Enhancing Protein Solubility via Glycosylation: From Chemical Synthesis to Machine Learning Predictions.

Glycosylation is a valuable tool for modulating protein solubility; however, the lack of reliable research strategies has impeded efficient progress in understanding and applying this modification. This study aimed to bridge this gap by investigating the solubility of a model glycoprotein molecule, the carbohydrate-binding module (CBM), through a two-stage process. In the first stage, an approach involving chemical synthesis, comparative analysis, and molecular dynamics simulations of a library of glycoforms was employed to elucidate the effect of different glycosylation patterns on solubility and the key factors responsible for the effect. In the second stage, a predictive mathematical formula, innovatively harnessing machine learning algorithms, was derived to relate solubility to the identified key factors and accurately predict the solubility of the newly designed glycoforms. Demonstrating feasibility and effectiveness, this two-stage approach offers a valuable strategy for advancing glycosylation research, especially for the discovery of glycoforms with increased solubility.

Prevalence, Diversity, and Virulence of Campylobacter Carried by Migratory Birds at Four Major Habitats in China.

Campylobacter species, especially C. jejuni and C. coli, are the main zoonotic bacteria causing human gastroenteritis. A variety of Campylobacter species has been reported in wild birds, posing a potential avian-human transmission pathway. Currently, there has been little surveillance data on Campylobacter carriage in migratory birds in China. In the current work, fresh fecal droppings from individual migratory birds were collected at four bird wintering/stopover sites in China from May 2020 to March 2021. Nucleic acid was extracted and tested for Campylobacter with PCR-based methods. Overall, 73.8% (329/446) of the samples were positive for Campylobacter, demonstrating location and bird host specificity. Further speciation revealed the presence of C. jejuni, C. coli, C. lari, C. volucris, and an uncharacterized species, which all harbored a variety of virulence factors. Phylogenetic analysis performed on concatenated 16S rRNA-atpA-groEL genes elucidated their genetic relationship, demonstrating both inter- and intra-species diversity. The wide distribution and high diversity of Campylobacter spp. detected in migratory birds in China indicated potential transmission across territories. The existence of virulence factors in all of these species highlighted their public health importance and the necessity of monitoring and controlling Campylobacter and other pathogens carried by migratory birds.

Association between the American Heart Association's new "Life's Essential 8" metrics and kidney stone.

PURPOSE: The incidence of kidney stone disease has increased worldwide, resulting in high medical costs and social burden. Kidney stone disease shares some common features with the risk factors of cardiovascular diseases (CVDs). We investigated the association between cardiovascular health (CVH) based on the Life's Essential 8 (LE8) score developed by the American Heart Association and the incidence of kidney stone disease. METHODS: We analyzed the data of 29,469 US adults aged 20 years or above from the National Health and Nutrition Examination Survey, 2007-2018. According to the LE8 score, CVH was divided into three categories: poor, intermediate, and ideal. Logistic regression was used to determine the association between CVH and the incidence of kidney stone disease by estimating odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The average age of the participants was 48.6 years, and 50% of the participants were women. The numbers of participants with poor, intermediate, and ideal CVH were 4149, 19,782, and 5538, respectively. After adjusting for related confounding factors, ideal CVH was associated with a reduction in the odds of kidney stone occurrence as compared to poor CVH (adjusted OR [aOR]: 0.45, 95% CI: 0.35-0.57, p < 0.001). Moreover, if the ideal CVH metrics was ≥ 6, the odds of kidney stone occurrence decreased by up to 61% (aOR: 0.39, 95% CI: 0.30-0.51). CONCLUSIONS: In the present study, ideal CVH, a factor indicative of a healthy lifestyle, was associated with lower odds of kidney stone occurrence.

The relationship between C-reactive protein/albumin ratio and mortality in hypertensive patients: A national cohort study.

BACKGROUND AND AIMS: The impact of inflammation on the prognosis of hypertension has received some attention. The current study examined the association between C-reactive protein to albumin ratio (CAR), a novel indicator of inflammatory response, and mortality in individuals with hypertension. METHODS AND RESULTS: A total of 9561 eligible individuals diagnosed with hypertension were included in the final analysis. CAR was calculated as ratio of C-reactive protein to serum albumin concentration. Patients were categorized into tertiles based on their baseline CAR levels. The Kaplan-Meier survival method was employed to compare the survival times of patients throughout the follow-up period. Multivariable analysis was conducted using the Cox proportional regression model. In the entire study population, 3262 (27%) experienced all-cause mortality. Patients in tertile 3 exhibited a higher risk of mortality (23% vs. 28% vs. 31%, P < 0.001) in comparison to those in the other tertiles. The findings from the multivariable Cox regression analysis demonstrated that when patients in tertile 1 were used as the reference group, the highest CAR tertile displayed a 60% increased risk of all-cause mortality (HR, 1.60 [95%CI, 1.23-2.09] P < 0.001). CONCLUSION: Among hypertensive patients, elevated CAR was found to be associated with an increased risk of all-cause mortality. Therefore, CAR might be used for risk stratification within this population, facilitating the implementation of closer follow-up and the optimization of treatment strategies.

Observation of the nonanalytic behavior of optical phonons in monolayer hexagonal boron nitride.

Phonon splitting of the longitudinal and transverse optical modes (LO-TO splitting), a ubiquitous phenomenon in three-dimensional polar materials, will break down in two-dimensional (2D) polar systems. Theoretical predictions propose that the LO phonon in 2D polar monolayers becomes degenerate with the TO phonon, displaying a distinctive "V-shaped" nonanalytic behavior near the center of the Brillouin zone. However, the full experimental verification of these nonanalytic behaviors has been lacking. Here, using monolayer hexagonal boron nitride (h-BN) as a prototypical example, we report the comprehensive and direct experimental verification of the nonanalytic behavior of LO phonons by inelastic electron scattering spectroscopy. Interestingly, the slope of the LO phonon in our measurements is lower than the theoretically predicted value for a freestanding monolayer due to the screening of the Cu foil substrate. This enables the phonon polaritons in monolayer h-BN/Cu foil to exhibit ultra-slow group velocity (~5 × 10-6 c, c is the speed of light) and ultra-high confinement (~ 4000 times smaller wavelength than that of light). These exotic behaviors of the optical phonons in h-BN presents promising prospects for future optoelectronic applications.

NEAT1 Deficiency Promotes Corneal Epithelial Wound Healing by Activating cAMP Signaling Pathway.

Purpose: This study aimed to investigate the role of the long non-coding RNA (lncRNA) NEAT1 in corneal epithelial wound healing in mice. Methods: The central corneal epithelium of wild-type (WT), MALAT1 knockout (M-KO), NEAT1 knockout (N-KO), and NEAT1 knockdown (N-KD) mice was scraped to evaluate corneal epithelial and nerve regeneration rates. RNA sequencing of the corneal epithelium from WT and N-KO mice was performed 24 hours after debridement to determine the role of NEAT1. Quantitative PCR (qPCR) and ELISA were used to confirm the bioinformatic analysis. The effects of the cAMP signaling pathway were evaluated in N-KO and N-KD mice using SQ22536, an adenylate cyclase inhibitor. Results: Central corneal epithelial debridement in N-KO mice significantly promoted epithelial and nerve regeneration rates while suppressing inflammatory cell infiltration. Furthermore, the expression of Atp1a2, Ppp1r1b, Calm4, and Cngb1, which are key components of the cAMP signaling pathway, was upregulated in N-KO mice, indicative of its activation. Furthermore, the cAMP pathway inhibitor SQ22536 reversed the accelerated corneal epithelial wound healing in both N-KO and N-KD mice. Conclusions: NEAT1 deficiency contributes to epithelial repair during corneal wound healing by activating the cAMP signaling pathway, thereby highlighting a potential therapeutic strategy for corneal epithelial diseases.

Unraveling the pharmacodynamic substances and possible mechanism of Trichosanthis Pericarpium in the treatment of coronary heart disease based on plasma pharmacochemistry, network pharmacology and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Coronary heart disease (CHD) is a chronic disease that seriously threatens people's health and even their lives. Currently, there is no ideal drug without side effects for the treatment of CHD. Trichosanthis Pericarpium (TP) has been used for several years in the treatment of diseases associated with CHD. However, there is still a need for systematic research to unravel the pharmacodynamic substances and possible mechanism of TP in the treatment of coronary heart. AIM OF THE STUDY: The purpose of current study was to explore the pharmacodynamic substances and potential mechanisms of TP in the treatment of CHD via integrating network pharmacology with plasma pharmacochemistry and experimental validation. MATERIALS AND METHODS: The effect of TP intervention in CHD was firstly assessed on high-fat diet combined with isoprenaline-induced CHD rats and H2O2-induced H9c2 cells, respectively. Then, the LC-MS was utilized to identify the absorbed components of TP in the plasma of CHD rats, and this was used to develop a network pharmacology prediction to obtain the possible active components and mechanisms of action. Molecular docking and immunohistochemistry were used to explore the interaction between TP and key targets. Subsequently, the efficacy of the active ingredients was investigated by in vitro cellular experiments, and their metabolic pathways in CHD rats were further analyzed. RESULTS: The effects of TP on amelioration of CHD were verified by in vivo and in vitro experiments. Plasma pharmacochemistry and network pharmacology screened six active components in plasma including apigenin, phenylalanine, quercetin, linoleic acid, luteolin, and tangeretin. The interaction of these compounds with potential key targets AKT1, IL-1ß, IL-6, TNF-α and VEGFA were preliminarily verified by molecular docking. And immunohistochemical results showed that TP reduced the expression of AKT1, IL-1ß, IL-6, TNF-α and VEGFA in CHD rat hearts. Then cellular experiments confirmed that apigenin, phenylalanine, quercetin, linoleic acid, luteolin, and tangeretin were able to reduce the ROS level in H2O2-induced HUVEC cells and promote the migration and tubule formation of HUVEC cells, indicating the pharmacodynamic effects of the active components. Meanwhile, the metabolites of TP in CHD rats suggested that the pharmacological effects of TP might be the result of the combined effects of the active ingredients and their metabolites. CONCLUSION: Our study found that TP intervention in CHD is characterized by multi-component and multi-target regulation. Apigenin, phenylalanine, linoleic acid, quercetin, luteolin, and tangeretin are the main active components of TP. TP could reduce inflammatory response and endothelial damage by regulating AKT1, IL-1ß, IL-6, TNF-α and VEGFA, reduce ROS level to alleviate the oxidative stress situation and improve heart disease by promoting angiogenesis to regulate endothelial function. This study also provides an experimental and scientific basis for the clinical application and rational development of TP.

Periodontal Ligament Stem Cell-Derived Exosomes Regulate Muc5ac Expression in Rat Conjunctival Goblet Cells via Regulating Macrophages Toward an Anti-Inflammatory Phenotype.

BACKGROUND: Several studies have reported the protective effects of mesenchymal stem cell-derived exosomes (MSC-Exos) in reducing inflammation and decreasing conjunctival goblet cell (CGC) loss in dry eye disease. However, whether MSC-Exos provide anti-inflammatory profiles in macrophages, thus contributing to CGC protection, has remained elusive. METHODS: Macrophages were incubated with PKH26-labeled periodontal ligament mesenchymal stem cell-derived exosomes (PDLSC-Exos) for 12 h, and uptake of PDLSC-Exos by macrophages was observed by a confocal fluorescence microscope. The mRNA expression of TNF-α, IL-10, and Arg1 was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression of TNF-α and IL-10 were quantified using western blotting. Then, CGCs were exposed to different macrophage supernatants and qRT-PCR was used to detect the Muc5ac mRNA expression of CGCs in response to or absence of cholinergic stimulation. ELISA was used to determine the Muc5ac secretion of CGCs in response to cholinergic stimulation. RESULTS: The uptake of PDLSC-Exos by M1 macrophages facilitates M2 macrophage polarization with the elevated expressions of IL-10 and Arg1. In macrophage supernatant-treated CGCs systems, PDLSC-Exo-treated M1 macrophage supernatant significantly enhanced the Muc5ac expression of CGCs in response to, or in the absence of, cholinergic stimulation, while the addition of PDLSC-Exos to the control macrophage supernatant did not generate a change in Muc5ac expression. Conversely, the addition of PDLSC-Exos to the diluted control macrophage supernatant induced a significant increase in Muc5ac expression. CONCLUSION: PDLSC-Exos could protect CGCs against M1 macrophage-mediated inflammation, and the protective effects of PDLSC-Exos are partly attributable to their effects on M1 macrophages.

Exploring shared therapeutic targets in diabetic cardiomyopathy and diabetic foot ulcers through bioinformatics analysis.

Advanced diabetic cardiomyopathy (DCM) patients are often accompanied by severe peripheral artery disease. For patients with DCM combined with diabetic foot ulcer (DFU), there are currently no good therapeutic targets and drugs. Here, we investigated the underlying network of molecular actions associated with the occurrence of these two complications. The datasets were downloaded from the Gene Expression Omnibus (GEO) database. We performed enrichment and protein-protein interaction analyses, and screened for hub genes. Construct transcription factors (TFs) and microRNAs regulatory networks for validated hub genes. Finally, drug prediction and molecular docking verification were performed. We identified 299 common differentially expressed genes (DEGs), many of which were involved in inflammation and lipid metabolism. 6 DEGs were identified as hub genes (PPARG, JUN, SLC2A1, CD4, SCARB1 and SERPINE1). These 6 hub genes were associated with inflammation and immune response. We identified 31 common TFs and 2 key miRNAs closely related to hub genes. Interestingly, our study suggested that fenofibrate, a lipid-lowering medication, holds promise as a potential treatment for DCM combined with DFU due to its stable binding to the identified hub genes. Here, we revealed a network involves a common target for DCM and DFU. Understanding these networks and hub genes is pivotal for advancing our comprehension of the multifaceted complications of diabetes and facilitating the development of future therapeutic interventions.

Association between the cardiometabolic index and chronic kidney disease: a cross-sectional study.

BACKGROUND: Central obesity is a risk factor for chronic kidney disease (CKD). However, the exact correlation between the cardiometabolic index (CMI), an indicator of central obesity, and CKD remains unclear. Here, we aimed to investigate the correlation between the CMI and CKD in the general American population. METHODS: This cross-sectional study involved 64,313 members of the general population (≥ 20 years of age) with data in the National Health and Nutrition Examination Survey (NHANES) 1999-2020. The individuals were grouped into three categories by CMI tertile: T1 group (n = 7,029), T2 group (n = 7,356), and T3 group (n = 7,380). Logistic regression analysis was performed, with NHANES recommended weights, to assess the association between the CMI and CKD. RESULTS: A total of 21,765 participants were included; the overall prevalence of CKD was 12.2%. From the low to the high CMI tertile, the prevalence of CKD increased from 8.9% to 16.0% (P < 0.001). After full adjustment for confounders, the higher tertile of CMI (OR: 1.08, 95% CI: 1.03 - 1.13, P = 0.002) had the higher risk of CKD. Compared with the T1 group, the groups with higher CMI levels had a higher CKD risk (T2: OR: 1.01, 95%CI: 0.87-1.18, P = 0.812; T3: OR: 1.22, 95%CI: 1.05-1.43, P = 0.013). CONCLUSIONS: Higher CMI was independently associated with higher CKD risk in the general population.

GOLM1 Promotes Pulmonary Fibrosis through Upregulation of NEAT1.

Idiopathic pulmonary fibrosis (IPF) is a lethal progressive disease with elusive molecular mechanisms and limited therapeutic options. Aberrant activation of fibroblasts is a central hallmark of lung fibrosis. Here, we report that Golgi membrane protein 1 (GOLM1, also known as GP73 or GOLPH2) was increased in the lungs of patients with pulmonary fibrosis and mice with bleomycin (BLM)-induced pulmonary fibrosis. Loss of GOLM1 inhibited proliferation, differentiation, and extracellular matrix deposition of fibroblasts, whereas overexpression of GOLM1 exerted the opposite effects. Similarly, worsening pulmonary fibrosis after BLM treatment was observed in GOLM1-knock-in mice, whereas BLM-treated Golm1-knockout mice exhibited alleviated pulmonary fibrosis and collagen deposition. Furthermore, we identified long noncoding RNA NEAT1 downstream of GOLM1 as a potential mediator of pulmonary fibrosis through increased GOLM1 expression. Depletion of NEAT1 inhibited fibroblast proliferation and extracellular matrix production and reversed the profibrotic effects of GOLM1 overexpression. Additionally, we identified KLF4 as a downstream mediator of GOLM1 signaling to NEAT1. Our findings suggest that GOLM1 plays a pivotal role in promoting pulmonary fibrosis through the GOLM1-KLF4-NEAT1 signaling axis. Targeting GOLM1 and its downstream pathways may represent a novel therapeutic strategy for treating pulmonary fibrosis.

Clinical outcomes of stromal lenticule rotation to correct mixed astigmatism.

PURPOSE: To describe a stromal lenticule rotation surgical technique to correct mixed astigmatism and evaluate the initial clinical outcomes of this innovative approach. METHODS: This retrospective case series included five eyes from five patients with mixed astigmatism that underwent intrastromal lenticule rotation surgery. The eyes were evaluated for uncorrected visual acuity, corrected distance visual acuity, manifest refraction, central corneal thickness, corneal volume, anterior and posterior K readings, and corneal higher order aberrations (HOAs) (including total HOAs, spherical aberrations, coma, and trefoil) using the Scheimpflug-Placido topographer before and 3 months after surgery. The corneal epithelium and stroma were imaged using anterior segment optical coherence tomography (AS-OCT) postoperatively. A paired-sample t-test was used to analyse the data. RESULTS: Clinical improvement was found in the uncorrected distance visual acuity (0.64 ± 0.11 logMAR vs. 0.20 ± 0.17 logMAR) and spherical and cylindrical diopters (D) (+2.65 ± 1.32 D vs. -0.05 ± 0.51 D and -4.95 ± 0.94 D vs. -1.10 ± 0.78 D, respectively). Anterior flat keratometry readings showed a steep trend (40.65 ± 1.24 D vs. 42.73 ± 0.63 D). Anterior corneal astigmatism decreased from 4.50 ± 0.55 D to 2.05 ± 0.73 D. According to the AS-OCT images, no significant epithelial remodelling was observed postoperatively. Although no significant differences were found among the increased corneal HOAs, the coma and trefoil changed much more than spherical aberrations 3 months postoperatively. CONCLUSIONS: The results for these five eyes suggest that the autologous stromal lenticule rotation technique is safe and effective; it may be an economical and feasible surgical option for correcting mixed astigmatism.

Investigating the crosstalk between chronic stress and immune cells: implications for enhanced cancer therapy.

Chronic stress has a substantial influence on the tumor microenvironment (TME), leading to compromised effectiveness of anti-cancer therapies through diverse mechanisms. It disrupts vital functions of immune cells that play a critical role in anti-tumor immunity, such as the inhibition of dendritic cells (DCs) and lymphocytes, while simultaneously enhancing the activity of immune cells that support tumor growth, such as myeloid-derived suppressor cells and tumor-associated macrophages. Furthermore, chronic stress exerts a significant impact on crucial mechanisms within the TME, including angiogenesis, DNA repair, hypoxia, extracellular matrix deposition, and tumor metabolism. These alterations in the TME, induced by stress, result from the activation of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system, in conjunction with epigenetic modifications. In conclusion, chronic stress significantly influences the TME and impedes the efficacy of anti-cancer treatments, underscoring the importance of targeting stress pathways to improve therapeutic results.

Single-molecule scale quantification reveals interactions underlying protein-protein interface: from forces to non-covalent bonds.

Protein-protein interactions (PPIs) between the B-cell lymphoma 2 (Bcl-2) family are considered a major driving force in cell cycle regulation and signaling. However, how this interfacial noncovalent interaction is achieved molecularly remains poorly understood. Herein, anti-apoptotic protein (Bcl-2) and pro-apoptotic protein (BAX) were used as models and their PPIs were explored for the first time using atomic force microscopy-based single-molecule force spectroscopy (SMFS) and in silico approaches. In addition, we used advanced analytical models, including multiple kinetic models, thermodynamic models, Poisson distributions, and contact angle molecular recognition to fully reveal the complexity of the BAX/Bcl-2 interaction interfaces. We propose that the binding kinetics between BAX/Bcl-2 are mainly mediated by specific (hydrogen bonding) and non-specific forces (hydrophobic interactions and electrostatic interactions) and show that the complicated multivalent binding interaction induces stable BAX/Bcl-2 complexes. This study enriches our understanding of the molecular mechanisms by which BAX interacts with Bcl-2. It provides valuable insights into the physical factors that need to be considered when designing PPI inhibitors.

AgingReG: a curated database of aging regulatory relationships in humans.

Aging and cellular senescence are characterized by a progressive loss of physiological integrity, which could be triggered by aging factors such as physiological, pathological and external factors. Numerous studies have shown that gene regulatory events play crucial roles in aging, increasing the need for a comprehensive repository of regulatory relationships during aging. Here, we established a manually curated database of aging factors (AgingReG, https://bio.liclab.net/Aging-ReG/), focusing on the regulatory relationships during aging with experimental evidence in humans. By curating thousands of published literature, 2157 aging factor entries (1345 aging gene entries, 804 external factor entries and eight aging-related pathway entries) and related regulatory information were manually curated. The regulatory relationships were classified into four types according to their functions: (i) upregulation, which indicates that aging factors upregulate the expression of target genes during aging; (ii) downregulation, which indicates that aging factors downregulate the expression of target genes during aging; (iii) activation, which indicates that aging factors influence the activity of target genes during aging and (iv) inhibition, which indicates that aging factors inhibit the activation of target molecule activity, leading to declined or lost target activity. AgingReG involves 651 upregulating pairs, 632 downregulating pairs, 330 activation-regulating pairs and 34 inhibition-regulating pairs, covering 195 disease types and more than 800 kinds of cells and tissues from 1784 published literature studies. AgingReG provides a user-friendly interface to query, browse and visualize detailed information about the regulatory relationships during aging. We believe that AgingReG will serve as a valuable resource database in the field of aging research. Database URL: https://bio.liclab.net/Aging-ReG/.

Effect of various hepatectomy procedures on circulating tumor cells in postoperative patients: a case-matched comparative study.

Background: The objective of this study is to elucidate the prevalence of systemic circulating tumor cells (CTCs) prior to and following resection of hepatocellular carcinoma (HCC), and to compare the disparities in postoperative CTCs in terms of quantity and classifications between the open liver resection (OPEN) and laparoscopic liver resection (LAP) cohorts. Patients materials and methods: From September 2015 to May 2022, 32 consecutive HCC patients who underwent laparoscopic liver resection at Southwest Hospital were retrospectively enrolled in this study. The clinicopathological data were retrieved from a prospectively collected computer database. Patients in the OPEN group matched at a 1:1 ratio with patients who underwent open liver resection during the study period on age, gender, tumor size, number of tumors, tumor location, hepatitis B surface antigen (HBsAg) positivity, alpha-fetoprotein (AFP) level, TNM and Child-Pugh staging from the database of patients to form the control group. The Can-Patrol CTC enrichment technique was used to enrich and classify CTCS based on epithelial-mesenchymal transformation phenotypes. The endpoint was disease-free survival (DFS), and the Kaplan-Meier method and multiple Cox proportional risk model were used to analyze the influence of clinicopathological factors such as total CTCs and CTC phenotype on prognosis. Results: The mean age of the 64 patients with primary liver cancer was 52.92 years (23-71), and 89.1% were male. The postoperative CTC clearance rate was more significant in the OPEN group. The total residual CTC and phenotypic CTC of the LAP group were significantly higher than those of the OPEN group (p = 0.017, 0.012, 0.049, and 0.030, respectively), which may increase the possibility of metastasis (p = 0.042). In Kaplan-Meier analysis, DFS was associated with several clinicopathological risk factors, including Barcelona Clinical Liver Cancer (BCLC) stage, tumor size, and vascular invasion. Of these analyses, BCLC Stage [p = 0.043, HR (95% CI) =2.03(1.022-4.034)], AFP [p = 0.007, HR (95% CI) =1.947 (1.238-3.062)], the number of positive CTCs [p = 0.004, HR (95% CI) =9.607 (2.085-44.269)] and vascular invasion [p = 0.046, HR (95% CI) =0.475 (0.22-1.023)] were significantly associated with DFS. Conclusion: In comparison to conventional OPEN technology, LAP technology has the capacity to augment the quantity of epithelial, mixed, and mesenchymal circulating tumor cells (CTCs). Following the surgical procedure, there was a notable increase in the total CTCs, epithelial CTCs, and mixed CTCs within the LAP group, indicating a potential drawback of LAP in facilitating the release of CTCs.

Mechanism of multidrug resistance to chemotherapy mediated by P­glycoprotein (Review).

Multidrug resistance (MDR) seriously limits the clinical application of chemotherapy. A mechanism underlying MDR is the overexpression of efflux transporters associated with chemotherapeutic drugs. P­glycoprotein (P­gp) is an ATP­binding cassette (ABC) transporter, which promotes MDR by pumping out chemotherapeutic drugs and reducing their intracellular concentration. To date, overexpression of P­gp has been detected in various types of chemoresistant cancer and inhibiting P­gp­related MDR has been suggested. The present review summarizes the mechanisms underlying MDR mediated by P­gp in different tumors and evaluated the related signaling pathways, with the aim of improving understanding of the current status of P­gp­mediated chemotherapeutic resistance. This review focuses on the main mechanisms of inhibiting P­gp­mediated MDR, with the aim of providing a reference for the study of reversing P­gp­mediated MDR. The first mechanism involves decreasing the efflux activity of P­gp by altering its conformation or hindering P­gp­chemotherapeutic drug binding. The second inhibitory mechanism involves inhibiting P­gp expression to reduce efflux. The third inhibitory mechanism involves knocking out the ABCB1 gene. Potential strategies that can inhibit P­gp include certain natural products, synthetic compounds and biological techniques. It is important to screen lead compounds or candidate techniques for P­gp inhibition, and to identify inhibitors by targeting the relevant signaling pathways to overcome P­gp­mediated MDR.

Elevated urine albumin creatinine ratio increases cardiovascular mortality in coronary artery disease patients with or without type 2 diabetes mellitus: a multicenter retrospective study.

BACKGROUND: Albuminuria has been suggested as an atherosclerotic risk factor among the general population. However, whether this association will be amplified in patients with coronary artery disease (CAD) is unknown. It is also unknown whether diabetes mellitus confounds the association. We aim to analyse the prognosis of elevated urine albumin creatinine ratio (uACR) in the CAD population with or without type 2 diabetes mellitus (T2DM). METHODS: This multi-center registry cohort study included 5,960 patients with CAD. Patients were divided into T2DM and non-T2DM group, and baseline uACR levels were assessed on three grades (low: uACR < 10 mg/g, middle: 10 mg/g ≤ uACR < 30 mg/g, and high: uACR ≥ 30 mg/g). The study endpoints were cardiovascular mortality and all-cause mortality. RESULTS: During the median follow-up of 2.2 [1.2-3.1] years, 310 (5.2%) patients died, of which 236 (4.0%) patients died of cardiovascular disease. CAD patients with elevated uACR had a higher risk of cardiovascular mortality (middle: HR, 2.32; high: HR, 3.22) than those with low uACR, as well as all-cause mortality. Elevated uACR increased nearly 1.5-fold risk of cardiovascular mortality (middle: HR, 2.33; high: HR, 2.34) among patients without T2DM, and increased 1.5- fold to 3- fold risk of cardiovascular mortality in T2DM patients (middle: HR, 2.49; high: HR, 3.98). CONCLUSIONS: Even mildly increased uACR could increase the risk of cardiovascular mortality in patients with CAD, especially when combined with T2DM.

Combined versus sequential penetrating keratoplasty and cataract surgery for herpes simplex keratitis: a retrospective study.

Purpose: To compare the surgical outcomes of combined penetrating keratoplasty (PK) and cataract surgery with those of sequential surgery (cataract surgery after PK) for herpes simplex keratitis (HSK). Methods: The medical records of consecutive patients diagnosed with HSK who underwent combined or sequential PK and cataract surgery in active and stable stages between June 2015 and June 2022 were reviewed retrospectively. Complications, graft survival, endothelial cell density (ECD), and final BCVA were compared and analyzed between both surgical methods in each stage. Results: A total of 171 eyes of 171 patients were enrolled, including active stage (69 combined, 46 sequential) and stable stage (34 combined, 22 sequential). The average follow up was 24.2 ± 15.8 months (range, 3 months - 48 months). The final BCVA had obvious improvement and the postoperative ECD was not different in combined and sequential groups of each stage. In sequential group of active stage, 66.7% of persistent epithelial defects and 50% of HSK recurrence occurred within 3 months after cataract surgery; nevertheless, compared to that in sequential group, capsular rupture (p = 0.021), persistent epithelial defects (p = 0.027), and HSK recurrence (p = 0.035) occurred more frequently in combined group, leading to a lower graft survival rate (p = 0.045); at the last visit, 46.4 and 67.4% of grafts remained clear in combined and sequential groups, respectively. By contrary, 82.4 and 50.0% of grafts remained clear in stable stages of combined and sequential groups at the last visit, respectively, and a higher graft survival rate was observed in combined group (p = 0.030). Conclusion: Although the postoperative ECD is not different between two surgical groups in each stage, sequential surgery in active stage of HSK seems to have advantages in less complications and higher graft survival rate, whereas combined surgery in stable stage has a better outcome than that in sequential surgery.