Research advances in understanding crosstalk between organs and pancreatic ß-cell dysfunction.

Obesity has increased dramatically worldwide. Being overweight or obese can lead to various conditions, including dyslipidaemia, hypertension, glucose intolerance and metabolic syndrome (MetS), which may further lead to type 2 diabetes mellitus (T2DM). Previous studies have identified a link between ß-cell dysfunction and the severity of MetS, with multiple organs and tissues affected. Identifying the associations between pancreatic ß-cell dysfunction and organs is critical. Research has focused on the interaction between the liver, gut and pancreatic ß-cells. However, the mechanisms and related core targets are still not perfectly elucidated. The aims of this review were to summarize the mechanisms of ß-cell dysfunction and to explore the potential pathogenic pathways and targets that connect the liver, gut, adipose tissue, muscle, and brain to pancreatic ß-cell dysfunction.

Correlations between growth differentiation factor 15 (GDF-15) serum levels and gene polymorphism with type 2 diabetes mellitus.

Purpose: To date, the relationship between Growth Differentiation Factor 15 (GDF-15) gene polymorphism and the risk of type 2 diabetes mellitus (T2DM) has not been clarified. Our study aims to explore the association between serum GDF-15 levels and related gene polymorphism with the risk of T2DM in a Chinese rural Yao population. Methods: This was a 1:1 case-control study with 179 T2DM patients and 179 age- and sex-matched control participants. Serum GDF-15 levels were measured by enzyme-linked immunosorbent assay, and polymorphisms (rs1059519, rs1059369, rs1804826 and rs1054564) were genotyped by MassArray mass spectrometry. Results: Serum GDF-15 (sGDF-15) levels were higher in patients with T2DM and glycosylated hemoglobin (HbA1c) ≥ 6.5 % compared to that in controls (p < 0.001). The area under the curve (AUC) corresponding to sGDF-15 levels was 0.626. Serum GDF-15 was positively correlated with fasting plasma glucose (FPG) (rs = 0.150, p < 0.001) and HbA1c (rs = 0.160, p < 0.001). The frequency of GDF-15 gene rs1054564 GC + CC genotype was significantly associated with increased risk of T2DM compared to GG genotype (OR = 1.724, 95CI: 1.046-2.841, p = 0.033). Frequencies of rs1804826 T allele (ß additive = 113.318, p = 0.026) and rs1054564 C allele (ß additive = 247.282, p = 0.001, ß dominant = 286.109, p = 0.001) was significantly correlated with higher sGDF-15. The rs1059519 C allele was negatively correlated with FPG (ß recessive = -0.607, p = 0.047) and HbA1c (ß recessive = -0.456, p = 0.020). Conclusion: Serum GDF-15 levels were positively correlated with FPG and HbA1c. The GDF-15 rs1054564 GC + CC genotype was associated with a significantly higher T2DM risk. The rs1059519 C allele was negatively correlated with FPG and HbA1c.

Association between Copper Exposure and Cognitive Function: A Cross-Sectional Study in a County, Guangxi, China.

There has been growing attention to the impact of copper exposure on cognitive function; however, current research on the specific information regarding urinary copper and cognitive function is limited, particularly detailed analyses in the Chinese adult population. This study aimed to explore the association between copper exposure and cognitive function in a cross-sectional design. A total of 2617 participants in a county, Guangxi Zhuang Autonomous Region (Guangxi), China, were included. The mini-mental state examination (MMSE) was used to assess cognitive function, and inductively coupled plasma mass spectrometry was used to measure urinary metal levels. Spearman's rank correlation was used to analyze the correlation between urinary copper levels and various cognitive function assessment indices. After adjusting for potential confounders, binary logistic regression was used to explore the association between urinary copper levels and the risk of cognitive impairment (CI) as revealed by MMSE, and restricted cubic spline regression was further used to explore the dose-response relationship. The results showed a negative correlation between urinary copper levels and orientation, attention and calculation, memory, language ability, and MMSE total scores (P < 0.05). Compared with the low copper exposure group, the high exposure group showed a 58.5% increased risk of CI (OR = 1.585, 95%CI: 1.125 to 2.235, P = 0.008). A significant linear dose-response relationship was observed between urinary copper levels and the risk of CI (P overall = 0.045, P nonlinearity = 0.081). Our findings suggest that higher copper exposure may be associated with CI in the population of a county, Guangxi, China.

Linggui Zhugan Decoction Improves High Glucose-Induced Autophagy in Podocytes.

Objective To explore the influence of Linggui Zhugan Decoction (LGZGD) on high glucose induced podocyte autophagy Methods LGZGD containing serum were prepared by intragastric administation of 4.2 g·kg-1 (low dose), 8.4 g·kg-1 (medium dose), and 12.6 g·kg-1 (high dose) LGZGD into SD rats respectively. MPC5 and AB8/13 cells were treated with 60 mmol/L glucose to establish diabetic nephropathy podocyte model in vitro. Podocytes, MPC5 and AB8.13, were divided into control group, high glucose group, low dose LGZGD group, medium dose LGZGD group, and high dose LGZGD group, respectively. For the three LGZGD groups, before LGZGD intervention, podocytes were treated with 60 mmol/L glucose for 3 days. After treated with LGZGD containing serum, cells were collected to analyze cell migration using Transwell assay, proliferation using CCK8, apoptosis and cell cycle using flow cytometry,, autophagosome formation using transmission electron microscopy, and expression levels of Beclin-1, Atg5, LC3II/I, and P62 proteins using western blot.Results Compared with the control group, the proliferation and migration of MPC5 and AB8.13 cells in high glucose group showed slightly decreased, whereas these parameters restored after intervention with low and medium concentrations of LGZGD, with the medium dose LGZGD having the best effect. Flow cytometry analysis showed that the medium dose LGZGD group had a lower apoptosis rate (P < 0.05) and higher survival rate (P > 0.05) compared to the high dose group. High glucose arrested podocytes in G1 phase, whereas LGZGD shifted podocytes from being predominant in G1 phase to increasing into G2. High dose LGZGD significanly reduced increased autophagosome formation due to high glucose in both podocytes (P < 0.05). Western blot analysis showed that Beclin-1, Atg5, LC3Ⅱ/Ⅰ, and P62 expressions were increased in MPC5 cells treated with high glucose, and reversed after adminstration of low and medium doses of LGZGD (P < 0.05). Conclusion LGZGD reduced apoptosis and enhanced autophagy in high glucose treated podocytes via regulating Beclin-1/LC3II/I/Atg5 expression.

METTL3 promotes immature dental pulp stem cells-induced angiogenesis by regulating ETS1 mRNA stability in an m6A-HuR-dependent manner.

Angiogenesis serves as the determinate element of pulp regeneration. Dental pulp stem cell (DPSC) implantation can promote the regeneration of dental pulp tissue. Herein, the role of m6A methyltransferase methyltransferase-like 3 (METTL3) in regulating DPSCs-induced angiogenesis during pulp regeneration therapy was investigated. Cell DPSC viability, HUVEC migration, and angiogenesis ability were analyzed by CCK-8 assay, wound healing, Transwell assay, and tube formation assay. The global and EST1 mRNA m6A levels were detected by m6A dot blot and Me-RIP. The interactions between E26 transformation-specific proto-oncogene 1(ETS1), human antigen R(HuR), and METTL3 were analyzed by RIP assay. The relationship between METTL3 and the m6A site of ETS1 was performed by dual-luciferase reporter assay. ETS1 mRNA stability was examined with actinomycin D. Herein, our results revealed that human immature DPSCs (hIDPSCs) showed stronger ability to induce angiogenesis than human mature DPSCs (hMDPSCs), which might be related to ETS1 upregulation. ETS1 knockdown inhibited DPSCs-induced angiogenesis. Our mechanistic experiments demonstrated that METTL3 increased ETS1 mRNA stability and expression level on DPSCs in an m6A-HuR-dependent manner. ETS1 upregulation abolished sh-METTL3's inhibition on DPSCs-induced angiogenesis. METTL3 upregulation promoted DPSCs-induced angiogenesis by enhancing ETS1 mRNA stability in an m6A-HuR-dependent manner. This study reveals a new mechanism by which m6A methylation regulates angiogenesis in DPSCs, providing new insights for stem cell-based tissue engineering.

Neohesperidin alleviates the inhibitory effect of bisphenol A on the myogenic differentiation of umbilical cord mesenchymal stem cells via the IGF1R/AKT1/RHOA signaling pathway.

Bisphenol A (BPA), a typical environmental endocrine disruptor, has raised concerns among researchers due to its toxicological effects. Whether neohesperidin (NEO) can intervene in the toxic effects of BPA remains unknown. This study aims to investigate the effects and mechanisms of NEO on the myogenic differentiation of umbilical cord-derived mesenchymal stem cells (UC-MSCs) exposed to BPA. Sheep UC-MSCs were isolated, characterized, and induced to myogenic differentiation. BPA decreased cell viability, cell migration, and the expressions of myogenic marker genes, leading to myogenic differentiation inhibition, which were reversed by NEO. Network pharmacology suggested the IGF1R/AKT1/RHOA pathway as potential targets of BPA and NEO regulating muscle development. Western blot results showed that NEO could reverse the down-regulation of the pathway proteins induced by BPA, and counteract the effects of picropodophyllin (PPP) or MK-2206 dihydrochloride (MK-2206) in the myogenic differentiation of sheep UC-MSCs. Additionally, the expression levels of (p-) IGF1R, AKT1, and RHOA were positively correlated. Taken together, the mechanisms of NEO resistance to BPA involved the IGF1R/AKT1/RHOA signaling pathway. These findings provide a scientific basis for alleviating BPA toxicity, preventing and treating muscular dysplasia, and promoting muscle damage repair.

Electron Spin Broken-Symmetry of Fe-Co Diatomic Pairs to Promote Kinetics of Bifunctional Oxygen Electrocatalysis for Zinc-Air Batteries.

Designing bifunctional catalysts to reduce the oxygen evolution reaction (OER) and oxygen reduction reaction (ORR) reaction barriers while accelerating the reaction kinetics is perceived to be a promising strategy to improve the performance of Zinc-air batteries. Unsymmetric configuration in single-atom catalysts has attracted attention due to its unique advantages in regulating electron orbitals. In this work, a seesaw effect in unsymmetric Fe-Co bimetallic monoatomic configurations is proposed, which can effectively improve the OER/ORR bifunctional activity of the catalyst. Compared with the symmetrical model of Fe-Co, a strong charge polarization between Co and Fe atoms in the unsymmetric model is detected, in whom the spin-down electrons around Co atoms are much higher than those spin-up electrons. The seesaw effect occurred between Co atoms and Fe atoms, resulting in a negative shift of the d-band center, which means that the adsorption of oxygen intermediates is weakened and more conducive to their dissociation. The optimized reaction kinetics of the catalyst leads to excellent performance in ZABs, with a peak power density of 215 mW cm-2 and stable cycling for >1300 h and >4000 cycles. Flexible Zinc-air batteries have also gained excellent performance to demonstrate their potential in the field of flexible wearables.

Adherence to a Mediterranean diet is associated with a lower risk of diabetic kidney disease among individuals with hyperglycemia: a prospective cohort study.

BACKGROUND: Type 2 diabetes is associated with a variety of complications, including micro- and macrovascular complications, neurological manifestations and poor wound healing. Adhering to a Mediterranean Diet (MED) is generally considered an effective intervention in individuals at risk for type 2 diabetes mellitus (T2DM). However, little is known about its effect with respect to the different specific manifestations of T2DM. This prompted us to explore the effect of MED on the three most significant microvascular complications of T2DM: diabetic retinopathy (DR), diabetic kidney disease (DKD), and vascular diabetic neuropathies (DN). METHODS: We examined the association between the MED and the incidence of these microvascular complications in a prospective cohort of 33,441 participants with hyperglycemia free of microvascular complications at baseline, identified in the UK Biobank. For each individual, we calculated the Alternate Mediterranean Diet (AMED) score, which yields a semi-continuous measure of the extent to which an individual's diet can be considered as MED. We used Cox proportional hazard models to analyze hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for demographics, lifestyle factors, medical histories and cardiovascular risk factors. RESULTS: Over a median of 12.3 years of follow-up, 3,392 cases of microvascular complications occurred, including 1,084 cases of diabetic retinopathy (DR), 2,184 cases of diabetic kidney disease (DKD), and 632 cases of diabetic neuropathies (DN), with some patients having 2 or 3 microvascular complications simultaneously. After adjusting for confounders, we observed that higher AMED scores offer protection against DKD among participants with hyperglycemia (comparing the highest AMED scores to the lowest yielded an HR of 0.79 [95% CIs: 0.67, 0.94]). Additionally, the protective effect of AMED against DKD was more evident in the hyperglycemic participants with T2DM (HR, 0.64; 95% CI: 0.50, 0.83). No such effect, however, was seen for DR or DN. CONCLUSIONS: In this prospective cohort study, we have demonstrated that higher adherence to a MED is associated with a reduced risk of DKD among individuals with hyperglycemia. Our study emphasizes the necessity for continued research focusing on the benefits of the MED. Such efforts including the ongoing clinical trial will offer further insights into the role of MED in the clinical management of DKD.

Selumetinib overcomes ITGA2-induced 5-fluorouracil resistance in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most malignant tumor in the world. 5-fluorouracil (5­FU) -based chemotherapy is the first-line chemotherapy scheme for CRC, whereas acquired drug resistance poses a huge obstacle to curing CRC patients and the mechanism is still obscure. Therefore, identification of genes associated with 5­FU chemotherapy and seeking second-line treatment are necessary means to improve survival and prognosis of patients with CRC. METHODS: The Cancer Therapeutics Response Portal (CTRP) database and Genomics of Drug Sensitivity in Cancer (GDSC) database were used to identify CRC-related genes and potential second-line therapies for 5-FU-resistant CRC. The single-cell RNA sequencing data for CRC tissues were obtained from a GEO dataset. The relationship between ITGA2 and 5-FU-resistant was investigated in vitro and in vivo models. RESULTS: ACOX1 and ITGA2 were identified as risk biomarkers associated with 5-FU-resistance. We developed a risk signature, consisting of ACOX1 and ITGA2, that was able to distinguish well between 5-FU-resistance and 5-FU-sensitive. The single-cell sequencing data showed that ITGA2 was mainly enriched in malignant cells. ITGA2 was negatively correlated with IC50 values of most small molecule inhibitors, of which selumetinib had the highest negative correlation. Finally, knocking down ITGA2 can make 5-FU-resistant CRC cells sensitive to 5-FU and combining with selumetinib can improve the therapeutic effect of 5-FU resistant cells. CONCLUSION: In summary, our findings demonstrated the critical role of ITGA2 in enhancing chemotherapy resistance in CRC cells and suggested that selumetinib can restore the sensitivity of chemotherapy-resistant CRC cells to 5-FU by inhibiting ITGA2 expression.

The levels of women's awareness, experience, acceptability and preference for Vaginal Human Papillomavirus (HPV) self-sampling in three provinces of China: a cross-sectional study.

BACKGROUND: The primary screening technique for precancerous lesions and cervical cancer is human papillomavirus (HPV) testing, and HPV self-sampling has been shown to be consistent with clinician sampling in terms of the accuracy of the results and may improve cervical cancer screening rates. The aim of this study was to understand the level of awareness, experience, acceptability, and preference for vaginal HPV self-sampling among women in Jiangsu, Zhejiang, and Shanghai, China, and to analyze the possible influencing factors to determine the feasibility of implementing self-sampling. METHODS: Overall, 1793 women were included in the data analysis. A self-administered questionnaire was utilized. In addition to descriptive analysis, univariate and multivariate analyses were used to explore the associations between sociodemographic features, history of cervical cancer screening, and the level of awareness, experience, acceptability, and preference for HPV self-samples. RESULTS: The participants' level of awareness of and experience with HPV self-sampling were moderate. A total of 88.8% of participants rated the acceptability as "high", and self-sampling was preferred by 64.2% of them for cervical cancer screening. People aged 45 to 54 years showed a preference for both clinician sampling(OR = 1.762 (1.116-2.163)) and self-sampling (OR = 1.823 (1.233-2.697)). Those who had graduated from high school or above (OR = 2.305 (1.517-3.503), OR = 2.432 (1.570-3.768), OR = 3.258 (2.024-5.244)) preferred clinician-sampling, and those with a bachelor's degree or above (OR = 1.664 (1.042-2.657)) preferred self-sampling. Middle- and high-income individuals showed no preference for either sampling method (OR < 1). CONCLUSIONS: HPV self-sampling is widely accepted, but awareness, experience and preferences need to be improved. These results may help to adjust public health strategies for the early inclusion of HPV self-sampling as a screening method in national initiatives to prevent cervical cancer.

Treatment of Ulnar Coronoid Process Fracture Using the Anterior Neurovascular Interval Approach: A Retrospective Clinical Study with Short- to Mid-term Follow-up.

OBJECTIVE: Numerous surgical techniques for addressing ulnar coronoid process fractures are available; however, a consensus on the optimal approach remains elusive. This study aimed to use the anterior neurovascular interval approach for the surgical management of ulnar coronoid process fractures and to evaluate its clinical outcomes over short- to mid-term follow-up. METHODS: This retrospective clinical study included 20 patients with ulnar coronoid process fractures who were treated using the anterior neurovascular interval approach between January 2018 and December 2022. Participants comprised 16 males and four females, aged between 20 and 64 years (mean, 34.3 ± 12.44 years). Clinical and radiological evaluations were based on elbow joint range of motion (ROM), Visual analogue scale (VAS), and Mayo elbow performance score (MEPS). A paired t-test was used to compare the pre-operative and final follow-up VAS and MEPS scores. RESULTS: The follow-up duration for all patients was at least 12 months (average, 12.65 ± 1.60 months). At the final follow-up, measurements of elbow ROM included a mean extension of 2.85 ± 3.17°, mean flexion of 135 ± 7.25°, mean pronation of 86.4 ± 4.56°, and mean supination of 84.85 ± 5.54°. All participants reached their target MEPS, with an average score of 97.25 ± 4.72 points, and the final mean VAS score was 0.2 ± 0.52 points. The VAS score was significantly lower and MEPS score was higher at the final follow-up than those before surgery (p < 0.05). Throughout the follow-up period, all the fractures united, and the stability of the affected elbows was satisfactory. CONCLUSION: Employing the anterior neurovascular interval approach for open reduction and internal fixation to manage coronoid process fractures effectively facilitates anatomical restoration and robust fixation of ulnar coronoid process fractures.

Tanshinone IIA Liposomes Treat Doxorubicin-Induced Glomerulonephritis by Modulating the Microenvironment of Fibrotic Kidneys.

Renal fibrosis plays a key role in the pathogenesis of chronic kidney disease (CKD), in which the persistent high expression of transforming growth factor ß1 (TGF-ß1) and α-smooth muscle actin (α-SMA) contributes to the progression of CKD to renal failure. In order to improve the solubility, bioavailability, and targeting of tanshinone IIA (Tan IIA), a novel targeting material, aminoethyl anisamide-polyethylene glycol-1,2-distearoyl-sn-glycero-3-phosphate ethanolamine (AEAA-PEG-DSPE, APD) modified Tan IIA liposomes (APD-Tan IIA-L) was constructed. An animal model of glomerulonephritis induced by doxorubicin in BALB/c mice was established. APD-Tan IIA-L significantly decreased blood urea nitrogen and serum creatinine (SCr), and the consequences of renal tissue oxidative stress indicators showed that APD-Tan IIA-L downregulated malondialdehyde, upregulated superoxide dismutase, catalase, and glutathione peroxidase. Masson's trichrome staining showed that the deposition of collagen in the APD-Tan IIA-L group decreased significantly. The pro-fibrotic factors (fibronectin, collagen I, TGF-ß1, and α-SMA) and epithelial-mesenchymal transition marker (N-cadherin) were significantly inhibited by APD-Tan IIA-L. By improving the microenvironment of fibrotic kidneys, APD-Tan IIA-L attenuated TGF-ß1-induced excessive proliferation of fibroblasts and alleviated oxidative stress damage to the kidney, providing a new strategy for the clinical treatment of renal fibrosis.

IDEAL-IQ combined with intravoxel incoherent motion diffusion-weighted imaging for quantitative diagnosis of osteoporosis.

BACKGROUND: Osteoporosis (OP) is a common chronic metabolic bone disease characterized by decreased bone mineral content and microstructural damage, leading to increased fracture risk. Traditional methods for measuring bone density have limitations in accurately distinguishing vertebral bodies and are influenced by vertebral degeneration and surrounding tissues. Therefore, novel methods are needed to quantitatively assess changes in bone density and improve the accurate diagnosis of OP. METHODS: This study aimed to explore the applicative value of the iterative decomposition of water and fat with echo asymmetry and least-squares estimation-iron (IDEAL-IQ) sequence combined with intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) for the diagnosis of osteoporosis. Data from 135 patients undergoing dual-energy X-ray absorptiometry (DXA), IDEAL-IQ, and IVIM-DWI were prospectively collected and analyzed. Various parameters obtained from IVIM-DWI and IDEAL-IQ sequences were compared, and their diagnostic efficacy was evaluated. RESULTS: Statistically significant differences were observed among the three groups for FF, R2*, f, D, DDC values, and BMD values. FF and f values exhibited negative correlations with BMD values, with r=-0.313 and - 0.274, respectively, while R2*, D, and DDC values showed positive correlations with BMD values, with r = 0.327, 0.532, and 0.390, respectively. Among these parameters, D demonstrated the highest diagnostic efficacy for osteoporosis (AUC = 0.826), followed by FF (AUC = 0.713). D* exhibited the lowest diagnostic performance for distinguishing the osteoporosis group from the other two groups. Only D showed a significant difference between genders. The AUCs for IDEAL-IQ, IVIM-DWI, and their combination were 0.74, 0.89, and 0.90, respectively. CONCLUSIONS: IDEAL-IQ combined with IVIM-DWI provides valuable information for the diagnosis of osteoporosis and offers evidence for clinical decisions. The superior diagnostic performance of IVIM-DWI, particularly the D value, suggests its potential as a more sensitive and accurate method for diagnosing osteoporosis compared to IDEAL-IQ. These findings underscore the importance of integrating advanced imaging techniques into clinical practice for improved osteoporosis management and highlight the need for further research to explore the full clinical implications of these imaging modalities.

Initial COVID-19 severity influenced by SARS-CoV-2-specific T cells imprints T-cell memory and inversely affects reinfection.

The immunoprotective components control COVID-19 disease severity, as well as long-term adaptive immunity maintenance and subsequent reinfection risk discrepancies across initial COVID-19 severity, remain unclarified. Here, we longitudinally analyzed SARS-CoV-2-specific immune effectors during the acute infection and convalescent phases of 165 patients with COVID-19 categorized by severity. We found that early and robust SARS-CoV-2-specific CD4+ and CD8+ T cell responses ameliorate disease progression and shortened hospital stay, while delayed and attenuated virus-specific CD8+ T cell responses are prominent severe COVID-19 features. Delayed antiviral antibody generation rather than titer level associates with severe outcomes. Conversely, initial COVID-19 severity imprints the long-term maintenance of SARS-CoV-2-specific adaptive immunity, demonstrating that severe convalescents exhibited more sustained virus-specific antibodies and memory T cell responses compared to mild/moderate counterparts. Moreover, initial COVID-19 severity inversely correlates with SARS-CoV-2 reinfection risk. Overall, our study unravels the complicated interaction between temporal characteristics of virus-specific T cell responses and COVID-19 severity to guide future SARS-CoV-2 wave management.

Bone protective effects of the polysaccharides from Grifola frondosa on ovariectomy-induced osteoporosis in mice via inhibiting PINK1/Parkin signaling, oxidative stress and inflammation.

BACKGROUND: Polysaccharides from Grifola frondosa(GFP) have gained worldwide attention owing to their promising biological activities and potential health benefits. PURPOSE: This study aimed to investigate the effects of GFP on alleviation of osteoporosis in ovariectomized (OVX) mice and examine the underlying mechanism. METHOD: A mouse model of postmenopausal osteoporosis was established by OVX method, Forty eight C57BL/6 female mice were randomly divided into Normal group, OVX alone (Model group, n = 8), OVX + 10 mg/kg GFP (GFP-L group, n = 8), OVX + 20 mg/kg GFP (GFP-M group, n = 8), OVX + 40 mg/kg GFP (GFP-H group, n = 8), OVX + 10 mg/kg Estradiol valerate (Positive group, n = 8). RESULTS: The results showed that compared with Model group, the concentrations of interleukin (IL)-1ß, interleukin (IL)-6 and Tumor necrosis factor-α (TNF-α) were significantly reduced, the activity of superoxide dismutase (SOD) and glutathione (GSH) were significantly increased, the content of myeloperoxidase (MPO) and malondialdehyde (MDA) were significantly reduced, and the proteins levels of PINK1, Parkin, Beclin-1 and LC3-II were significantly decreased in the GFP groups. CONCLUSION: This study demonstrates that GFP alleviates ovariectomy-induced osteoporosis via reduced secretion of inflammatory cytokines, improvement in the oxidative stress status in the body, and inhibition of the PINK1/Parkin signaling pathway.

Exosomes derived from induced cardiopulmonary progenitor cells alleviate acute lung injury in mice.

Cardiopulmonary progenitor cells (CPPs) constitute a minor subpopulation of cells that are commonly associated with heart and lung morphogenesis during embryonic development but completely subside after birth. This fact offers the possibility for the treatment of pulmonary heart disease (PHD), in which the lung and heart are both damaged. A reliable source of CPPs is urgently needed. In this study, we reprogrammed human cardiac fibroblasts (HCFs) into CPP-like cells (or induced CPPs, iCPPs) and evaluated the therapeutic potential of iCPP-derived exosomes for acute lung injury (ALI). iCPPs were created in passage 3 primary HCFs by overexpressing GLI1, WNT2, ISL1 and TBX5 (GWIT). Exosomes were isolated from the culture medium of passage 6-8 GWIT-iCPPs. A mouse ALI model was established by intratracheal instillation of LPS. Four hours after LPS instillation, ALI mice were treated with GWIT-iCPP-derived exosomes (5 × 109, 5 × 1010 particles/mL) via intratracheal instillation. We showed that GWIT-iCPPs could differentiate into cell lineages, such as cardiomyocyte-like cells, endothelial cells, smooth muscle cells and alveolar epithelial cells, in vitro. Transcription analysis revealed that GWIT-iCPPs have potential for heart and lung development. Intratracheal instillation of iCPP-derived exosomes dose-dependently alleviated LPS-induced ALI in mice by attenuating lung inflammation, promoting endothelial function and restoring capillary endothelial cells and the epithelial cells barrier. This study provides a potential new method for the prevention and treatment of cardiopulmonary injury, especially lung injury, and provides a new cell model for drug screening.

Association between multiple-heavy-metal exposures and systemic immune inflammation in a middle-aged and elderly Chinese general population.

BACKGROUND: Exposure to heavy metals alone or in combination can promote systemic inflammation. The aim of this study was to investigate potential associations between multiple plasma heavy metals and markers of systemic immune inflammation. METHODS: Using a cross-sectional study, routine blood tests were performed on 3355 participants in Guangxi, China. Eight heavy metal elements in plasma were determined by inductively coupled plasma mass spectrometry. Immunoinflammatory markers were calculated based on peripheral blood WBC and its subtype counts. A generalised linear regression model was used to analyse the association of each metal with the immunoinflammatory markers, and the association of the metal mixtures with the immunoinflammatory markers was further assessed using weighted quantile sum (WQS) regression. RESULTS: In the single-metal model, plasma metal Fe (log10) was significantly negatively correlated with the levels of immune-inflammatory markers SII, NLR and PLR, and plasma metal Cu (log10) was significantly positively correlated with the levels of immune-inflammatory markers SII and PLR. In addition, plasma metal Mn (log10 conversion) was positively correlated with the levels of immune inflammatory markers NLR and PLR. The above associations remained after multiple corrections. In the mixed-metal model, after WQS regression analysis, plasma metal Cu was found to have the greatest weight in the positive effects of metal mixtures on SII and PLR, while plasma metals Mn and Fe had the greatest weight in the positive effects of metal mixtures on NLR and LMR, respectively. In addition, blood Fe had the greatest weight in the negative effects of the metal mixtures for SII, PLR and NLR. CONCLUSION: Plasma metals Cu and Mn were positively correlated with immunoinflammatory markers SII, NLR and PLR. While plasma metal Fe was negatively correlated with immunoinflammatory markers SII, NLR, and PLR.

Associations of Heavy Metals with Cognitive Function: An Epigenome-Wide View of DNA Methylation and Mediation Analysis.

OBJECTIVE: Exposure to heavy metals has been reported to be associated with impaired cognitive function, but the underlying mechanisms remain unclear. This pilot study aimed to identify key heavy metal elements associated with cognitive function and further explore the potential mediating role of metal-related DNA methylation. METHODS: Blood levels of arsenic, cadmium, lead, copper, manganese, and zinc and genome-wide DNA methylations were separately detected in peripheral blood in 155 older adults. Cognitive function was evaluated using the Mini-Mental State Examination (MMSE). Least absolute shrinkage and selection operator penalized regression and Bayesian kernel machine regression were used to identify metals associated with cognitive function. An epigenome-wide association study examined the DNA methylation profile of the identified metal, and mediation analysis investigated its mediating role. RESULTS: The MMSE scores showed a significant decrease of 1.61 (95% confidence interval [CI]: -2.64, -0.59) with each 1 standard deviation increase in ln-transformed arsenic level; this association was significant in multiple-metal models and dominated the overall negative effect of 6 heavy metal mixture on cognitive function. Seventy-three differentially methylated positions were associated with blood arsenic (p < 1.0 × 10-5). The methylation levels at cg05226051 (annotated to TDRD3) and cg18886932 (annotated to GAL3ST3) mediated 24.8% and 25.5% of the association between blood arsenic and cognitive function, respectively (all p < 0.05). INTERPRETATION: Blood arsenic levels displayed a negative association with the cognitive function of older adults. This finding shows that arsenic-related DNA methylation alterations are critical partial mediators that may serve as potential biomarkers for further mechanism-related studies. ANN NEUROL 2024;96:87-98.