Shugan Jieyu capsule effects on peripheral blood micro-124, micro-132, and brain-derived neurotrophic factor in patients with mild to moderate depression.

BACKGROUND: To assess the effectiveness of Shugan Jieyu capsules on peripheral blood miR-124, miR-132, and brain-derived neurotrophic factor (BDNF) levels in patients with mild to moderate depression following coronary artery intervention [percutaneous coronary intervention (PCI)] for coronary heart disease. AIM: To evaluate the therapeutic efficacy of Shugan Jieyu capsules and their effects on the peripheral blood levels of miR-124, miR-132, and BDNF in patients with mild to moderate depression following PCI for coronary heart disease. METHODS: Patients with mild-to-moderate depression of the liver-qi stagnation type after PCI for coronary heart disease at the 305th Hospital of the People's Liberation Army were enrolled from June 2022 to November 2023 and randomly assigned to two groups: Experimental (treated with Shugan Jieyu capsules) and control (treated with escitalopram oxalate tablets). This study compared the antidepressant effects of these treatments using 17-item Hamilton Rating Scale for Depression (HAMD-17) scores, metabolic equivalents, low-density lipoprotein cholesterol, BDNF, high-sensitivity C-reactive protein levels, miR-124 and miR-132 levels, distribution of immune-related lymphocyte subsets, and traditional Chinese medicine syndrome scores before and after 6 weeks of treatment. RESULTS: No significant difference was observed in any index between the two groups before treatment (P > 0.05). After treatment, the total efficacy rates were 93.33% and 90.00% in the experimental and control groups, respectively. Experimental group had significantly lower scores for the main and secondary syndromes compared to the control group (P < 0.05). No significant difference was observed in the metabolic equivalents between the two groups before and after treatment (P > 0.05). The levels of low-density lipoprotein cholesterol, high-sensitivity C-reactive protein, and miR-132 were significantly lower, whereas those of miR-124, BDNF, CD3+T lymphocytes, CD3+CD4+T helper lymphocytes, and CD3+CD4+/CD3+CD8+ cells were significantly higher in the experimental group compared to the control group (P < 0.05). The incidence of adverse reactions during experimental group was significantly lower than that in control group (P < 0.05). CONCLUSION: Shugan Jieyu capsules have good efficacy in patients with mild-to-moderate depression after PCI, and its mechanism may contribute to the regulation of miR-124, miR-132, BDNF levels, and lymphoid immune cells.

An Investigation of the Correlation Between Retinal Nerve Fiber Layer Thickness with Blood Biochemical Indices and Cognitive Dysfunction in Patients with Type 2 Diabetes Mellitus.

Objective: The study aimed to explore the correlation between retinal nerve fiber layer thickness (RNFLT) with blood biochemical indicators and cognitive dysfunction in patients with type 2 diabetes mellitus (T2DM) and the possible mechanism, thereby providing more theoretical basis for the occurrence and prevention of diabetes related complications. Methods: Eighty T2DM patients treated in our hospital from March 2022 to September 2022 were selected as the study subjects, and the clinical data of the patients were retrospectively analyzed. All patients underwent fundus fluorescein angiography (FFA) to analyze the changes in retinal blood vessels. Patients who met the inclusion criteria were divided as the diabetic retinopathy (DR) group (n=46) and simple diabetes group (n=34). The RNFLT, blood biochemical indexes and changes in cognitive functions of the patients were detected. The correlation between RNFLT with blood biochemical indexes and cognitive dysfunction was analyzed. Results: Compared with the simple diabetes group, patients in the DR group had much lower mean, nasal, inferior and superior thicknesses (P<0.01). There existed no significant difference in blood pressure, body mass index (BMI), blood lipids (triglycerides, cholesterol, low-density lipoprotein, high-density lipoprotein) between the two groups (P>0.05). Compared with the simple diabetes group, patients in the DR group had much higher fasting blood glucose (FBG), hemoglobin A1c (HbA1c), fasting insulin (FINS), insulin resistance (HOMA-IR) index, apolipoprotein B (ApoB)/apolipoprotein A1 (ApoA1) (P<0.001). Besides, the DR group had sharply lower scores on the Mini-Mental State Examination (MMSE) scale and higher levels of the Trail Making Test-A (TMT-A) and TMT-B (P<0.001). Spearman correlation analysis confirmed that the mean RNFLT was negatively correlated with the levels of FBG, HbA1c, HOMA-IR index, TMT-A and TMT-B (P<0.05), positively correlated with the score of mini-mental state examination (MMSE) (P<0.05), and was no significant correlation with FINS and ApoB/ApoA1 (P>0.05). Conclusion: DR patients had significantly reduced RNFLT, elevated levels of blood glucose related indicators, and cognitive dysfunction. There existed a correlation between RNFLT and FBG, HbA1c, HOMA-IR index, TMT-A, TMT-B and MMSE.

Industry Perspective on First-in-Human and Clinical Pharmacology Strategies to Support Clinical Development of T-Cell Engaging Bispecific Antibodies for Cancer Therapy.

T-cell-engaging bispecific antibodies (TCEs) that target tumor antigens and T cells have shown great promise in treating cancer, particularly in hematological indications. The clinical development of TCEs often involves a lengthy first-in-human (FIH) trial with many dose-escalation cohorts leading up to an early proof of concept (POC), enabling either a no-go decision or dose selection for further clinical development. Multiple factors related to the target, product, disease, and patient population influence the efficacy and safety of TCEs. The intricate mechanism of action limits the translatability of preclinical models to the clinic, thereby posing challenges to streamline clinical development. In addition, unlike traditional chemotherapy, the top dose and recommended phase II doses (RP2Ds) for TCEs in the clinic are often not guided by the maximum tolerated dose (MTD), but rather based on the integrated dose-response assessment of the benefit/risk profile. These uncertainties pose complex challenges for translational and clinical pharmacologists (PK/PD scientists), as well as clinicians, to design an efficient clinical study that guides development. To that end, experts in the field, under the umbrella of the American Association of Pharmaceutical Scientists, have reviewed learnings from published literature and currently marketed products to share perspectives on the FIH and clinical pharmacology strategies to support early clinical development of TCEs.

Characteristics of the gut microbiota and serum metabolites in postmenopausal women with reduced bone mineral density.

Introduction: Emerging evidence suggests that the gut microbiota is closely associated with bone homeostasis. However, little is known about the relationships among the bone mineral density (BMD) index, bone turnover markers, and the gut microbiota and its metabolites in postmenopausal women. Methods: In this study, to understand gut microbiota signatures and serum metabolite changes in postmenopausal women with reduced BMD, postmenopausal individuals with normal or reduced BMD were recruited and divided into normal and OS groups. Feces and serum samples were collected for 16S rRNA gene sequencing, liquid chromatography coupled with mass spectrometry (LC-MS)-based metabolomics and integrated analysis. Results: The results demonstrated that bacterial richness and diversity were greater in the OS group than in the normal group. Additionally, distinguishing bacteria were found among the two groups and were closely associated with the BMD index and bone turnover markers. Metabolomic analysis revealed that the expression of serum metabolites, such as etiocholanolone, testosterone sulfate, and indole-3-pyruvic acid, and the corresponding signaling pathways, especially those involved in tryptophan metabolism, fatty acid degradation and steroid hormone biosynthesis, also changed significantly. Correlation analysis revealed positive associations between normal group-enriched Bacteroides abundance and normal group-enriched etiocholanolone and testosterone sulfate abundances; in particular, Bacteroides correlated positively with BMD. Importantly, the tryptophan-indole metabolism pathway was uniquely metabolized by the gut bacteria-derived tnaA gene, the predicted abundance of which was significantly greater in the normal group than in the control group, and the abundance of Bacteroides was strongly correlated with the tnaA gene. Discussion: Our results indicated a clear difference in the gut microbiota and serum metabolites of postmenopausal women. Specifically altered bacteria and derived metabolites were closely associated with the BMD index and bone turnover markers, indicating the potential of the gut microbiota and serum metabolites as modifiable factors and therapeutic targets for preventing osteoporosis.

Comparison of dose selection based on target engagement versus inhibition of receptor-ligand interaction for checkpoint inhibitors.

Immune checkpoint inhibitors block the interaction between a receptor on one cell and its ligand on another cell, thus preventing the transduction of an immunosuppressive signal. While inhibition of the receptor-ligand interaction is key to the pharmacological activity of these drugs, it can be technically challenging to measure these intercellular interactions directly. Instead, target engagement (or receptor occupancy) is commonly measured, but may not always be an accurate predictor of receptor-ligand inhibition, and can be misleading when used to inform clinical dose projections for this class of drugs. In this study, a mathematical model explicitly representing the intercellular receptor-ligand interaction is used to compare dose prediction based on target engagement or receptor-ligand inhibition for two checkpoint inhibitors, atezolizumab and magrolimab. For atezolizumab, there is little difference between target engagement and receptor-ligand inhibition, but for magrolimab, the model predicts that receptor-ligand inhibition is significantly less than target engagement. The key variables explaining the difference between these two drugs are the relative concentrations of the target receptors and their ligands. Drug-target affinity and receptor-ligand affinity can also have divergent effects on target engagement and inhibition. These results suggest that it is important to consider ligand-receptor inhibition in addition to target engagement and demonstrate the impact of using modeling for efficacious dose estimation.

Evaluating serum CXCL12, sCD22, Lp-PLA2 levels and ratios as biomarkers for diagnosis of Alzheimer's disease.

BACKGROUND: Grasping the underlying mechanisms of Alzheimer's disease (AD) is still a work in progress, and existing diagnostic techniques encounter various obstacles. Therefore, the discovery of dependable biomarkers is essential for early detection, tracking the disease's advancement, and steering treatment strategies. AIM: To explore the diagnostic potential of serum CXCL12, sCD22, Lp-PLA2, and their ratios in AD, aiming to enhance early detection and inform targeted treatment strategies. METHODS: The study was conducted in Dongying people's Hospital from January 2021 to December 2022. Participants included 60 AD patients (AD group) and 60 healthy people (control group). Using a prospective case-control design, the levels of CXCL12, sCD22 and Lp-PLA2 and their ratios were detected by enzyme-linked immunosorbent assay kit in the diagnosis of AD. The differences between the two groups were analyzed by statistical methods, and the corresponding ratio was constructed to improve the specificity and sensitivity of diagnosis. RESULTS: Serum CXCL12 levels were higher in the AD group (47.2 ± 8.5 ng/mL) than the control group (32.8 ± 5.7 ng/mL, P < 0.001), while sCD22 levels were lower (14.3 ± 2.1 ng/mL vs 18.9 ± 3.4 ng/mL, P < 0.01). Lp-PLA2 levels were also higher in the AD group (112.5 ± 20.6 ng/mL vs 89.7 ± 15.2 ng/mL, P < 0.05). Significant differences were noted in CXCL12/sCD22 (3.3 vs 1.7, P < 0.001) and Lp-PLA2/sCD22 ratios (8.0 vs 5.2, P < 0.05) between the groups. Receiver operating characteristic analysis confirmed high sensitivity and specificity of these markers and their ratios in distinguishing AD, with area under the curves ranging from 0.568 to 0.787. CONCLUSION: Serum CXCL12 and Lp-PLA2 levels were significantly increased, while sCD22 were significantly decreased, as well as increases in the ratios of CXCL12/sCD22 and Lp-PLA2/sCD22, are closely related to the onset of AD. These biomarkers and their ratios can be used as potential diagnostic indicators for AD, providing an important clinical reference for early intervention and treatment.

UNVEILING THE PROTECTIVE MECHANISMS OF PUERARIN AGAINST ACUTE LUNG INJURY: A COMPREHENSIVE EXPLORATION OF THE ROLES AND MECHANISMS OF MST1/ERS SIGNALING.

ABSTRACT: Objectives: Puerarin, the principal active constituent extracted from Pueraria, is believed to confer protection against sepsis-induced lung injury. The study aimed to elucidate the role and mechanism of Mst1/ERS in puerarin-mediated protection against acute lung injury (ALI). Methods: Monolayer vascular endothelial cell permeability was assessed by gauging the paracellular flow of FITC-dextran 40,000 (FD40). ELISA was employed for the quantification of inflammatory cytokines. Identification of target proteins was conducted through western blotting. Histological alterations and apoptosis were scrutinized using hematoxylin-eosin staining and TUNEL staining, respectively. The ultrastructure of the endoplasmic reticulum was observed via transmission electron microscopy. Results: Puerarin significantly protected mice from LPS-induced ALI, reducing lung interstitial width, neutrophil and lymphocyte infiltration, pulmonary interstitial and alveolar edema, and lung apoptosis. Puerarin treatment also markedly attenuated levels of TNF-α and IL-1ß in both alveolar lavage fluid and serum. Furthermore, puerarin significantly attenuated LPS-induced increases in Mst1, GRP78, CHOP, and Caspase12 protein expression and blunted LPS-induced decrease in ZO-1 protein expression in lung tissues. Puerarin obviously reduced endoplasmic reticulum expansion and vesiculation. Similarly, puerarin significantly mitigated the LPS-induced reduction in HUVEC cell viability and ZO-1 expression. Puerarin also attenuated LPS-induced increase in apoptosis, TNF-α and IL-1ß, FD40 flux, and Mst1, GRP78, CHOP, and Caspase12 expression in HUVEC cells. Nevertheless, the inhibitory impact of puerarin on vascular endothelial cell injury, lung injury, and endoplasmic reticulum stress (ERS) was diminished by Mst1 overexpression. Conclusion: These findings demonstrated that the Mst1/ERS signaling pathway played a pivotal role in the development of LPS-induced vascular endothelial cell dysfunction and ALI. Puerarin exhibited the ability to attenuate LPS-induced vascular endothelial cell dysfunction and ALI by inhibiting the Mst1/ERS signaling pathway.

Spherical Silver Nanoparticles Located on Reduced Graphene Oxide Nanocomposites as Sensitive Electrochemical Sensors for Detection of L-Cysteine.

A new, simple, and effective one-step reduction method was applied to prepare a nanocomposite with spherical polycrystalline silver nanoparticles attached to the surface of reduced graphene oxide (Ag@rGO) at room temperature. Equipment such as X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and Fourier transform infrared spectroscopy (FTIR) was used to characterize the morphology and composition of the Ag@rGO nanocomposite. A novel electrochemical sensor for detecting L-cysteine was proposed based on fixing Ag@rGO onto a glassy carbon electrode. The electrocatalytic behavior of the sensor was studied via cyclic voltammetry and amperometry. The results indicate that due to the synergistic effect of graphene with a large surface area, abundant active sites, and silver nanoparticles with good conductivity and high catalytic activity, Ag@rGO nanocomposites exhibit significant electrocatalytic activity toward L-cysteine. Under optimal conditions, the constructed Ag@rGO electrochemical sensor has a wide detection range of 0.1-470 µM for L-cysteine, low detection limit of 0.057 µM, and high sensitivity of 215.36 nA M-1 cm-2. In addition, the modified electrode exhibits good anti-interference, reproducibility, and stability.

Inflammatory biomarkers predict higher risk of hyperglycemic crises but not outcomes in diabetic patients with COVID-19.

Background: Inflammation is a predictor of severe complications in patients with COVID-19 infection under a variety of clinical settings. A few studies suggested that COVID-19 infection was a trigger of hyperglycemic crises including diabetic ketoacidosis (DKA) and/or hyperglycemic hyperosmolar state (HHS). However, the association between inflammation and hyperglycemic crises in diabetic patients with COVID-19 infection is unclear. Methods: One hundred and twenty-four patients with type 2 diabetes mellitus (T2DM) and COVID-19 infection from January 2023 to March 2023 were retrospectively analyzed. Demographic, clinical, and laboratory data, especially inflammatory markers including white blood cell (WBC), neutrophils, neutrophil-to-lymphocyte ratio (NLR), c-reactive protein (CRP) and procalcitonin (PCT) were collected and compared between patients with or without DKA and/or HHS. Multivariable logistic regression analysis was conducted to explore the association between inflammatory biomarkers and the prevalence of hyperglycemic crises. Patients were followed up 6 months for outcomes. Results: Among 124 diabetic patients with COVID-19, 9 were diagnosed with DKA or HHS. Comparing COVID-19 without acute diabetic complications (ADC), patients with DKA or HHS showed elevated levels of c-reactive protein (CRP, P=0.0312) and procalcitonin (PCT, P=0.0270). The power of CRP and PCT to discriminate DKA or HHS with the area under the receiver operating characteristics curve (AUROC) were 0.723 and 0.794, respectively. Multivariate logistic regression indicated 1.95-fold and 1.97-fold increased risk of DKA or HHS with 1-unit increment of CRP and PCT, respectively. However, neither CRP nor PCT could predict poor outcomes in diabetic patients with COVID-19. Conclusion: In this small sample size study, we firstly found that elevated serum CRP and PCT levels increased the risk of hyperglycemic crises in T2DM patients with COVID-19 infection. More study is needed to confirm our findings.

Association Between the Water Distribution in the Human Body and 25-Hydroxyvitamin D Among the Type 2 Diabetes Mellitus Population: A Possible Pathway Between Vitamin D and Diabetic Nephropathy.

Purpose: To explore the association between the water distribution in the human body and 25-hydroxyvitamin D among patients with type 2 diabetes mellitus (T2DM), and to analyze whether water distribution is a mediator between vitamin D and T2DM complications. Patients and Methods: In total, 533 T2DM inpatients were included from August 1, 2016 to April 1, 2023. Water distribution indicators, whether from the whole body, arms, trunk, or legs, were measured to calculate the association with vitamin D using linear regression analysis. Subgroups based on age, sex, body mass index, and macrovascular complications were established to clarify changes in the association between vitamin D and water distribution in different populations. Mediation analysis was applied to evaluate the correlation between vitamin D, water distribution, and T2DM complications. Results: There was a negative correlation between 25-hydroxyvitamin D and the ratio of extracellular water (ECW)/total body water (TBW) both in the whole body (P=0.045, ß=-0.008) and in certain parts. A U-shaped restricted cubic spline curve further presented an inflection point (approximately 23 ng/mL 25-hydroxyvitamin D) in the relationship between 25-hydroxyvitamin D and the ECW/TBW of the whole body. A negative correlation was observed between ECW/TBW and vitamin D in the obese subgroup (P=0.015, ß=-0.038). In the total effect of vitamin D on diabetic nephropathy (DN), the mediation effect of ECW/TBW accounted for 15.44%. Conclusion: A correlation between vitamin D and water distribution was observed, and a high ECW/TBW was one of the pathways through which low vitamin D levels might affect DN.

Metformin Protects Against Acute Kidney Injury Induced by Lipopolysaccharide via Up-Regulating the MCPIP1/SIRT1 Pathway.

In the present study, we aimed to explore the effect and underlying mechanism of metformin on lipopolysaccharide (LPS)-induced acute kidney injury (AKI). A total of 24 BALB/C mice were randomly divided into four groups: control group, LPS group and metformin group (50 or 100 mg/kg). The histological changes and cell apoptosis in kidney tissues were detected by hematoxylin-eosin staining and terminal-deoxynucleotidyl transferase-mediated nick end labeling assay, respectively. Enzyme-linked immunosorbent assay was applied to determine serum levels of blood urea nitrogen (BUN), kidney injury molecule-1 (Kim-1), creatinine (Cre), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß). Western blotting analysis were carried out to confirm the expressions of monocyte chemotactic protein-inducible protein 1 (MCPIP1), silent information regulator sirtuin 1 (SIRT1), and NF-κB p65 (acetyl K310). Compared with the control group, the mice in LPS group had glomerular capillary dilatation, renal interstitial edema, tubular cell damage and apoptosis. The serum levels of BUN, KIM-1, Cre, TNF-α, and IL-1ß in LPS group were significantly higher than those in control group. Moreover, LPS also elevated the expressions of MCPIP1 and NF-κB p65 (acetyl K310) but decreased the expression of SIRT1 in kidney tissues. However, metformin distinctly decreased LPS-induced renal dysfunction, the serum levels of BUN, KIM-1, Cre, TNF-α, and IL-1ß. In addition, metformin markedly increased the expressions of MCPIP1 and SIRT1 but decreased the expression of NF-κB p65 (acetyl K310) in kidney tissues. Metformin prevented LPS-induced AKI by up-regulating the MCPIP1/SIRT1 signaling pathway and subsequently inhibiting NF-κB-mediated inflammation response.

Mitigating bisphenol A-induced apoptosis in KGN cells: the therapeutic role of 1,25-dihydroxyvitamin D3 through upregulation of PGC-1α expression and inhibition of the mitochondrial cytochrome c pathway.

PURPOSE: This study investigated the potential of 1,25-dihydroxyvitamin D3 (1,25(OH)2VD3) to mitigate bisphenol A (BPA)-induced apoptosis in human ovarian granulosa KGN cells with the aim of establishing a theoretical foundation for understanding of how vitamin D improved ovarian function in patients with polycystic ovary syndrome (PCOS). METHODS: The impact of varying concentrations of BPA and 1,25(OH)2VD3 on KGN cell viability was elucidated. It was established that BPA-induced apoptosis in KGN cells. Subsequently, KGN cells underwent pretreatment with 1,25(OH)2VD3, followed by exposure to BPA. The apoptosis rate, reactive oxygen species (ROS) levels, and mitochondrial function of the cells were meticulously assessed, along with the expression levels of genes associated with apoptosis as well as antioxidant and mitochondrial biogenesis. RESULTS: BPA induced a notable increase in apoptosis (P < 0.001) and oxidative stress (P < 0.001) in KGN cells, accompanied by a significant reduction in mitochondrial membrane potential (P < 0.001) and severe impairment of mitochondrial function. Following pretreatment of KGN cells with 1,25(OH)2VD3, there was a significant decrease in the apoptosis rate (P = 0.004), coupled with a reduction in ROS production (P = 0.002). Concomitantly, the upregulation of PGC-1α (P = 0.009) and SOD (P = 0.018) was observed, while mRNA expression of BAX (P = 0.011), Cyt c (P = 0.001), Apaf-1 (P = 0.012), caspase-9 (P < 0.001), and caspase-3 (P = 0.011) was downregulated. Notably, the mitigation of mitochondrial damage was evident through restored mitochondrial membrane potential (P < 0.001), as corroborated by electron microscope results. CONCLUSIONS: 1,25(OH)2VD3 mitigated BPA-induced damage and apoptosis in KGN cells by upregulating the expression of PGC-1α and impeding the mitochondrial cytochrome c (Cyt c) apoptotic pathway. This study established a novel theoretical foundation for utilizing vitamin D in the treatment of PCOS patients.

Long noncoding RNA lncPostn links TGF-ß and p53 signaling pathways to transcriptional regulation of cardiac fibrosis.

Cardiac fibroblasts are essential for the homeostasis of the extracellular matrix, whose remodeling in many cardiovascular diseases leads to fibrosis. Long noncoding RNAs (lncRNAs) are associated with cardiac pathologies, but their functions in cardiac fibroblasts and contributions to cardiac fibrosis remain unclear. Here, we aimed to identify fibroblast-enriched lncRNAs essential in myocardial infarction (MI)-induced fibrosis and explore the molecular mechanisms responsible for their functions. Global lncRNA profiling was performed in post-MI mouse heart ventricles and transforming growth factor-ß (TGF-ß)-treated primary cardiac fibroblasts and confirmed in published data sets. We identified the cardiac fibroblast-enriched lncPostn, whose expression is stimulated in cardiac fibrosis induced by MI and the extracellular growth factor TGF-ß. The promoter of lncPostn contains a functional TGF-ß response element, and lncPostn knockdown suppresses TGF-ß-stimulated cardiac fibroblast activation and improves cardiac functions post-MI. LncPostn stabilizes and recruits EP300 to the profibrotic periostin's promoter, representing a major mechanism for its transcriptional activation. Moreover, both MI and TGF-ß enhance lncPostn expression while suppressing the cellular growth gatekeeper p53. TGF-ß and p53 knockdown-induced profibrotic gene expression and fibrosis occur mainly through lncPostn and show additive effects. Finally, levels of serum lncPostn are significantly increased in patients' postacute MI and show a strong correlation with fibrosis markers, revealing a potential biomarker of cardiac fibrosis. Our findings identify the fibroblast-enriched lncPostn as a potent profibrotic factor, providing a transcriptional link between TGF-ß and p53 signaling pathways to regulate fibrosis in cardiac fibroblasts.NEW & NOTEWORTHY Cardiac fibroblasts are essential for the homeostasis of the extracellular matrix, whose remodeling in many cardiovascular diseases leads to fibrosis. Long noncoding RNAs are functional and contribute to the biological processes of cardiovascular development and disorders. Our findings identify the fibroblast-enriched lncPostn as a potent profibrotic factor and demonstrate that serum lncPostn level may serve as a potential biomarker of human cardiac fibrosis postacute myocardial infarction.

Association between serum lipoprotein(a) and mildly reduced eGFR: a cross-sectional study.

Lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease (CVD) and aortic stenosis. However, the data on the relationship between Lp(a) and mildly reduced estimated glomerular filtration rate (eGFR) has been disputed. This study was conducted to assess the relationship between Lp(a) concentrations and mildly reduced eGFR in healthy subjects.This community-based, cross-sectional study enrolled 1,064 volunteers aged ≥ 40 years who lived in Yonghong Community, Zhonglou District, Changzhou, China, between December 2016 and December 2017. A mildly reduced eGFR was defined as eGFR between 60 and 90 mL/min/1.73m2. A standardized questionnaire and biochemical measurements were used to gather information about participants. The serum concentration of Lp(a) was determined using the latex-enhanced immunoturbidimetric test. Of the total study population, 34.8% (n = 370) were men, and the mean age was 66.8 ± 8.5 years. A significant association existed between Lp(a) levels and the risk of mildly reduced eGFR. Individuals with the highest tertile of Lp(a) had higher odds of mildly reduced eGFR after adjusting for various confounders (adjusted odds ratio [OR]: 1.80, 95% confidence interval [CI]: 1.24-2.60, P = 0.0025) compared to those with the lowest tertile of Lp(a). Multivariable logistic regression of studies in which Lp(a) was presented as continuous variables showed consistent results (adjusted OR: 1.23 for 1-SD increment of Ln-Lp(a), 95% CI: 1.05-1.43). Subgroup analyses showed that study characteristics such as age, sex, obesity, diabetes, and hypertension status did not significantly affect the association (P for all interactions > 0.05). These results suggest that higher serum Lp(a) level was an independent risk factor for mildly reduced eGFR.

Landscape of molecular crosstalk between SARS-CoV-2 infection and cardiovascular diseases: emphasis on mitochondrial dysfunction and immune-inflammation.

BACKGROUND: SARS-CoV-2, the pathogen of COVID-19, is a worldwide threat to human health and causes a long-term burden on the cardiovascular system. Individuals with pre-existing cardiovascular diseases are at higher risk for SARS-CoV-2 infection and tend to have a worse prognosis. However, the relevance and pathogenic mechanisms between COVID-19 and cardiovascular diseases are not yet completely comprehended. METHODS: Common differentially expressed genes (DEGs) were obtained in datasets of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) infected with SARS-CoV-2 and myocardial tissues from heart failure patients. Further GO and KEGG pathway analysis, protein-protein interaction (PPI) network construction, hub genes identification, immune microenvironment analysis, and drug candidate predication were performed. Then, an isoproterenol-stimulated myocardial hypertrophy cell model and a transverse aortic constriction-induced mouse heart failure model were employed to validate the expression of hub genes. RESULTS: A total of 315 up-regulated and 78 down-regulated common DEGs were identified. Functional enrichment analysis revealed mitochondrial metabolic disorders and extensive immune inflammation as the most prominent shared features of COVID-19 and cardiovascular diseases. Then, hub DEGs, as well as hub immune-related and mitochondria-related DEGs, were screened. Additionally, nine potential therapeutic agents for COVID-19-related cardiovascular diseases were proposed. Furthermore, the expression patterns of most of the hub genes related to cardiovascular diseases in the validation dataset along with cellular and mouse myocardial damage models, were consistent with the findings of bioinformatics analysis. CONCLUSIONS: The study unveiled the molecular networks and signaling pathways connecting COVID-19 and cardiovascular diseases, which may provide novel targets for intervention of COVID-19-related cardiovascular diseases.

MiR-210 promotes bone formation in ovariectomized rats by regulating osteogenic/adipogenic differentiation of bone marrow mesenchymal stem cells through downregulation of EPHA2.

PURPOSE: In osteoporosis, the balance between osteogenic and adipogenic differentiation of mesenchymal stem cells (MSCs) is disrupted. The osteogenic differentiation of bone marrow MSCs (BMSCs) is important for improving osteoporosis. The aim of this study was to explore the role and molecular mechanism of miR-210 in the balance of osteogenic/adipogenic differentiation of BMSCs in postmenopausal osteoporosis. METHODS: Postmenopausal osteoporosis rat models were constructed by ovariectomy (OVX). BMSCs were isolated from the femur in rats of Sham and OVX groups. MiR-210 was overexpressed and suppressed by miR-210 mimics and inhibitor, respectively. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the relative mRNA expression of miR-210, ephrin type-A receptor 2 (EPHA2), alkaline phosphatase (ALP), osterix (OSX), osteocalcin (Bglap), Runt-related transcription factor 2 (Runx2), peroxisome proliferator activated receptor gamma, and fatty acid binding protein 4 (FABP4) in each group of rat femoral tissues or BMSCs. Western blot was applied to detect the protein expression level of EPHA2 in rat femoral tissues and cells. Alizarin red S staining and oil red O staining were performed to assess the osteogenic and adipogenic differentiation of BMSCs, respectively. In addition, the targeting relationship between miR-210 and EPHA2 was verified by a dual luciferase gene reporter assay. RESULTS: The expression of miR-210 was significantly reduced in femoral tissues and BMSCs of OVX rats, and its low expression was associated with reduced bone formation. The osteogenic differentiation was enhanced in OVX rats treated with miR-210 mimic. Overexpression of miR-210 in transfected BMSCs was also found to significantly promote osteogenic differentiation and even inhibit adipogenic differentiation in BMSCs, while knockdown of miR-210 did the opposite. Further mechanistic studies showed that miR-210 could target and inhibit the expression of EPHA2 in BMSCs, thus promoting osteogenic differentiation and inhibiting adipogenic differentiation of BMSCs. CONCLUSION: MiR-210 promotes osteogenic differentiation and inhibits adipogenic differentiation of BMSCs by down-regulating EPHA2 expression. As it plays an important role in the osteogenic/adipogenic differentiation of osteoporosis, miR-210 can serve as a potential miRNA biomarker for osteoporosis.

Total Syntheses of Cinchona Alkaloids via Photoredox-Catalyzed Deoxygenative Arylation.

Metallaphotoredox-enabled deoxygenative arylation of alcohols is a recently developed robust synthetic strategy for sp2-sp3 coupling by MacMillan. Inspired by this method, we report herein its first utilization in natural product total synthesis through realizing the coupling of 4-bromo-quinoline or 4-bromo-6-methoxyquinoline with quincorine or quincoridine, respectively. The alcohols were de novo synthesized in racemic form by a key step of the intramolecular Diels-Alder reaction or in an enantioselective manner by Ir/amine dual-catalyzed allylation. All members of the cinchona alkaloids could be prepared efficiently.

Machine learning models for prediction of invasion Klebsiella pneumoniae liver abscess syndrome in diabetes mellitus: a singled centered retrospective study.

OBJECTIVE: This study aimed to develop and validate a machine learning algorithm-based model for predicting invasive Klebsiella pneumoniae liver abscess syndrome(IKPLAS) in diabetes mellitus and compare the performance of different models. METHODS: The clinical signs and data on the admission of 213 diabetic patients with Klebsiella pneumoniae liver abscesses were collected as variables. The optimal feature variables were screened out, and then Artificial Neural Network, Support Vector Machine, Logistic Regression, Random Forest, K-Nearest Neighbor, Decision Tree, and XGBoost models were established. Finally, the model's prediction performance was evaluated by the ROC curve, sensitivity (recall), specificity, accuracy, precision, F1-score, Average Precision, calibration curve, and DCA curve. RESULTS: Four features of hemoglobin, platelet, D-dimer, and SOFA score were screened by the recursive elimination method, and seven prediction models were established based on these variables. The AUC (0.969), F1-Score(0.737), Sensitivity(0.875) and AP(0.890) of the SVM model were the highest among the seven models. The KNN model showed the highest specificity (1.000). Except that the XGB and DT models over-estimates the occurrence of IKPLAS risk, the other models' calibration curves are a good fit with the actual observed results. Decision Curve Analysis showed that when the risk threshold was between 0.4 and 0.8, the net rate of intervention of the SVM model was significantly higher than that of other models. In the feature importance ranking, the SOFA score impacted the model significantly. CONCLUSION: An effective prediction model of invasion Klebsiella pneumoniae liver abscess syndrome in diabetes mellitus could be established by a machine learning algorithm, which had potential application value.

1,25-Dihydroxyvitamin D inhibits hepatic diacyglycerol accumulation and ameliorates metabolic dysfunction in polycystic ovary syndrome rat models.

Introduction: We aimed to evaluate the influence of 1,25-dihydroxyvitamin D (1,25(OH)2D) on metabolic dysfunction and elucidate its underlying mechanism using a rat model of polycystic ovary syndrome (PCOS). Methods: Twenty-four Sprague-Dawley rats were randomly divided into four groups: control group (CON, 2 ml/kg of oral 0.5% CMC), 1,25VD group (oral 0.5% CMC and 2.5 ug/kg intraperitoneal 1,25(OH)2D), PCOS group (1 mg/kg oral letrozole), PCOS+1,25VD group (1 mg/kg oral letrozole orally 2.5 ug/kg intraperitoneal 1,25(OH)2D). The treatments were administered for 8 weeks. Body weight, estrus cycle, insulin tolerance, and oral glucose tolerance of the rats in the different groups were assessed. The rats were euthanized at the 8th weeks, and plasma, ovarian, and liver samples were collected and analyzed. The hepatic lipid profile was characterized using HPLC/MRM. Results: Letrozole-induced PCOS rats exhibited increased weight, insulin resistance, postprandial glucose abnormalities, and dyslipidemia. Compared with the PCOS group rats, the PCOS+1,25VD group rats showed reduced body weight, increased sensitivity to insulin, decreased postprandial glucose, and elevated levels of high-density lipoprotein cholesterol. Moreover, abnormally increased liver concentrations of total diacylglycerol (DG) and DG species in the PCOS rats were reversed by treatment with 1,25(OH)2D. Additionally, hepatic DG and insulin sensitivity were correlated. Conclusion: 1,25(OH)2D inhibited hepatic DG accumulation and ameliorated metabolic dysfunction in PCOS rat models.

Effects of dulaglutide combined with insulin degludec on glucose fluctuations and appetite in type 2 diabetes.

Introduction: The aim of this study was to describe appetite and glucose fluctuation in type 2 diabetes mellitus patients initiating treatment with dulaglutide combined with insulin degludec. Methods: This retrospective study of patients identified adults starting treatment with once-weekly (QW) dulaglutide combined with insulin degludec (experimental group) or insulin degludec alone (control group). Patients were followed for up to 6 months from treatment initiation. The clinical characteristics of patients, treatment patterns, CGM data, and appetite scores were obtained for the two groups. Results: A total of 236 patients were included in this study. SDBG, MAGE, LAGE, and PPGE of the experimental group were lower than the control group's (P < 0.05). The proportions of patients achieving a time in range (TIR) of ≥70% in the experimental group were higher than in the control group, with 43% and 10% on the second day, 88% and 47% on the fourth day, 95% and 47% on the seventh day, and 100% and 67% on the tenth day, respectively. Significant associations existed between TIR and the prevalence of islet function. At six months, 89.2% of patients in the experimental group were still using dulaglutide. Appetite decreased significantly at 1 week and increased at 3 months after treatment with dulaglutide. Conclusion: Dulaglutide combined with insulin degludec significantly reduces glucose fluctuations in patients with type 2 diabetes mellitus and improves the TIR rate. However, the treatment on appetite could decrease in the first three months.