Possible Role of Cellular Polyamine Metabolism in Neuronal Apoptosis.

Recent studies have shown that cellular levels of polyamines (PAs) are significantly altered in neurodegenerative diseases. Evidence from in vivo animal and in vitro cell experiments suggests that the cellular levels of various PAs may play important roles in the central nervous system through the regulation of oxidative stress, mitochondrial metabolism, cellular immunity, and ion channel functions. Dysfunction of PA metabolism related enzymes also contributes to neuronal injury and cognitive impairment in many neurodegenerative diseases. Therefore, in the current work, evidence was collected to determine the possible associations between cellular levels of PAs, and related enzymes and the development of several neurodegenerative diseases, which could provide a new idea for the treatment of neurodegenerative diseases in the future.

Status and developmental trends in recombinant collagen preparation technology.

Recombinant collagen is a pivotal topic in foundational biological research and epitomizes the application of critical bioengineering technologies. These technological advancements have profound implications across diverse areas such as regenerative medicine, organ replacement, tissue engineering, cosmetics and more. Thus, recombinant collagen and its preparation methodologies rooted in genetically engineered cells mark pivotal milestones in medical product research. This article provides a comprehensive overview of the current genetic engineering technologies and methods used in the production of recombinant collagen, as well as the conventional production process and quality control detection methods for this material. Furthermore, the discussion extends to foresee the strides in physical transfection and magnetic control sorting studies, envisioning an enhanced preparation of recombinant collagen-seeded cells to further fuel recombinant collagen production.

PM2.5 induced neurotoxicity through unbalancing vitamin B12 metabolism by gut microbiota disturbance.

Fine particulate matter (PM2.5) in the atmosphere is easily accompanied by toxic and harmful substances, causing serious harm to human health, including cognitive impairment. Vitamin B12 (VitB12) is an essential micronutrient that is synthesized by bacteria and contributes to neurotransmitter synthesis as a nutrition and signaling molecule. However, the relationship between VitB12 attenuation of cognitive impairment and intestinal microbiota regulation in PM2.5 exposure has not been elucidated. In this study, we demonstrated that PM2.5 caused behavioral defects and neuronal damage in Caenorhabditis elegans (C. elegans), along with significant gene expression changes in neurotransmitter receptors and a decrease in VitB12 content, causing behavioral defects and neuronal damage in C. elegans. Methylcobalamin (MeCbl), a VitB12 analog, alleviated PM2.5-induced neurotoxicity in C. elegans. Moreover, using in vivo and in vitro models, we discovered that long-term exposure to PM2.5 led to changes in the structure of the gut microbiota, resulting in an imbalance of the VitB12-associated metabolic pathway followed by cognitive impairment. MeCbl supplementation could increase the diversity of the bacteria, reduce harmful substance contents, and restore the concentration of short-chain fatty acids (SCFAs) and neurotransmitters to the level of the control group to some degree. Here, a new target to mitigate the harm caused by PM2.5 was discovered, supplying MeCbl for relieving intestinal and intracellular neurotransmitter disorders. Our results also provide a reference for the use of VitB12 to target the adjustment of the human intestinal microbiota to improve metabolic disorders in people exposed to PM2.5.

Treating solid tumors with TCR-based chimeric antigen receptor targeting extra domain B-containing fibronectin.

BACKGROUND: The suppression of chimeric antigen receptor (CAR) T cells by the tumor microenvironment (TME) is a crucial obstacle in the T-cell-based treatment of solid tumors. Extra domain B (EDB)-fibronectin is an oncofetal antigen expressed on the endothelium layer of the neovasculature and cancer cells. Though recognized as a T cell therapy target, engineered CAR T cells thus far have failed to demonstrate satisfactory in vivo efficacy. In this study, we report that targeting EDB-fibronectin by redirected TCR-CAR T cells (rTCR-CAR) bypasses the suppressive TME for solid tumor treatment and sufficiently suppressed tumor growth.We generated EDB-targeting CAR by fusing single-chain variable fragment to CD3ε, resulting in rTCR-CAR. Human primary T cells and Jurkat cells were used to study the EDB-targeting T cells. Differences to the traditional second-generation CAR T cell in signaling, immune synapse formation, and T cell exhaustion were characterized. Cytotoxicity of the rTCR-CAR T cells was tested in vitro, and therapeutic efficacies were demonstrated using xenograft models. METHODS: RESULTS: In the xenograft models, the rTCR-CAR T cells demonstrated in vivo efficacies superior to that based on traditional CAR design. A significant reduction in tumor vessel density was observed alongside tumor growth inhibition, extending even to tumor models established with EDB-negative cancer cells. The rTCR-CAR bound to immobilized EDB, and the binding led to immune synapse structures superior to that formed by second-generation CARs. By a mechanism similar to that for the conventional TCR complex, EDB-fibronectin activated the rTCR-CAR, resulting in rTCR-CAR T cells with low basal activation levels and increased in vivo expansion. CONCLUSION: Our study has demonstrated the potential of rTCR-CAR T cells targeting the EDB-fibronectin as an anticancer therapeutic. Engineered to possess antiangiogenic and cytotoxic activities, the rTCR-CAR T cells showed therapeutic efficacies not impacted by the suppressive TMEs. These combined characteristics of a single therapeutic agent point to its potential to achieve sustained control of solid tumors.

Extraction and characterization of polysaccharide from fermented mycelia of Coriolus versicolor and its efficacy for treating nonalcoholic fatty liver disease.

Coriolus versicolor, a popular traditional Chinese medicinal herb, is widely used in China to treat spleen and liver diseases; however, the beneficial effects of C. versicolor polysaccharides (CVPs) on nonalcoholic fatty liver disease (NAFLD) remain elusive. Herein we isolated and purified a novel CVP (molecular weight, 17,478 Da) from fermented mycelium powder. This CVP was composed of mannose, galacturonic acid, glucose, galactose, xylose, and fucose at a molar ratio of 22:1:8:15:10:3. Methylation, gas chromatography-mass spectrometry, and nuclear magnetic resonance analyses indicated that the CVP backbone consisted of →1)-ß-D-Man-(6,4→1)-α-D-Gal-(3→1)-α-D-Man-(4→1)-α-D-Gal-(6→, with branches of →1)-α-D-Glc-(6→1)-α-D-Man-(4,3→1)-ß-D-Xyl-(2→1)-ß-D-Glc on the O-6 position of →1)-ß-D-Man-(6,4→ of the main chain. The secondary branches linked to the O-4 position of →1)-α-D-Man-(4,3→ with the chain of →1)-α-D-Fuc-(4→1)-α-D-Man. Further, CVP treatment alleviated the symptoms of NAFLD in an HFD-induced mice model. CVP altered gut microbiota, predominantly suppressing microbes associated with bile acids both in the serum and cecal contents. In vitro data showed that CVP reduced HFD-induced hyperlipidemia via farnesoid X receptor. Our results improve our understanding of the mechanisms underlying the cholesterol- and lipid-lowering effects of CVP and indicate that CVP is a promising candidate for NAFLD therapy.

Synthesis and structural characterization of xylan acetate ester and its antinephritic effects in rats with experimental chronic kidney disease.

Acetic acid has been shown to be effective in chronic kidney disease (CKD). However, it is a low-molecular-weight compound that allows it to be absorbed in the upper digestive tract so that it cannot function in colon. To overcome these deficiencies, an acetate-releasing xylan derivative, xylan acetate ester (XylA), was synthesized and selected in this study for its potential in the treatment of CKD. IR, NMR and HPGPC were used to characterize the structure of XylA and its antinephritic effects was evaluated in vivo. The results showed that acetate was successfully grafted onto the C-2 and C-3 positions of xylan and with a molecular weight at 69157 Da. XylA treatments could relieve the symptoms of CKD in an adenine-induced chronic renal failure (CRF) model and an adriamycin-induced focal segmental glomerulosclerosis (FSGS) model in SD rats. Further study indicated that XylA could upregulate the short-chain fatty acids (SCFAs) in vitro and vivo. Nevertheless, the relative abundance of Phascolarctobacterium in colon was increased after XylA treatment. XylA could upregulate G-protein-coupled receptor 41 (GPR41) expression, inhibit glomerular cell apoptosis and promoting proliferation. Our study expands the application of xylan and provides a new idea for the treatment of CKD with acetic acid.

Astragalus polysaccharide ameliorates vascular endothelial dysfunction by stimulating macrophage M2 polarization via potentiating Nrf2/HO-1 signaling pathway.

BACKGROUND: Oxidative stress and chronic non-infectious inflammation caused vascular endothelial dysfunction (VED) is a critical and initiating factor in Type 2 diabetes induced vascular complications, while macrophage polarization plays a regulatory role in VED. Astragalus polysaccharide (APS) has been widely used for treating diabetic vascular diseases, but its mechanisms of action have not been fully elucidated. PURPOSE: This study aimed to investigate the modulatory effects of APS on macrophage polarization and to reveal the potential mechanisms of APS in LPS and HG stimulated macrophages and diabetic model rats. METHODS: In vitro and in vivo studies were used to explore the mechanism of APS. The macrophage polarization and reactive oxygen species (ROS) release was monitored by flow cytometry and the associated inflammatory factors were detected by ELISA. For oxidative stress regulatory pathway detection, protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Heme oxygenase-1 (HO-1) was measured by Western blotting. The vascular endothelial functions were measured by transwell, tube formation assay, scratch assay, adhesion assay. The thoracic aorta pathological changes were evaluated by Haematoxylin-eosin and immunohistochemistry. RESULTS: In vitro, APS inhibited the LPS/HG-stimulated THP-1 macrophage differentiated into macrophage M1, coupling with reduction in the ROS production and pro-inflammatory factors (TNF-α, IL-6, IL-12) release. Furthermore, endothelial cells proliferation and apoptosis were ameliorated after APS treatment. Meanwhile, APS-treated THP-1/macrophage occurred a differentiation into M2 polarization and anti-inflammatory factors (IL-4, IL-10, and Arg-1) release via enhancing Nrf2/HO-1 signaling pathway, which could be disturbed by using siNrf2. APS promoted the migration and angiogenesis of endothelial cells in co-cultured of HUVECs and macrophages under high glucose. Finally, similar results were observed in vivo, APS alleviated thoracic aorta complications of diabetic rats accompanied by a remarkable reduction in inflammation and an increased in the number of anti-inflammatory macrophage polarization. CONCLUSION: Our results demonstrated that APS ameliorated vascular endothelial dysfunction in diabetes by stimulating macrophage polarization to M2 via enhancing the Nrf2/HO-1 pathway.

Efficacy and Safety of Wuling Powder in the Treatment of Patients with Diabetic Nephropathy: A Systematic Review and Meta-Analysis.

Background: Wuling powder is a classical formula of traditional Chinese medicine (TCM), which is extensively applied to treat diabetic nephropathy (DN). However, there are no related reports on systematically evaluating the efficacy of Wuling powder in the treatment of DN. Targeted at this, this study was developed. Materials and Methods: This study systematically searched related articles from nine databases, including PubMed, Cochrane Library, Embase, Web of Science, China Knowledge Infrastructure (CNKI), China Biomedical CD-ROM (Sino Med), Wanfang database, Vipers database (VIP), and the China Clinical Trials Registry website. The randomized controlled trials (RCTs) involving Wuling Power to treat DN were included, which were published from the established data of the above databases to March 2022. In addition, the language of the studies was not restricted. Studies were meta-analyzed using the RevMan 5.4 software given in the Cochrane Collaboration Network. The treatment efficacy was measured using the weighted mean differences (WMD) and 95% confidence intervals (CI). Results: 24 studies were included for the final analysis. 24 h urine volume (WMD = 357.95; 95% CI [322.83, 393.06], p < 0.00001), 24 h urine protein quantification(24 h UPQ) (WMD = -1.30; 95% CI [-1.82, -0.78], p < 0.00001), serum creatinine (Scr) (WMD = -10.17; 95% CI [-11.13, -9.21], p < 0.00001), blood urea nitrogen (BUN) (WMD = -1.62; 95% CI [-2.30, -0.93], p < 0.00001), urinary albumin excretion rate (UAER) (WMD = -24.73; 95% CI [-35.46, -13.99], p < 0.00001), fasting blood glucose (FBG) (WMD = -0.63.95% CI [-0.97, -0.30], p = 0.002), glycated hemoglobin (WMD = -0.11; 95% CI [-0.30, 0.08], p=0.26), total cholesterol (TC) (WMD = -0.63; 95% CI [-1.23, -0.04], p=0.04), triglycerides (TG) (WMD = -0.46. 95% CI [-0.70, -0.23], p=0.0001), high-density lipoprotein cholesterol (HDL-C) (WMD = -0.32; 95% CI [0.03, 0.62], p=0.03), low-density lipoprotein cholesterol (LDL-C) (WMD = -0.57; 95% CI [-0.77, -0.37], p < 0.00001), and total effective rate (TER) (response ratio (RR) = 1.40; 95% CI [1.32, 1.48]; p < 0.00001) were concluded. The Wuling powder in the treatment of DN was statistically significant in all the above outcome indicators, and the efficacy of the treatment group was better than that of the control group. Conclusion: The results of this study provided evidence for the clinical application of Wuling powder to treat the DN, but it had to be further validated in higher-quality clinical studies.

CAR-T-Cell Therapy for Solid Tumors Positive for Fibronectin Extra Domain B.

(1) Background: The lack of specific targets has slowed the progress of CAR-T in treating solid tumors. Recent studies have revealed that EDB-FN (fibronectin extra domain B) may be an effective target for CAR-T treatment of solid tumors; EDB-FN is expressed in tumor and embryonic tissues, and antibody-cytokine fusion proteins targeting EDB-FN have been developed. However, the therapeutic effects of BBz CAR-engineered T-cells targeting EDB-FN in solid tumors have not been evaluated. (2) Results: In this study, we constructed a BBz CAR construct targeting EDB-FN, and the CAR molecule was expressed on the surface of T-cells by lentiviral transduction. In vitro, CAR-T-cells can be activated to express perforin and granzyme and lyse EDB-positive cells (U-87 MG cells, A549 cells, and HUVECs) and have no toxicity to EDB-negative cells (MCF-7). Compared to T-cells, CAR-T-cells can release cytokines after coculture with EDB-positive cell lines. In vivo, CAR-T-cells inhibited the progression of U-87 MG subcutaneous tumors and significantly reduced the blood vessel density in tumor tissue compared to T-cells, without obvious toxicity to mouse tissues and organs. Furthermore, CAR-T-cells overexpressing BiTE targeting EDB-FN can significantly improve their antitumor activity in vitro. (3) Conclusions: These results demonstrate that CAR-T-cells have specific antitumor and angiogenic activities in vivo and in vitro, suggesting that EDB-FN may be a potential solid tumor target for CAR-T therapy.

Heparosan-based self-assembled nanocarrier for zinc(II) phthalocyanine for use in photodynamic cancer therapy.

Zinc(II) phthalocyanine (ZnPc) is a promising photosensitizer in photodynamic therapy (PDT) for melanoma treatment. However, the poor solubility of ZnPc limits its application. To overcome this limitation, heparosan (HP)-based nanoparticles were prepared by anchoring the l-lysine-linked α-linolenic acid branch to the carboxylic acid group to produce amphiphilic conjugates named heparosan with an l-lysine-linked α-linolenic acid branch (HLA). HLA conjugates could self-assemble into spherical nanoparticles in aqueous media and encapsulate ZnPc to form HLA-ZnPc nanoparticles. The cellular uptake of ZnPc could be improved by HLA carriers. These nanoparticles presented excellent photodynamic-mediated toxicity against mouse melanoma cells (B16) by markedly upregulating the intracellular reactive oxygen species (ROS) levels while showing no cytotoxicity to either B16 or normal cells (L02 and HK-2 cells) in the dark. Furthermore, HLA-ZnPc displayed excellent stability in both powder and Roswell Park Memorial Institute (RPMI) 1640 medium, indicating its promise for application in drug delivery and PDT. These results revealed a strategy for HP-based enhancement of ZnPc in PDT efficacy.

Mucin-fused myeloid-derived growth factor (MYDGF164) exhibits a prolonged serum half-life and alleviates fibrosis in chronic kidney disease.

BACKGROUND AND PURPOSE: Although no effective therapy is available to stop or reverse CKD progression targeting its key feature, the loss of peritubular capillaries (PTCs) leading to interstitial fibrosis, myeloid-derived growth factor (MYDGF) with tissue-repairing activities enlightens its therapeutic potential for CKD. However, the extremely short circulatory lifetime (15 min) restricts its application. EXPERIMENTAL APPROACH: We selected a tandem repeated (TR) region of human CD164 as a carrier to fuse with MYDGF and then investigated for biophysical and pharmacokinetic changes. The MYDGF164 bioactivities were validated in HUVECs and then assessed in HK-2 cells. We also investigated its efficacy in unilateral ureteral obstruction (UUO)-treated mice and in adenine-induced CKD rats. KEY RESULTS: MYDGF164 was modified with sialoglycans, improving its resistance to serum proteases and increasing its hydrodynamic radius. The half-life of MYDGF164 was significantly prolonged but retained its original cell proliferation, anti-apoptosis, and tubulogenesis activities. It selectively stimulated the proliferation in endothelial and epithelial cells through phosphorylating MAPK1/3. MYDGF164 alleviated capillary rarefaction, hypoxia, renal fibrosis, and tubular atrophy in UUO mice and in adenine-induced CKD rats. MYDGF164 restored renal function, with normalized creatinine and urea levels in adenine-induced CKD rats. Histopathology and immunohistochemistry revealed that MYDGF164 protection was related to its cell-proliferative, anti-apoptosis, and angiogenesis activities. CONCLUSIONS AND IMPLICATIONS: This study is the first successful example of using a tandem repeated region of hCD164 as a cargo protein for the pharmacokinetic improvement of therapeutic proteins. Our findings highlight the potential of MYDGF164 in alleviating renal fibrosis in CKD.

Preparation and characterization of 2-deacetyl-3-O-sulfo-heparosan and its antitumor effects via the fibroblast growth factor receptor pathway.

Heparosan, with a linear chain of disaccharide repeating units of â†’ 4) ß-D-glucuronic acid (GlcA) (1 â†’ 4)-α-D-N-acetylglucosamine (GlcNAc) (1→, is a potential starting chemical for heparin synthesis. However, the chemoenzymatic synthesis of single-site sulfated heparosan and its antitumor activity have not been studied. In this study, 2-deacetyl-3-O-sulfo-heparosan (DSH) was prepared successively by the N-deacetylation chemical reaction and enzymatic modification of human 3-O-sulfotransferase-1 (3-OST-1). Structural characterization of DSH was shown the success of the sulfation with the sulfation degree of 0.87. High performance gel permeation chromatography (HPGPC) analysis revealed that DSH had only one symmetrical sharp peak with a molecular weight of 9.6334 × 104 Da. Biological function studies showed that DSH could inhibit tumor cell (A549, HepG2 and HCT116) viability and induce the apoptosis of A549 cells. Further in vitro mechanistic studies showed that DSH may induce apoptosis via the JNK signaling pathway, and the upstream signal of this process may be fibroblast growth factor receptors. These results indicated that DSH could be developed as one of a potential chemical for tumor treatment.

Toll-like receptor 3 ablation prevented high-fat diet-induced obesity and metabolic disorder.

Inflammation in insulin-sensitive tissues (e.g., liver, visceral adipose tissue [VAT]) plays a major role in obesity and insulin resistance. Recruitment of innate immune cells drives the dysregulation of glucose and lipid metabolism. We aimed to seek the role of Toll like receptor 3 (TLR3), a pattern recognition receptor involved in innate immunity, obesity and the metabolic disorder. TLR3 expression in liver and VAT from diet induced obese mice and in VAT from overweight women was examined. Body weight, glucose homeostasis and insulin sensitivity were evaluated in TLR3 wild-type and knockout (KO) mice on a chow diet (CD) or high-fat diet for 15 weeks. At euthanasia, blood was collected, and plasma biochemical parameters and adipokines were determined with commercial kits. Flow cytometry was used to measure macrophage infiltration and activation in VAT. Standard western blot, immunohistochemistry and quantative PCR were used to assess molecules in pathways about lipid and glucose metabolism, insulin and inflammation in tissues of liver and VAT. Utilizing human and animal samples, we found that expression of TLR3 was upregulated in the liver and VAT in obese mice as well as VAT in overweight women. TLR3-deficiency protected against high-fat diet induced obesity, glucose intolerance, insulin resistance and lipid accumulation. Lipolysis was enhanced in VAT and hepatic lipogenesis was inhibited in TLR3 KO animals. Macrophages infiltration into adipose tissue was attenuated in TLR3 KO mice, accompanied with inhibition of NF-κB-dependent AMPK/Akt signaling pathway. These findings demonstrated that TLR3 ablation prevented obesity and metabolic disorders, thereby providing new mechanistic links between inflammation and obesity and associated metabolic abnormalities in lipid/glucose metabolism.

A visible and near-infrared dual-fluorescent probe for discrimination between Cys/Hcy and GSH and its application in bioimaging.

Biothiols such as cysteine (Cys), homocysteine (Hcy) and glutathione (GSH) play important roles in various physiological and pathological processes, and due to their similar structures and reaction activities, it is still challenging to simultaneously discriminate between GSH and Cys/Hcy in vivo. Hence, a novel fluorescent probe for simultaneously discriminating GSH and Cys/Hcy in biological samples is highly desirable. Herein, we presented two enhanced fluorescent probes (Cy1 and Cy2) with doubly-activated dual emission for sensitive and discriminative detection of Cys/Hcy and GSH. The probes were constructed with IR-780 and NBD linked via an ether bond, which responds to GSH with near infrared (NIR) emission at 810 nm (λex = 720 nm) and Cys/Hcy with visible green emission at 550 nm (λex = 470 nm). The probe Cy2 is operable in human serum samples, thus holding promise for its diagnosis-related application. Notably, the results of fluorescence microscopy imaging indicated that Cy2 is suitable for visualization of exogenous and endogenous biothiols in living cells. Furthermore, desirable results were obtained when the probe Cy2 was applied for bioimaging in tumor-bearing mice and acute liver injury (ALI) mice models, which revealed encouraging clinical values of this probe.

Ambient PM2.5 chronic exposure leads to cognitive decline in mice: From pulmonary to neuronal inflammation.

Fine particulate matter 2.5 (PM2.5), one of the main components of air pollutants, seriously threatens human health. Possible neuronal dysfunction induced by PM2.5 has received extensive attention. However, there is little evidence for the specific biochemical mechanism of neuronal injury induced by PM2.5. Moreover, the pathway for PM2.5 transport from peripheral circulation to the central nervous system (CNS) is still unclear. In the current work, C57BL/6 mice were chronically exposed to ambient PM2.5 for 3, 6, 9, and 12 months. Exposure to ambient PM2.5 resulted in a significant reduction of cognitive ability in mice by Morris water maze test. PM2.5 exposure induced a neuroinflammatory reaction after cognitive impairment, while inflammation in the hypothalamus and olfactory bulb tissue occurred earlier. The expression levels of integrity tight junction proteins in the blood-brain barrier (BBB) were reduced by PM2.5 exposure. Pulmonary inflammation occurred much earlier and diminished at later stage of PM2.5 exposure. The results indicated that chronic exposure to ambient PM2.5 led to cognitive decline in mice; CNS dysfunction may be due to neuroinflammatory reactions; the reduced integrity of the BBB allowed the influence of pulmonary inflammation to neuronal alterations. The work may provide promising therapeutic or preventive targets for air pollution-induced neurodegenerative disease.

Isolation, structural characterization of polysaccharide from Cephalosporium sinensis mycelia and its anti-nephritic effects in adenine-induced CKD rats.

In this study, a new polysaccharide (CSMP, Mw = 16,685 Da) was isolated and purified from Cephalosporium sinensis mycelia. Monosaccharide composition analysis indicated that CSMP consists of mannose, glucose and galactose. A detailed structural analysis revealed that CSMP has a backbone consisting of →2,6)-ß-D-Manp-(1→ and →3,6)-ß-D-Manp-(1→, as well as two branched chains including of α-D-Manp-(1→6)-α-D-Glcp-(1→ and α-D-Glcp-(1→4)-α-D-Glcp-(1→3)-ß-D-Galp-(1→2)-ß-D-Manp-(1→ attached to C6 of →2,6)-ß-D-Manp-(1→ and →3,6)-ß-D-Manp-(1→. Orally administrated CSMP showed renal protection function in adenine-induced chronic kidney disease (CKD) rats. Further analysis demonstrated that CSMP increased relative abundance of the genera Lactobacillus group, Clostridium coccoides group and Bifidobacterium, and decreased Echerichia subgroup. CSMP increased acetate, propionate and butyrate levels both in colon and cecum. The mechanisms behind these effects could be related to the down-regulation nuclear factor kappa-B (NF-κB) level by up-regulating expression of G protein-coupled receptor 41 (GPR41) and improvement regulatory T cells (Tregs) ratio by inhibiting histone deacetylase (HDAC) activity. These results indicated that CSMP could be developed as one of the potential drugs in the treatment of CKD.

IL-1R-/- alleviates cognitive deficits through microglial M2 polarization in AD mice.

The neuroinflammatory response is considered a crucial event in the pathology of Alzheimer's disease (AD). Neurotoxic amyloid ß (Aß) oligomers activate neuronal glial cells, leading to the elevated generation of a large variety of inflammatory factors. Therefore, the regulation of interleukin-1 receptor (IL-1R) activity is believed to be a potential target for AD therapy. However, previous evidence of the role of IL-1R in AD-related neuroinflammation is ambiguous. To reveal the exact role of IL-1R in AD and related inflammatory reactions, we generated IL-1R-/- AD mice. Based on the Morris water maze results, 4-month-old IL-1R-/- AD mice showed better learning and memory ability than that of AD mice. However, IL-1R-/- had little influence on amyloid precursor protein proteolysis, while IL-1R-/- increased ADAM17 expression level. Surprisingly, IL-1R-/- even enhanced glial activation. IL-1R-/- indeed attenuated inflammatory cytokine secretion, especially that of cytokins associated with M1 polarization, while it led to increased levels of some cytokins associated with M2 polarization. Finally, we found that IL-1R-/- reduced the phagocytic ability of microglia. Taken together, these results suggest that IL-1R deficiency may alleviate cognitive deficits in AD mice in a manner that is partially dependent on ADAM17 regulation and microglia M2 repolarization.

An orally administered butyrate-releasing xylan derivative reduces inflammation in dextran sulphate sodium-induced murine colitis.

Butyrate has been shown to be effective in ulcerative colitis (UC). However, its oral administration is rare due to its rancid odour and unpleasant taste. In this study, the effect of a butyrate-releasing polysaccharide derivative, xylan butyrate ester (XylB), was evaluated in a dextran sodium sulphate (DSS)-induced UC model in C57BL/6 mice. Linear xylan was extracted from corn cobs. The C-2 and C-3 positions of the linear xylan were esterified with butyrate, forming XylB. The protective and therapeutic effects of XylB against UC were determined in a DSS-induced mouse model. The results showed that XylB treatments reversed the imbalance between pro- and anti-inflammatory cytokines. Moreover, XylB rebalanced the gut microbiota that interfered with DSS treatment and significantly decreased the relative abundance of the genera Oscillibacter, Ruminococcaceae UCG-009, Erysipelatoclostridium, and Defluviitaleaceae UCG-01. XylB increased butyrate content in the colon, upregulated G-protein coupled receptor 109A protein expression, inhibited histone deacetylase (HDAC) activity, and exerted anti-inflammatory activity through autophagy pathway activation and nuclear factor-κB (NF-κB) inhibition. XylB reduces inflammatory intestinal damage in mice, suggesting that it would be a potential drug for the treatment of UC and could be used to overcome the limitations of the oral administration of sodium butyrate.

[Role of Hippo signaling pathway in mice hypospadias induced by vinclozolin].

OBJECTIVE: To observe the role of Hippo signaling pathway in mice hypospadias induced by vinclozolin. METHODS: After 8 weeks of ICR mice were conceived, they were divided randomly into the treatment and the control groups(10 for each group). Vinclozolin was orally administraed to the pregnant mice in the treatment group with 400 mg/(kg·d) during gestation days 12-18, while those of the control group were treated with equal volume of soybean oil. About 60 days after birth, 20 penises of the mouse offspring were taken randomly from both of the two groups separately. And furthermore, the relative expression abundance of Hippo signaling pathway key genes(Mst1, Lats1, Taz, Yap), androgen receptor gene Ar of all the samples were measured by the real-time quantity reverse transcript polymerase chain reaction(qPCR). The Yes-related protein(Yap) and its phosphorylation in the downstream of Hippo signaling pathway were measured by Western blot. RESULTS: Compared with the male mice of the control group, the anal genital distances of the treatment group were significantly shortened((9. 2501±2. 5504) vs. (16. 1253±1. 3562) mm, P<0. 05), the quality of the penises was significantly less than((0. 0293±0. 0075) vs. (0. 4731±0. 004) g, P<0. 05), the length of the penises was shorter((5. 3875±0. 4524) vs. (12. 4688±1. 2290) mm, P<0. 05), and the diameters of the penises were also less than the control((1. 5513±0. 1158) vs. (2. 6013±0. 1469) mm, P<0. 05). All the genes in the penises of the control group were expressed. The Yap and Ar in the treatment group's penises were not expressed, the expression abundance of Mst1 and Lats1 was higher than that of the control(6. 6097±1. 3188 vs. 0. 3517±0. 1524, 5. 7071±2. 7210 vs. 0. 1235±0. 0658, P<0. 05), and the expression abundance of Taz was lower than that of the control(0. 3937±0. 1519 vs. 3. 2329±0. 4339, P<0. 05). The expression of Yap was decreased in the treatment group(0. 3348±0. 0639 vs. 0. 8023±0. 4275, P<0. 05), and the phosphorylation level of Yap was higher than that of the control group(3. 9940±0. 2177 vs. 0. 3128±0. 0867, P<0. 05). CONCLUSION: In the model of mice hypospadias induced by vinclozolin, the Ar was not expressed, the Hippo signaling pathway was activated and the phosphorylation of Yap was increased. This pathway may play an important role in the model.

Berberine Induces Cell Apoptosis through Cytochrome C/Apoptotic Protease-Activating Factor 1/Caspase-3 and Apoptosis Inducing Factor Pathway in Mouse Insulinoma Cells.

OBJECTIVE: To investigate apoptotic effects of berberine, a significant alkaloids component existing in Rhizoma coptidis, and its possible acting mechanism in insulinoma cells. METHODS: Different concentrations of berberine were used to treat mouse insulinoma (MIN6) cells for various period of time. The viability and apoptosis of the cells were analyzed using methylthiazolyldiphenvl-tetrazolium bromide assay, flow cytometry and enzyme-linked immuno sorbent assay. Changes in the relating pro- and anti-apoptosis proteins were detected by western-blotting. RESULTS: The half-maximal inhibitory concentration (IC50) of berberine was 5.7 µmol/L on MIN6 cells viability for 16 h. Berberine caused a 20% reduction (P<0.05) in cell number after only 4-h incubation; which reached 50% after 24 h (P<0.01). Berberine treatment for 16 h significantly increased the level of DNA fragmentation. The flow cytometry showed the apoptotic rate increased 2.9- and 4.6-fold after treating with berberine (5 µmol/L) for 8 and 16 h, while 3- and 8.7-fold after 10 µmol/L treatment for 8 and 16 h (P<0.01). Berberine treatment dramatically elevated the expression ratio of Bax to Bcl-2. Meanwhile, berberine notably increased the apoptosis-inducing factors and cytochrome C transforming from the mitochondria to the cytoplasm. Apoptotic protease-activating factor 1 (Apaf-1) was subsequently activated after cytochrome C release. Furthermore, caspase-3 and poly adenosine diphosphate-ribose polymerase were also activated to trigger apoptosis cascade. CONCLUSION: High concentration (5 and 10 µmol/L) of berberine could induce the apoptosis of MIN6 cells through cytochrome C/Apaf-1/caspase-3 and apoptosis inducing factor (AIF) pathway.