70.3 mg g-1. The fibrous CuHCF/chitosan composite had the highest qm among the three composites. In summary, the modified chitosan can selectively and effectively remove Cs+ from complicated aqueous solutions.

Adsorption of Co2+ and Sr2+ in aqueous solution by a novel fibrous chitosan biosorbent.

In this study, a novel fibrous chitosan biosorbent was prepared using LiOH/KOH/urea/H2O (4.5:7:8:80.5 by weight) as spinning solvent. The fibrous chitosan exhibited a higher adsorption capacity and a faster adsorption rate for Co2+ and Sr2+, compared with spherical chitosan due to its high specific surface area (16.9 m2 g-1), uniform fineness (24.1 µm), and good mechanical strength. The adsorption capacity of fibrous chitosan for Co2+ and Sr2+ was 31.3 mg g-1 and 20.0 mg g-1, respectively, which was higher than that of spherical chitosan (22.5 mg g-1for Co2+ and 8.9 mg g-1 for Sr2+). The coordination between -NH2/-OH of chitosan and the nuclide ions was the rate-limiting step. The improvement of adsorption performance was due to the higher specific surface area which increased the exposure degree of functional groups (adsorptive sites). This new wet-spun fibrous chitosan biosorbent showed great potential in the adsorptive removal of nuclides ions from aqueous solution.

[Effect of electroacupuncture on protein expressions of SOCS3 and IRS-1 in hypothalamus and pancreas islet morphology in diabetic fatty rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on protein expressions of suppressor of cytokine signaling 3 (SOCS3) and insulin receptor substrate-1 (IRS-1) in hypothalamus and morphology of pancreas islet in Zucker diabetic fatty (ZDF) rats, and to explore its possible mechanism on improving plasma glucose and insulin resistance of type 2 diabetes mellitus (T2DM). METHODS: Twelve SPF male ZDF rats were selected and fed with high-fat diet for 4 weeks to establish the T2DM model, after modeling, the rats were randomly divided into a model group and an EA group, 6 rats in each one. Besides, 6 SPF male Zucker lean rats were selected as a blank group. In the EA group, EA was applied at "Pishu" (BL 20), "Weiwanxiashu" (EX-B 3), "Zusanli" (ST 36) and "Sanyinjiao" (SP 6), with continuous wave, 15 Hz in frequency, 2 mA in intensity, once a day, 20 min each time, 6 times a week for 4 weeks. The fasting plasma glucose (FPG) was measured before and after intervention. The serum level of fasting insulin (FINS) was measured by radioimmunoassay, and the homeostasis model assessment of insulin resistance index (HOMA-IR) was calculated; the morphological change of pancreas islets was observed by HE staining; the protein expressions of SOCS3 and IRS-1 in hypothalamus were detected by Western blot. RESULTS: Before intervention, compared with the blank group, FPG in the model group and the EA group was increased (P<0.01). After intervention, compared with the blank group, FPG, serum level of FINS and HOMA-IR were increased (P<0.01), the protein expression of SOCS3 was increased while IRS-1 was decreased in the hypothalamus in the model group (P<0.01). Compared with the model group, FPG, serum level of FINS and HOMA-IR were decreased (P<0.01), the protein expression of SOCS3 was decreased while IRS-1 was increased in the hypothalamus in the EA group (P<0.01). In the model group, the shape of pancreas islets was irregular, the area of pancreas islets and the number of islet ß cell nuclei were decreased, the nuclei of islet ß cell was compensatory enlargement. In the EA group, the shape and the area of pancreas islets and the number of islet ß cell nuclei were improved, the compensatory increase of islet ß cell nuclei was alleviated compared with the model group. CONCLUSION: Electroacupuncture can reduce the fasting plasma glucose, improve the morphology of pancreas islets, and alleviate the insulin resistance in ZDF rats. The mechanism may relate to the down-regulation of SOCS3 and up-regulation of IRS-1 in the hypothalamus, and improving the function of hypothalamus in regulating peripheral glucose metabolism.

Effect of Tanshinone IIA on Gut Microbiome in Diabetes-Induced Cognitive Impairment.

Diabetes-induced cognitive impairment (DCI) presents a major public health risk among the aging population. Previous clinical attempts on known therapeutic targets for DCI, such as depleted insulin secretion, insulin resistance, and hyperglycaemia have delivered poor patient outcomes. However, recent evidence has demonstrated that the gut microbiome plays an important role in DCI by modulating cognitive function through the gut-brain crosstalk. The bioactive compound tanshinone IIA (TAN) has shown to improve cognitive and memory function in diabetes mellitus models, though the pharmacological actions are not fully understood. This study aims to investigate the effect and underlying mechanism of TAN in attenuating DCI in relation to regulating the gut microbiome. Metagenomic sequencing analyses were performed on a group of control rats, rats with diabetes induced by a high-fat/high-glucose diet (HFD) and streptozotocin (STZ) (model group) and TAN-treated diabetic rats (TAN group). Cognitive and memory function were assessed by the Morris water maze test, histopathological assessment of brain tissues, and immunoblotting of neurological biomarkers. The fasting blood glucose (FBG) level was monitored throughout the experiments. The levels of serum lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunoassays to reflect the circulatory inflammation level. The morphology of the colon barrier was observed by histopathological staining. Our study confirmed that TAN reduced the FBG level and improved the cognitive and memory function against HFD- and STZ-induced diabetes. TAN protected the endothelial tight junction in the hippocampus and colon, regulated neuronal biomarkers, and lowered the serum levels of LPS and TNF-α. TAN corrected the reduced abundance of Bacteroidetes in diabetic rats. At the species level, TAN regulated the abundance of B. dorei, Lachnoclostridium sp. YL32 and Clostridiodes difficile. TAN modulated the lipid metabolism and biosynthesis of fatty acids in related pathways as the main functional components. TAN significantly restored the reduced levels of isobutyric acid and butyric acid. Our results supported the use of TAN as a promising therapeutic agent for DCI, in which the underlying mechanism may be associated with gut microbiome regulation.

Effect of dendrobium mixture in alleviating diabetic cognitive impairment associated with regulating gut microbiota.

Dendrobium mixture (DM) is a patent Chinese herbal formulation consisting of Dendrobii Caulis, Astragali Radix, Rehmanniae Radix as the main ingredients. DM has been shown to alleviate diabetic related symptoms attributed to its anti-hyperglycaemic and anti-inflammatory activities. However, the effect on diabetic induced cognitive dysfunction has not been investigated. This study aims to investigate the effect of DM in improving diabetic cognitive impairment and associated mechanisms. Our study confirmed the anti-hyperglycaemic effect of DM and showed its capacity to restore the cognitive and memory function in high fat/high glucose and streptozotocin-induced diabetic rats. The neuroprotective effect was manifested as improved learning and memory behaviours, restored blood-brain barrier tight junction, and enhanced expressions of neuronal survival related biomarkers. DM protected the colon tight junction, and effectively lowered the circulated proinflammatory mediators including tumour necrosis factor-α, interleukin-6 and lipopolysaccharides. In the gut microbiota, DM corrected the increase in the abundance of Firmicutes, the increase in the ratio of Firmicutes/Bacteroidetes, and the decrease in the abundance of Bacteroidetes in diabetic rats. It also reversed the abundance of Lactobacillus, Ruminococcus and Allobaculum genera. Short chain fatty acids, isobutyric acid and ethylmethylacetic acid, were negatively and significantly correlated to Ruminococcus and Allobaculum. Isovaleric acid was positively and significantly correlated with Lactobacillus, which all contributing to the improvement in glucose level, systemic inflammation and cognitive function in diabetic rats. Our results demonstrated the potential of DM as a promising therapeutic agent in treating diabetic cognitive impairment and the underlying mechanism may be associated with regulating gut microbiota.