Angiostrongylus cantonensis induces energy imbalance and dyskinesia in mice by reducing the expression of melanin-concentrating hormone.

BACKGROUND: Infection with Angiostrongylus cantonensis (AC) in humans or mice can lead to severe eosinophilic meningitis or encephalitis, resulting in various neurological impairments. Developing effective neuroprotective drugs to improve the quality of life in affected individuals is critical. METHODS: We conducted a Gene Ontology enrichment analysis on microarray gene expression (GSE159486) in the brains of AC-infected mice. The expression levels of melanin-concentrating hormone (MCH) were confirmed through real-time quantitative PCR (RT-qPCR) and immunofluorescence. Metabolic parameters were assessed using indirect calorimetry, and mice's energy metabolism was evaluated via pathological hematoxylin and eosin (H&E) staining, serum biochemical assays, and immunohistochemistry. Behavioral tests assessed cognitive and motor functions. Western blotting was used to measure the expression of synapse-related proteins. Mice were supplemented with MCH via nasal administration. RESULTS: Postinfection, a marked decrease in Pmch expression and the encoded MCH was observed. Infected mice exhibited significant weight loss, extensive consumption of sugar and white fat tissue, reduced movement distance, and decreased speed, compared with the control group. Notably, nasal administration of MCH countered the energy imbalance and dyskinesia caused by AC infection, enhancing survival rates. MCH treatment also increased the expression level of postsynaptic density protein 95 (PSD95) and microtubule-associated protein-2 (MAP2), as well as upregulated transcription level of B cell leukemia/lymphoma 2 (Bcl2) in the cortex. CONCLUSIONS: Our findings suggest that MCH improves dyskinesia by reducing loss of synaptic proteins, indicating its potential as a therapeutic agent for AC infection.

Research progress on Sirtuins (SIRTs) family modulators.

Sirtuins (SIRTs) represent a class of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that exert a crucial role in cellular signal transduction and various biological processes. The mammalian sirtuins family encompasses SIRT1 to SIRT7, exhibiting therapeutic potential in counteracting cellular aging, modulating metabolism, responding to oxidative stress, inhibiting tumors, and improving cellular microenvironment. These enzymes are intricately linked to the occurrence and treatment of diverse pathological conditions, including cancer, autoimmune diseases, and cardiovascular disorders. Given the significance of histone modification in gene expression and chromatin structure, maintaining the equilibrium of the sirtuins family is imperative for disease prevention and health restoration. Mounting evidence suggests that modulators of SIRTs play a crucial role in treating various diseases and maintaining physiological balance. This review delves into the molecular structure and regulatory functions of the sirtuins family, reviews the classification and historical evolution of SIRTs modulators, offers a systematic overview of existing SIRTs modulation strategies, and elucidates the regulatory mechanisms of SIRTs modulators (agonists and inhibitors) and their clinical applications. The article concludes by summarizing the challenges encountered in SIRTs modulator research and offering insights into future research directions.

SIRT6 Reduces Rheumatoid Arthritis Injury by Inhibiting MyD88-ERK Signaling Pathway.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease characterized by destruction of synovial joints, abnormal immune responses and chronic inflammatory manifestations, which seriously affects patients' well-being. We explored this study to ascertain the effect and mechanism of silent information regulator 6 (SIRT6) on RA. METHODS: Genes of RA patients and normal volunteers were analyzed using Gene Expression Omnibus (GEO), Kyoto-Encyclopedia of Genes and Genomes (KEGG) and Disconet databases. Serum samples of RA patients and normal subjects were collected before detection of myeloid differentiation factor-88 (MyD88)-extracellular signal-regulated kinase (ERK) pathway proteins expression with Western blot. In vitro RA fibroblast-like synoviocytes (FLS) cell model (RA-FLS) was established by treating RSC-364 with recombinant rat IL-1ß (10 ng/mL) after which SIRT6 and MyD88 adenoviruses treatment was carried out. The enzyme linked immunoassay (ELISA), real time polymerase chain reaction (RT-PCR) and Western blot were respectively used to measure inflammatory factors, related messenger ribonucleic acid (mRNA) and protein expressions. Also, we constructed RA rat model with bovine type II collagen (BIIC) and complete Freund's adjuvant, before treatment with SIRT6 and MyD88 adenoviruses. RESULTS: Low expression of SIRT6 gene were detected in RA patients. Also, levels of MyD88, ERK and phosphorylated extracellular signal-regulated protein kinase (p-ERK) protein expressions in RA patients were increased, whilst that of SIRT6 protein decreased. Compared to FLS cells in Control group, inflammatory factors levels of rats in Model batch increased significantly. SIRT6 adenovirus treatment potentially and significantly inhibited inflammation including suppression of increased inflammatory factors induced by MyD88. In comparison with FLS cells in Control group, Model batch cells' MyD88, interleukin (IL)-1ß, IL-21, IL-22, IL-6, IL-17, tumor necrosis factor-alpha (TNF-α) and monocyte chemo-attractant protein-1 (MCP-1) mRNA expressions increased but SIRT6 gene treatment could reduce mRNA expression of the aforesaid factors, even after MyD88 adenovirus treatment. Besides, overpressed SIRT6 negatively regulated levels of MyD88, ERK and p-ERK proteins expressions. SIRT6 demonstrated anti-RA effect by regulating MyD88-ERK pathway and inhibiting inflammatory response in RA rats. CONCLUSIONS: SIRT6 could potentially inhibit the inflammatory response of RA via a regulatory mechanism mainly relating to MyD88-ERK signal pathway. Thus, SIRT6 and its agonists may serve as new targets for developing drugs that can potentially treat RA.

[Spatial Distribution, Risk, and Influencing Factors of River Water-Sediment Heavy Metals in the Lower Reaches of the Qianhe River].

The spatial distribution of heavy metals in rivers is affected by human activities and the natural environment, posing a risk to human health related to heavy metal pollution. In order to study the characteristics, health risk levels, and influencing factors of heavy metal distribution and pollution in the lower reaches of the Qianhe River, 19 surface sediments and 20 water samples were collected, and the contents of As, Cd, Cr, Cu, Mn, Ni, Pb, and Zn were measured by inductively coupled plasma mass spectrometry(ICP-MS). Using the DEM, air temperature, precipitation and other 11 factors as independent variables, the spatial differentiation of heavy metal pollution in sediments were explored based on geo-detector and geo-weighted regression model. The results showed that the eight heavy metal contents in the lower reaches of the Qianhe River did not exceed the "Surface Water Environmental Quality Standards" Ⅱ for water-like bodies, in which the variation coefficient of Pb element was 3.11, and the high content areas were mainly concentrated around Dongling Smelting Company and Fengxiang Railway Station. The average Rc value of adult carcinogens in water bodies was 7.72 E-06, showing a low risk level, and the children's carcinogens average Rc value was 1.17 E-04, showing a strong risk degree. The non-carcinogen risks for adults and children were both tolerable. The total high R value for children was mainly concentrated around Fengxiang Railway Station, posing a high risk. Sedimentation of heavy metals, except As and Mn, exceeded the soil background value in Shaanxi Province. The average content of Cd element was 1.12 mg·kg-1, which was 12 times the soil background value in Shaanxi Province. The pollution of Cd, Zn, and Pb was high, and distributed mainly in Changqing Village, Nanwan Village and Niujiatan Village, Gaozhuang, and Dongling Smelting Company. PLIzone of heavy metals in the sediments in the study area was 1.71, which was light pollution. DEM, temperature and precipitation were the main natural factors influencing the spatial pattern of heavy metal pollution load index(PLI) in sediments, and their nonlinear interactions were enhanced, which may play a role in the spread of heavy metals in sediments. This research can provide a scientific basis for urban planning and human health risks prevention in the Qianhe River.

Systemic inflammatory response index as an independent risk factor for ischemic stroke in patients with rheumatoid arthritis: a retrospective study based on propensity score matching.

OBJECTIVE: To investigate the relationship between systemic inflammatory response index (SIRI) and ischemic stroke (IS) in rheumatoid arthritis (RA) patients. METHODS: Fifty-two RA patients with IS, who were admitted to Wujin Hospital Affiliated with Jiangsu University between 2015 and 2019, were selected as the study group, and 236 RA patients without IS were selected as the control group. Propensity score matching (PSM) function of SPSS 26.0 was used to carry out 1:1 propensity score matching for gender, age, blood pressure, blood glucose, blood lipid, and smoking history of patients in the two groups, and the caliper value was set as 0.02 to obtain covariate balanced samples between groups. When performing blood tests, the following are determined: rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), mean platelet volume (MPV), calculated SIRI = (neutrophil × monocyte)/lymphocyte, and completed 28-joint disease activity score (DAS28-CRP). The differences in inflammatory markers between the two groups were compared, the independent risk factors were analyzed by logistic regression, and the auxiliary diagnostic value was evaluated by the receiver operating characteristic (ROC) curve. RESULTS: A total of 48 pairs of patients were successfully matched. SIRI in the study group was higher than that in the control group (p < 0.05), and the mean platelet volume (MPV) was lower in the study group than in the control group (p < 0.05). SIRI, DAS28-CRP (r = 0.508, p < 0.01), ESR (r = 0.359, p < 0.05), and CRP (r = 0.473, p < 0.01) were positively correlated. Logistic regression analysis showed that SIRI was an independent IS risk factor in RA patients (odds ratio, 1.30; 95% confidence interval, approximately 1.008-1.678). The optimal threshold for SIRI-assisted diagnosis of patients with RA and IS was 1.62, the area under the ROC curve was 0.721 (p < 0.01), sensitivity was 54.17%, and specificity was 83.33%. CONCLUSION: SIRI was independently associated with the occurrence of ischemic stroke in patients with RA. Thus, RA patients with elevated SIRI should be closely monitored. Key points • RA patients with IS had fewer traditional risk factors such as hypertension and diabetes, while inflammatory indicators were significantly increased. • The SIRI have drawn attention in recent years as novel non-specific inflammatory markers. However, only a few studies have been conducted to investigate their value in RA. • This study completes the gaps in the research on the relationship between SIRI and the risk of IS occurrence in RA patients.

Overexpression of P2X4 receptor in Schwann cells promotes motor and sensory functional recovery and remyelination via BDNF secretion after nerve injury.

Of the seven P2X receptor subtypes, P2X4 receptor (P2X4R) is widely distributed in the central nervous system, including in neurons, astrocytes, and microglia. Accumulating evidence supports roles for P2X4R in the central nervous system, including regulating cell excitability, synaptic transmission, and neuropathic pain. However, little information is available about the distribution and function of P2X4R in the peripheral nervous system. In this study, we find that P2X4R is mainly localized in the lysosomes of Schwann cells in the peripheral nervous system. In cultured Schwann cells, TNF-a not only enhances the synthesis of P2X4R protein but also promotes P2X4R trafficking to the surface of Schwann cells. TNF-a-induced BDNF secretion in Schwann cells is P2X4R dependent. in vivo experiments reveal that expression of P2X4R in Schwann cells of injured nerves is strikingly upregulated following nerve crush injury. Moreover, overexpression of P2X4R in Schwann cells by genetic manipulation promotes motor and sensory functional recovery and accelerates nerve remyelination via BDNF release following nerve injury. Our results suggest that enhancement of P2X4R expression in Schwann cells after nerve injury may be an effective approach to facilitate the regrowth and remyelination of injured nerves.