Association of systemic immune-inflammation index with insulin resistance and prediabetes: a cross-sectional study.

Background and Objective: Previous research suggested a relationship between the Systemic Immune-Inflammation Index (SII) and multiple adverse health conditions. However, the role of SII in prediabetes and insulin resistance (IR) remains poorly understood. Therefore, this study aims to explore the potential relationship between SII and prediabetes and IR, providing data support for effective diabetes prevention by reducing systemic inflammation. Methods: Linear regression models were used to assess the correlation between continuous SII and risk markers for type 2 diabetes (T2D). Subsequently, multivariate logistic regression models and subgroup analyses were employed to evaluate the association between SII tertiles and prediabetes and IR, controlling for various confounding factors. Finally, restricted cubic spline graphs were used to analyze the nonlinear relationship between SII and IR and prediabetes. Results: After controlling for multiple potential confounders, SII was positively correlated with fasting blood glucose (FBG) (ß: 0.100; 95% CI: 0.040 to 0.160), fasting serum insulin (FSI) (ß: 1.042; 95% CI: 0.200 to 1.885), and homeostasis model assessment of insulin resistance (HOMA-IR) (ß: 0.273; 95% CI: 0.022 to 0.523). Compared to participants with lower SII, those in the highest tertile had increased odds of prediabetes (OR: 1.17; 95% CI: 1.02-1.34; p for trend < 0.05) and IR (OR: 1.35; 95% CI: 1.18 to 1.51; p for trend<0.001). Conclusions: Our study results demonstrate an elevated association between SII levels and both IR and prediabetes, indicating SII as a straightforward and cost-effective method identifying individuals with IR and prediabetes.

[The Reduction of CD4+ T Lymphocytes after the Treatment of Follicular Lymphoma with the Bendamustine Containing Regimen May Predict the Occurrence of Infection and Efficacy].

OBJECTIVE: To investigate the effectiveness, safety, and related prognostic factors of the treatment of follicular lymphoma (FL) with a regimen containing Bendamustine. METHODS: The clinical data of 129 FL patients who were treated with Bendamustine containing regimen were collected from January 1,2020 to October 30,2022 in the Hematology Department of Lianyungang Second People's Hospital and Jiangsu Provincial People's Hospital. The patients were divided into three groups: Bendamustine plus Rituximab (BR), Bendamustine plus Obinutuzumab (GB), Rituximab + Cyclophosphamide + Epirubicin / Doxorubicin + Vindesine + Prednisone (R-CHOP). The efficacy, safety and related prognostic factors of the treatment of FL with a regimen based on Bendamustine were retrospectively analyzed. RESULTS: The ORR was 98% for the BR group, 94% for the GB group, and 72.3% for the R-CHOP group, while the CR rate was 61.2%,70% and 40.4%, respectively. The ORR and CR rates of the R-CHOP group were statistically different from those of the BR group and GB group (P < 0.05). The 3-year PFS rate of the BR group, GB group, and R-CHOP group was 89.6%, 90.9%, 48.9%, respectively. There was a statistically significant difference in 3-year PFS between the R-CHOP group, BR group, and GB group (P < 0.05), while there was no statistically significant difference in 3-year OS（P ＞0.05）. Hematological adverse reactions were mainly bone marrow suppression. Lymphocytes and CD4+T lymphocytes decreased to the lowest level about 6 months after treatment, and the incidence of lymphopenia in BR group and GB group was higher than that in R-CHOP group, with a statistical difference (P < 0.05). The higher incidence of non-Hematological adverse reactions were pulmonary infection, EB virus infection, hepatitis B virus reactivation, and gastrointestinal reactions without statistical difference in 3 groups (P >0.05), and were all controllable. The Receiver operating characteristic of CD4+T lymphocyte count showed that AUC of BR group was 0.802, and the critical value was 258/uL; AUC of GB group was 0.754 with a critical value of 322/uL. CONCLUSION: The treatment of FL with the Bendamustine containing regimen has good efficacy and controllable adverse reactions, but lymphocytopenia was significant after treatment, and the curative efficacy in combination with various CD20 monoclonal antibodies was different. The lowest CD4+T lymphocyte count can be used as a predictive factor for the occurrence of infection and efficacy of the Bendamustine containing regimen for FL.

Association between alcohol consumption and chronic kidney disease: a population-based survey.

BACKGROUND: Alcohol consumption is associated with both beneficial and harmful effects, and the role of alcohol consumption in chronic kidney disease (CKD) remains inconclusive. This study aimed to investigate the relationship between alcohol consumption and CKD or estimated glomerular filtration rate (eGFR). METHODS: This study enrolled adults from the second Taiwanese Survey on Prevalences of Hypertension, Hyperglycemia, and Hyperlipidemia, conducted in 2007. Participants were categorized into frequent drinkers, occasional drinkers, and nondrinkers. The amount of alcohol consumption was assessed by standard drinks per week. The primary outcome was the presence of CKD, and the secondary outcome was the eGFR. RESULTS: Among 3967 participants with a mean age of 47.9 years and a CKD prevalence of 11.7%, 13.8% were frequent drinkers, and 23.1% were occasional drinkers. The average amount of alcohol consumed was 3.3 drinks per week. Frequent drinkers (odds ratio [OR] 0.622, 95% confidence interval [CI] 0.443-0.874) and occasional drinkers (OR 0.597 95% CI 0.434-0.821) showed a lower prevalence of CKD than nondrinkers. Consumption of a larger number of standard drinks was associated with a lower prevalence of CKD (OR 0.872, 95% CI 0.781-0.975). Frequent drinkers and those who consumed a larger number of standard drinks per week showed higher eGFRs. CONCLUSION: Within the range of moderate alcohol intake, those who consumed more alcohol had a higher eGFR and reduced prevalence of CKD. The potentially harmful effects of heavy drinking should be taken into consideration, and alcohol intake should be limited to less than light to moderate levels.

Growth, nutrient removal, and lipid productivity promotion of Chlorella sorokiniana by phosphate solubilizing bacteria Bacillus megatherium in swine wastewater: Performances and mechanisms.

Effects of a phosphorus-solubilizing bacteria (PSB) Bacillus megatherium on growth and lipid production of Chlorella sorokiniana were investigated in synthesized swine wastewater with dissolved inorganic phosphorus (DIP), insoluble inorganic phosphorus (IIP), and organic phosphorus (OP). The results showed that the PSB significantly promoted the algal growth in OP and IIP, by 1.10 and 1.78-fold, respectively. The algal lipid accumulation was also greatly triggered, respectively by 4.39, 1.68, and 1.38-fold in DIP, IIP, and OP. Moreover, compared with DIP, OP improved the oxidation stability of algal lipid by increasing the proportion of saturated fatty acids (43.8 % vs 27.9 %), while the PSB tended to adjust it to moderate ranges (30.2-41.6 %). Further, the transcriptome analysis verified the OP and/or PSB-induced up-regulated genes involving photosynthesis, lipid metabolism, signal transduction, etc. This study provided novel insights to enhance microalgae-based nutrient removal combined with biofuel production in practical wastewater, especially with complex forms of phosphorus.

A pyridinium-based strategy for lysine-selective protein modification and chemoproteomic profiling in live cells.

Protein active states are dynamically regulated by various modifications; thus, endogenous protein modification is an important tool for understanding protein functions and networks in complicated biological systems. Here we developed a new pyridinium-based approach to label lysine residues under physiological conditions that is low-toxicity, efficient, and lysine-selective. Furthermore, we performed a large-scale analysis of the ∼70% lysine-selective proteome in MCF-7 cells using activity-based protein profiling (ABPP). We quantifically assessed 1216 lysine-labeled peptides in cell lysates and identified 386 modified lysine sites including 43 mitochondrial-localized proteins in live MCF-7 cells. Labeled proteins significantly preferred the mitochondria. This pyridinium-based methodology demonstrates the importance of analyzing endogenous proteins under native conditions and provides a robust chemical strategy utilizing either lysine-selective protein labeling or spatiotemporal profiling in a living system.

ß-Carbonyl sulfonium enables cysteine-specific bioconjugation for activity-based protein profiling in live cells.

Chemical labeling methods for proteins are highly researched. Herein, we introduced ß-carbonyl sulfonium compounds for selective cysteine modification in proteins within biological systems. Structural tuning led to sulfonium-based probes with high reactivity and selectivity. These probes show excellent biocompatibility, cell uptake, and specificity towards cysteine profiling in live cells.

A novel subpopulation of monocytes with a strong interferon signature indicated by SIGLEC-1 is present in patients with in recent-onset type 1 diabetes.

AIMS/HYPOTHESIS: Type 1 diabetes is a T cell-mediated autoimmune disease characterised by pancreatic beta cell destruction. In this study, we explored the pathogenic immune responses in initiation of type 1 diabetes and new immunological targets for type 1 diabetes prevention and treatment. METHODS: We obtained peripheral blood samples from four individuals with newly diagnosed latent autoimmune diabetes in adults (LADA) and from four healthy control participants. Single-cell RNA-sequencing (scRNA-seq) was performed on peripheral blood mononuclear cells to uncover transcriptomic profiles of early LADA. Validation was performed through flow cytometry in a cohort comprising 54 LADA, 17 adult-onset type 2 diabetes, and 26 healthy adults, matched using propensity score matching (PSM) based on age and sex. A similar PSM method matched 15 paediatric type 1 diabetes patients with 15 healthy children. Further flow cytometry analysis was performed in both peripheral blood and pancreatic tissues of non-obese diabetic (NOD) mice. Additionally, cell adoptive transfer and clearance assays were performed in NOD mice to explore the role of this monocyte subset in islet inflammation and onset of type 1 diabetes. RESULTS: The scRNA-seq data showed that upregulated genes in peripheral T cells and monocytes from early-onset LADA patients were primarily enriched in the IFN signalling pathway. A new cluster of classical monocytes (cluster 4) was identified, and the proportion of this cluster was significantly increased in individuals with LADA compared with healthy control individuals (11.93% vs 5.93%, p=0.017) and that exhibited a strong IFN signature marked by SIGLEC-1 (encoding sialoadhesin). These SIGLEC-1+ monocytes expressed high levels of genes encoding C-C chemokine receptors 1 or 2, as well as genes for chemoattractants for T cells and natural killer cells. They also showed relatively low levels of genes for co-stimulatory and HLA molecules. Flow cytometry analysis verified the elevated levels of SIGLEC-1+ monocytes in the peripheral blood of participants with LADA and paediatric type 1 diabetes compared with healthy control participants and those with type 2 diabetes. Interestingly, the proportion of SIGLEC-1+ monocytes positively correlated with disease activity and negatively with disease duration in the LADA patients. In NOD mice, the proportion of SIGLEC-1+ monocytes in the peripheral blood was highest at the age of 6 weeks (16.88%), while the peak occurred at 12 weeks in pancreatic tissues (23.65%). Adoptive transfer experiments revealed a significant acceleration in diabetes onset in the SIGLEC-1+ group compared with the SIGLEC-1- or saline control group. CONCLUSIONS/INTERPRETATION: Our study identified a novel group of SIGLEC-1+ monocytes that may serve as an important indicator for early diagnosis, activity assessment and monitoring of therapeutic efficacy in type 1 diabetes, and may also be a novel target for preventing and treating type 1 diabetes. DATA AVAILABILITY: RNA-seq data have been deposited in the GSA human database ( https://ngdc.cncb.ac.cn/gsa-human/ ) under accession number HRA003649.

Traceless Peptide and Protein Modification via Rational Tuning of Pyridiniums.

Herein, we report a versatile reaction platform for tracelessly cleavable cysteine-selective peptide/protein modification. This platform offers highly tunable and predictable conjugation and cleavage by rationally estimating the electron effect on the nucleophilic halopyridiniums. Cleavable peptide stapling, antibody conjugation, enzyme masking/de-masking, and proteome labeling were achieved based on this facile pyridinium-thiol-exchange protocol.

Covalent PROTAC design method based on a sulfonyl pyridone probe.

Covalent proteolysis-targeting chimeras (PROTACs) offer enhanced selectivity, prolonged action, and increased efficacy against challenging target proteins. The conventional approach relies on covalent ligands, but our study presents an innovative method employing an N-sulfonyl pyridone warhead to selectively target tyrosine (Tyr) residues. The von Hippel-Lindau (VHL) moiety is transferred from the warhead to the exposed Tyr, allowing us to design a STING degrader (DC50 0.53 µM, Dmax 56.65%). This approach showcases the potential of nucleophilic amino acid labeling probes, particularly for proteins lacking easily accessible cysteine residues, opening new possibilities for covalent PROTAC design and targeted protein degradation therapies.

Antibacterial and antioxidant activities of a novel biosynthesized selenium nanoparticles using Rosa roxburghii extract and chitosan: Preparation, characterization, properties, and mechanisms.

Developing efficient and safe antibacterial agents to inhibit pathogens including Physalospora piricola and Staphylococcus aureus is of great importance. Herein, a novel compound composed of Rosa roxburghii procyanidin, chitosan and selenium nanoparticle (RC-SeNP) was bio-synthesized, with the average diameter and zeta potential being 84.56 nm and -25.60 mV, respectively. The inhibition diameter of the RC-SeNP against P. piricola and S. aureus reached 18.67 mm and 13.13 mm, and the maximum scavenging activity against DPPH and ABTS reached 96.02% and 98.92%, respectively. Moreover, the RC-SeNP completely inhibited the propagation P. piricola and S. aureus on actual apples, suggesting excellent in vivo antimicrobial capacity. The transcriptome analysis and electron microscope observation indicated that the antibacterial activity would be attributed to adhering to and crack the cell walls as well as damage the cytomembrane and nucleus. Moreover, the RC-SeNP effectively maintained the vitamin C, total acid, and water contents of red bayberry, demonstrating potential application for fruit preservation. At last, the RC-SeNP showed no cell toxicity and trace selenium residual dose (0.03 mg/kg on apple, 0.12 mg/kg on red bayberry). This study would enlighten future development on novel nano-bioantibacterial agents for sustainable agriculture.

Pyridinium-Based Strategy for a Bioorthogonal Conjugation-Assisted Purification Method for Profiling Cell Surface Proteome.

Cell surface proteins (CSPs) are valuable targets for therapeutic agents, but achieving highly selective CSP enrichment in cellular physiology remains a technical challenge. To address this challenge, we propose a newly developed sulfo-pyridinium ester (SPE) cross-linking probe, followed by two-step imaging and enrichment. The SPE probe showed higher efficiency in labeling proteins than similar NHS esters at the level of cell lysates and demonstrated specificity for Lys in competitive experiments. More importantly, this probe could selectively label the cell membranes in cell imaging with only negligible labeling of the intracellular compartment. Moreover, we successfully performed this strategy on MCF-7 live cells to label 425 unique CSPs from 1162 labeled proteins. Finally, we employed our probe to label the CSPs of insulin-cultured MCF-7, revealing several cell surface targets of key functional biomarkers and insulin-associated pathogenesis. The above results demonstrate that the SPE method provides a promising tool for the selective labeling of cell surface proteins and monitoring transient cell surface events.

4-Iodine N-Methylpyridinium-Mediated Peptide Synthesis.

Through systematic optimization of halopyridinium compounds, we established a peptide coupling protocol utilizing 4-iodine N-methylpyridinium (4IMP) for solid-phase peptide synthesis (SPPS). The 4IMP coupling reagent is easily prepared, bench stable, and cost-effective. Employing 4IMP in the SPPS process has showcased remarkable chemoselectivity and efficiency, effectively eliminating racemization and epimerization. This achievement has been substantiated through the successful synthesis of a range of peptides via the direct utilization of commercially available amino acid substrates for SPPS.

Micromonospora profundi TRM 95458 converts glycerol to a new osmotic compound.

Plant growth and agricultural productivity was greatly limited by soil salinity and alkalization. The application of salt-tolerant rhizobacteria could effectively improve plant tolerance to saline-alkali stress. Micromonospora profundi TRM 95458 was obtained from the rhizosphere of chickpea (Cicer arietinum L.) as a moderate salt-tolerant rhizobacteria. A new osmotic compound (ABAGG) was isolated from the fermentation broth of M. profundi TRM 95458. The chemical structure of the new compound was elucidated by analyzing nuclear magnetic resonance (NMR) and high-resolution mass (HRMS) data. M. profundi TRM 95458 could convert glycerol into ABAGG. The accumulation of ABAGG varied depending on the amount of glycerol and glycine added to the fermentation medium. In addition, the concentration of NaCl affected the ABAGG content obviously. The highest yield of ABAGG was observed when the salt content of the fermentation medium was 10 g/L. The study indicated that salt stress led to the accumulation of ABAGG using glycerol and glycine as substrates, suggesting ABAGG might aid in the survival and adaptation of the strain in saline-alkaline environments as a new osmotic compound.

Development of Lysine Crotonyl-Mimic Probe to Covalently Identify H3K27Cr Interacting Proteins.

Histone lysine crotonylation (Kcr) is one newly discovered acylation modification and regulates numerous pathophysiological processes. The binding affinity between Kcr and its interacting proteins is generally weak, which makes it difficult to effectively identify Kcr-interacting partners. Changing the amide of crotonyl to an ester increased reactivity with proximal cysteines and retained specificity for Kcr antibody. The probe "H3g27Cr" was designed by incorporating the ester functionality into a H3K27 peptide. Using this probe, multiple Kcr-interacting partners including STAT3 were successfully identified, and this has not been reported previously. Further experiments suggested that STAT3 possibly could form complexes with Histone deacetylase HDACs to downregulate the acetylation and crotonylation of Histone H3K27. Our unique design provided intriguing tools to further explore Kcr-interacting proteins and elucidate their working mechanisms.

Functional Involvement of ADRA1D in Cutaneous Melanoma Progression and Angiogenesis.

Cutaneous melanoma is a highly aggressive and malignant skin cancer, and its high recurrence rate and drug resistance increase the difficulty of treating advanced-stage patients. Studies have revealed that treatment via stimulation of alpha-1 adrenergic receptor (ADRA1) subtypes inhibits melanoma growth in mice. However, the associations between alpha-1D adrenergic receptor (ADRA1D) and cutaneous melanoma are poorly understood. Tissue specimens from 16 pairs of patients with a pigmented nevus and cutaneous melanoma were analyzed for ADRA1D expression using immunohistochemical staining. Western blotting and RT-qPCR were carried out in order to detect ADRA1D expression levels in melanoma cells and human epidermal melanocytes (HEMs), hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) levels in HUVECS. A375 cells were transfected with a lentivirus overexpressing ADRA1D. Wound-healing, Transwell, and cell proliferation assays were utilized to identify the ADRA1D effect on the migration, invasion, and proliferation of the two groups of A375 cells in vitro. In order to evaluate the function of ADRA1D in vivo, a melanoma xenograft model was developed in immunodeficient mice. ADRA1D was low expressed in cutaneous melanoma tissues. Overexpression of ADRA1D inhibited the tubulation and migration of HUVECs in vitro. Overexpression of ADRA1D significantly decreased the HIF-1α and VEGF expression. Overexpression of ADRA1D inhibited the invasion and proliferation of A375 melanoma cells in vitro and reduced its angiogenesis in vivo. ADRA1D inhibits cutaneous melanoma growth and angiogenesis. It attenuates melanoma cell proliferation and invasion. Meanwhile, its anti-angiogenic effect is achieved by negatively regulating the HIF-1α/VEGF axis in melanoma tissue, thereby attenuating the growth of cutaneous melanoma and reducing the potential of metastasis.

Bioorthogonal Fluoride-Responsive Azide and Alkynyl Pyridinium Click Cycloaddition in Vitro and in Live Cells.

The copper-free azide-alkyne cycloaddition was broadly applied in numerous research fields. Herein, we report a facile Cu-free click reaction utilizing fluoride-responsive azide and alkynyl pyridinium cycloaddition at ambient temperatures in aqueous media. The reactivity of alkynyl pyridinium was successfully masked by a silyl-protecting group at the alkyne group, and the deprotection could be readily achieved with the addition of F-, which renders the reactivity. The substrates were readily synthesized and proven to be stable at the bench. This bioorthogonal fluoride-responsive click reaction was then successfully employed in peptide modification, protein labeling, and cell imaging, suggesting its potential in various applications.