Lanthanum chloride exerts therapeutic potential for chronic kidney disease by suppressing nanohydroxyapatite-induced mitophagy and mitochondria-mediated apoptosis.

OBJECTIVE: To investigate the protective effect of lanthanum chloride on kidney injury in chronic kidney disease and its mechanism. METHODS: 1. Patients with CKD stage 2-5 were selected to analyze the effect of lanthanum-containing preparations on CKD. 2. Sixty healthy male Wistar rats were randomly divided into control group, model group, lanthanum chloride groups (0.03 ng/kg, 0.1 ng/kg, 0.3 ng/kg, q.3d., i.v.), and lanthanum carbonate group (0.3 g/kg, q.d., p.o.). The model group was given 2 % adenine suspension (200 mg/kg, q.d., p.o.) for the first two weeks, followed by adenine (200 mg/kg, b.i.d., p.o.) for 2 weeks, and all animals were sacrificed after eight weeks of administration. 3. The serum and kidneys of rats in each group were collected to detect the oxidative stress indicators and the expressions of LC3B-Ⅱ/Ⅰ, p62, Bcl-2, Bax, Caspase-3 and Cleaved Caspase-3. 4. Human renal tubular epithelial cells (HK-2 cells) were divided into control group, model group, lanthanum chloride group, pyrophosphate (PPI) group, chloroquine (CQ) group, rapamycin group, doxorubicin (DOX) group and N-acetyl-L-cysteine (NAC) group. The mitochondrial status, mitophagy and apoptosis levels were detected. RESULTS: 1.Lanthanum-containing preparations can significantly reduce the biochemical indexes of kidney injury in patients with CKD. 2. In the model group, the glomerular and renal tubular edema, the mitochondria were short and round, and the expression of LC3B-Ⅱ/Ⅰ and Bax increased, while the expression of P62, Bcl-2 and Caspase-3 decreased, and there was a significant improvement in the administration group, especially the 0.1 ng/kg group and lanthanum carbonate group. 3. In the HK-2 cell model group, mitochondrial membrane potential decreased, morphology changed and the results were reversed by lanthanum chloride. CONCLUSION: Lanthanum chloride may alter the morphology of nano-hydroxyapatite, thereby inhibiting its induced mitophagy and mitochondria-mediated apoptosis, and ultimately improve CKD renal injury effectively.

The Effects of Baitouweng Decoction on Salmonella Typhimurium Infection and Its Underlying Mechanisms Evaluated by In Vivo and In Vitro Experiments, Network Pharmacology Analysis, and Molecular Docking Technology.

Salmonella Typhimurium is a foodborne pathogen threatening livestock and human health. It is highly resistant to commonly used clinical antibiotics, and it is urgently needed to explore new anti-Salmonella treatment schemes. In this study, first, our in vivo mouse experiments showed that Baitouweng decoction (BTW), a classical Traditional Chinese Medicine (TCM) prescription, had good efficacy against Salmonella Typhimurium infection: mitigating weight loss of mice; lowering the bacterial load of liver, spleen, and colon; reducing the production of serum inflammatory factors (interleukin-1ß and tumor necrosis factor-α); and decreasing histological index scores than that in the Salmonella Typhimurium infection group. Furthermore, we explored the potential active components and molecular mechanism of BTW in the treatment of Salmonella Typhimurium infection. A total of 465 compounds of BTW were retrieved from herb website and 227 bioactive compounds were identified, 911 potential BTW-related targets and 1,602 disease targets of Salmonella Typhimurium infection were acquired by ten public analytical databases, among them, 188 genes were overlay targets of BTW-Salmonella Typhimurium; String, Metascape, and Cytoscape plug-in Molecular Complex Detection and ClueGo analysis pointed that BTW exerted an anti-Salmonella effect through a multicomponent, multitarget, and multipathway manner, including 10 hub targets (TNF, AKT CASP3, ALB, EGFR, JUN, MAPK, STAT3, VEGFA, and TP53) and 94 pathways such as cell apoptosis, inflammation, and metabolism. Finally, AutoDock Vina showed that the hub target AKT1 with menispermine and quercetin had good binding energy, which was confirmed by the in vitro cellular thermal shift assay and drug affinity responsive target stability assay. This study laid the foundation for further study of BTW mechanism and for further development of BTW anti-Salmonella.

Causal association between peripheral immune cells and IgA nephropathy: a Mendelian randomization study.

Background: The relationship between peripheral immune cells and immunoglobulin A nephropathy (IgAN) is widely known; however, causal evidence of this link is lacking. Here, we aimed to determine the causal effect of peripheral immune cells, specifically total white blood cells, lymphocytes, monocytes, basophils, eosinophils, and neutrophils, as well as lymphocyte subset traits, on the IgAN risk using a Mendelian randomization (MR) analysis. Methods: The inverse-variance weighted (IVW) method was used for the primary analysis. We applied three complementary methods, including the weighted median, MR-Egger regression, and MR-PRESSO, to detect and correct for the effect of horizontal pleiotropy. Additionally, we performed a multivariable MR (MVMR) analysis, adjusting for the effects of C-reactive protein (CRP) levels. The roles of specific lymphocyte subtypes and their significance have garnered interest. Bidirectional two-sample MR analysis was performed to test the potential causal relationships between immune traits, including median fluorescence intensities (MFIs) and the relative cell count (AC), and IgAN. Results: The IVW-MR analysis suggested a potential causal relationship between lymphocyte counts and IgAN in Europe (OR per 1-SD increase: 1.43, 95% CI: 1.08-1.88, P = 0.0123). The risk effect of lymphocytes remained even after adjusting for CRP levels using the MVMR method (OR per 1-SD increase: 1.44, 95% CI: 1.05-1.96, P = 0.0210). The other sensitivity analyses showed a consistent trend. The largest GWAS published to date was used for peripheral blood immunophenotyping to explore the potential causal relationship between peripheral immune cell subsets and IgAN. Six AC-IgAN and 14 MFI-IgAN pairs that reached statistical significance (P < 0.05) were detected. Notably, CD3, expressed in eight subsets of T cells, consistently showed a positive correlation with IgAN. The bidirectional MR analysis did not reveal any evidence of reverse causality. According to the sensitivity analysis, horizontal pleiotropy was unlikely to distort the causal estimates. Conclusions: Genetically determined high lymphocyte counts were associated with IgAN, supporting that high lymphocyte counts is causal risk factor for IgAN.

Endosialin-positive CAFs promote hepatocellular carcinoma progression by suppressing CD8+ T cell infiltration.

BACKGROUND AND AIMS: Endosialin, also known as tumor endothelial marker1 or CD248, is a transmembrane glycoprotein that is mainly expressed in cancer-associated fibroblasts (CAFs) in hepatocellular carcinoma (HCC). Our previous study has found that endosialin-positive CAFs could recruit and induce the M2 polarization of macrophages in HCC. However, whether they may regulate other types of immune cells to promoting HCC progression is not known. APPROACH AND RESULTS: The growth of both subcutaneous and orthotopic HCC tumors was significantly inhibited in endosialin knockout (ENKO) mice. Single-cell sequencing and flow cytometry analysis showed that tumor tissues from ENKO mice had increased CD8+ T cell infiltration. Mixed HCC tumor with Hepa1-6 cells and endosialin knockdown fibroblasts also showed inhibited growth and increased CD8+ T cell infiltration. Data from in vitro co-culture assay, chemokine array and antibody blocking assay, RNA-seq and validation experiments showed that endosialin inhibits the phosphorylation and nuclear translocation of STAT1 in CAFs. This inhibition leads to a decrease in CXCL9/10 expression and secretion, resulting in the suppression of CD8+ T cell infiltration. High level of endosialin protein expression was correlated with low CD8+ T infiltration in the tumor tissue of HCC patients. The combination therapy of endosialin antibody and PD-1 antibody showed synergistic antitumor effect compared with either antibody used individually. CONCLUSIONS: Endosialin could inhibit CD8+ T cell infiltration by inhibiting the expression and secretion of CXCL9/10 in CAFs, thus promote HCC progression. Combination therapy with endosialin antibody could increase the antitumor effect of PD-1 antibody in HCC, which may overcome the resistance to PD-1 blockade.

Dietary vitamin B3 supplementation induces the antitumor immunity against liver cancer via biased GPR109A signaling in myeloid cell.

The impact of dietary nutrients on tumor immunity remains an area of ongoing investigation, particularly regarding the specific role of vitamins and their mechanism. Here, we demonstrate that vitamin B3 (VB3) induces antitumor immunity against liver cancer through biased GPR109A axis in myeloid cell. Nutritional epidemiology studies suggest that higher VB3 intake reduces liver cancer risk. VB3 supplementation demonstrates antitumor efficacy in multiple mouse models through alleviating the immunosuppressive tumor microenvironment (TME) mediated by tumor-infiltrating myeloid cell, thereby augmenting effectiveness of immunotherapy or targeted therapy in a CD8+ T cell-dependent manner. Mechanically, the TME induces aberrant GPR109A/nuclear factor κB (NF-κB) activation in myeloid cell to shape the immunosuppressive TME. In contrast, VB3 activates ß-Arrestin-mediated GPR109A degradation and NF-κB inhibition to suppress the immunosuppressive polarization of myeloid cell, thereby activating the cytotoxic function of CD8+ T cell. Overall, these results expand the understanding of how vitamins regulate the TME, suggesting that dietary VB3 supplementation is an adjunctive treatment for liver cancer.

Association between non-injection drug use and hepatitis C infection among HIV-negative men who have sex with men.

BACKGROUND: Prior research predominantly examined the association between HIV-positive men who have sex with men (MSM) or those using injection drugs and hepatitis C virus (HCV) infection. However, limited attention has been given to understanding the association among HIV-negative MSM who do not inject drugs. This gap leaves apportion of the population unexamined, potentially overlooking important factor that may contribute to the transmission and prevalence of HCV. This study aims to investigate the relationship between non-injection drug use and HCV infection in this population. METHODS: In this cross-sectional study, we analyzed data on 118 MSM who reported use of non-injection drugs. The participants were recruited from two inner-city communities in Houston, TX, between 2004 and 2007 and were negative for both HIV and hepatitis B virus infection. Latent class analysis (LCA) was used to identify drug use latent classes. Multinomial logistic regression analysis was used to evaluate the association between drug use latent class and HCV infection. RESULTS: Four distinct latent classes of drug use were identified: class 1, persons ≥ 42 years of age who used only crack cocaine; class 2, persons approximately 42 years of age who used > 2 drugs; class 3, persons < 42 years of age who used > 5 drugs; and class 4, persons ≥ 42 years of age who used > 6 drugs. Class 4 was significantly associated with HCV infection. The odds of HCV infection in members of class 4 was 17 times higher than in class 2 members (adjusted odds ratio [aOR] = 16.9, 95% confidence interval [CI]: 1.4-205.4) and almost 22 times higher than in class 3 members (aOR = 21.8, 95% CI: 1.5-322.8). CONCLUSIONS: Among MSM with non-injection drug use, the subgroup of individuals who were ≥ 42 years of age and used multiple drugs (including heroin, speedball, methamphetamine, crack cocaine, and marijuana) had a high probability of HCV infection. Public health and education programs, as well as drug treatment and rehabilitation programs, should be developed for this high-risk subgroup of individuals to prevent HCV acquisition and transmission.

Cell-penetrating peptides TAT and 8R functionalize P22 virus-like particles to enhance tissue distribution and retention in vivo.

Virus-like particles (VLPs) are used as nanocontainers for targeted drug, protein, and vaccine delivery. The phage P22 VLP is an ideal macromolecule delivery vehicle, as it has a large exterior surface area, which facilitates multivalent genetic and chemical modifications for cell recognition and penetration. Arginine-rich cell-penetrating peptides (CPPs) can increase cargo transport efficiency in vivo. However, studies on the tissue distribution and retention of P22 VLPs mediated by TAT and 8R are lacking. This study aimed to analyze the TAT and 8R effects on the P22 VLPs transport efficiency and tissue distribution both in vitro and in vivo. We used a prokaryotic system to prepare P22 VLP self-assembled particles and expressed TAT-or 8R-conjugated mCherry on the VLP capsid protein as model cargoes and revealed that the level of P22 VLP-mCherry penetrating the cell membrane was low. However, both TAT and 8R significantly promoted the cellular uptake efficiency of P22 VLPs in vitro, as well as enhanced the tissue accumulation and retention of P22 VLPs in vivo. At 24 h postinjection, TAT enhanced the tissue distribution and retention in the lung, whereas 8R could be better accumulation in brain. Thus, TAT was superior in terms of cellular uptake and tissue accumulation in the P22 VLPs delivery system. Understanding CPP biocompatibility and tissue retention will expand their potential applications in macromolecular cargo delivery.

The impact of tumor resection on survival and functional outcomes for patients with primary central nervous system lymphoma.

PURPOSE: The role of tumor resection remains undetermined in treating primary central nervous system lymphomas (PCNSLs). This study aimed to clarify the impact of tumor resection on survival and functional outcomes, and to identify subgroups benefiting from resection. METHODS: We retrospectively reviewed records from 2010 to 2021 for PCNSL diagnosed at Chang Gung Memorial Hospital, Linkou. Patients were categorized by extent of resection: gross total resection (GTR), partial resection (PR), and biopsy. Univariate and multivariate analyses were performed to identify prognostic factors for survival and functional outcomes. Subgroup analysis was conducted to characterize patients who benefit from tumor resection. RESULTS: Of 88 patients, 12 had GTR, 25 had PR, and 51 received biopsy. GTR correlated with longer progression free survival (PFS) (HR 0.25, p=0.039), remaining significant in multivariate analysis (adjusted HR 0.09, p=0.004). In solitary PCNSLs, GTR also independently predicted longer PFS (adjusted HR 0.13, p= 0.023). Patients with dominant tumors measuring ≥ 3 cm trended towards improved overall survival (OS) with cytoreductive surgery versus biopsy (median survival 38.6 months vs 22.3 months, p=0.083). Age ≥ 60 years (adjusted OR 16.9, p = 0.008) and preoperative Karnofsky Performance Scale ≤ 70 (adjusted OR 4.97, p = 0.049) predicted poorer functional outcomes, while radiation therapy (adjusted OR 0.10, p = 0.033) was protective. CONCLUSIONS: GTR significantly improved PFS in treating PCNSLs, particularly in solitary cases. For patients with dominant tumors measuring ≥ 3 cm, cytoreductive surgery may improve OS. Neither cytoreductive surgery nor GTR correlated with poor functional outcomes.

Increasing the tumour targeting of antitumour drugs through anlotinib-mediated modulation of the extracellular matrix and the RhoA/ROCK signalling pathway.

Anlotinib has strong antiangiogenic effects and leads to vessel normalization. However, the "window period" characteristic in regulating vessel normalization by anlotinib cannot fully explain the long-term survival benefits achieved through combining it with other drugs. In this study, through RNA sequencing (RNA-seq) and label-free quantitative proteomics analysis, we discovered that anlotinib regulated the expression of components of the extracellular matrix (ECM), leading to a significant reduction in ECM stiffness. Our bioinformatic analysis revealed a potential positive relationship between the ECM pathway and gefitinib resistance, poor treatment outcomes for programmed death 1 (PD-1) targeting, and unfavourable prognosis following chemotherapy in lung cancer patients. We administered anlotinib in combination with these antitumour drugs and visualized their distribution using fluorescent labelling in various tumour types. Notably, our results demonstrated that anlotinib prolonged the retention time and distribution of antitumour drugs at the tumour site. Moreover, the combination therapy induced notable loosening of the tumour tissue structure. This reduction was associated with decreased interstitial fluid pressure and tumour solid pressure. Additionally, we observed that anlotinib effectively suppressed the Ras homologue family member A (RhoA)/Rho-associated protein kinase (ROCK) signalling pathway. These findings suggest that, in addition to its antiangiogenic and vessel normalization effects, anlotinib can increase the distribution and retention of antitumour drugs in tumours by modulating ECM expression and physical properties through the RhoA/ROCK signalling pathway. These valuable insights contribute to the development of combination therapies aimed at improving tumour targeting in cancer treatment.

CRISPR-Cas13d targeting suppresses repeat-associated non-AUG translation of C9orf72 hexanucleotide repeat RNA.

A hexanucleotide GGGGCC repeat expansion in the non-coding region of C9orf72 gene is the most common genetic mutation identified in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The resulting repeat RNA and dipeptide repeat proteins from non-conventional repeat translation have been recognized as important markers associated with the diseases. CRISPR-Cas13d, a powerful RNA targeting tool, has faced challenges in effectively targeting RNA with stable secondary structures. Here we report that CRISPR-Cas13d can be optimized to specifically target GGGGCC repeat RNA. Our results demonstrate that the CRISPR-Cas13d system can be harnessed to significantly diminish the translation of poly-dipeptides originating from the GGGGCC repeat RNA. This efficacy has been validated in various cell types, including induced pluripotent stem cells and differentiated motor neurons originating from C9orf72-ALS patients, as well as in C9orf72 repeat transgenic mice. These findings demonstrate the application of CRISPR-Cas13d in targeting RNA with intricate higher-order structures and suggest a potential therapeutic approach for ALS and FTD.

Trade optimality and micro-nutrient productivity: Assessing the impact of crop trade on nitrogen fertiliser use efficiency.

Intensification of agricultural practices has been pivotal in meeting the nutritional demands of a burgeoning global population. However, the widespread application of nitrogen (N) fertilisers has contributed to environmental pollution. In this study, we quantitatively assessed the role of international crop trade in optimising the productivity of micro-nutrients and its implications for N fertiliser use. Using a comprehensive dataset spanning from 1961 to 2019, we analysed the trade flows of seven key micro-nutrients-vitamin C (VC), vitamin B3 (VB3), vitamin B6 (VB6), calcium (Ca), magnesium (Mg), iron (Fe), and zinc (Zn)-embedded in agricultural products. We developed a novel framework to evaluate trade optimality and functionality based on the concentration-weighted productivity of micro-nutrients per kilogram of N fertiliser. Our findings reveal that while international trade has generally contributed to enhancing micro-nutrient productivity per unit of N fertiliser, trade optimality has shown a decreasing trend. High-productivity countries tend to export less relative to their potential, whereas countries with lower productivity import a larger share of crops. This decoupling suggests the need to re-evaluate trade policies to ensure that they align with sustainable agricultural practices and environmental conservation goals. We also identified potential savings in N fertiliser use through optimised trade practices, with estimated savings of 15-45 Tg of N per year. This could mitigate the negative agricultural impact and demonstrates the significant role that trade can play in achieving global sustainability targets. Overall, our research underscores the importance of aligning international crop trade with sustainable N management strategies to enhance micro-nutrient availability, improve environmental outcomes, and contribute to global efforts in achieving the Sustainable Development Goals.

Immunomodulatory properties of naïve and inflammation-informed dental pulp stem cell derived extracellular vesicles.

Mesenchymal stem cell derived extracellular vesicles (MSC EVs) are paracrine modulators of macrophage function. Scientific research has primarily focused on the immunomodulatory and regenerative properties MSC EVs derived from bone marrow. The dental pulp is also a source for MSCs, and their anatomical location and evolutionary function has primed them to be potent immunomodulators. In this study, we demonstrate that extracellular vesicles derived from dental pulp stem cells (DPSC EVs) have pronounced immunomodulatory effect on primary macrophages by regulating the NFκb pathway. Notably, the anti-inflammatory activity of DPSC-EVs is enhanced following exposure to an inflammatory stimulus (LPS). These inhibitory effects were also observed in vivo. Sequencing of the naïve and LPS preconditioned DPSC-EVs and comparison with our published results from marrow MSC EVs revealed that Naïve and LPS preconditioned DPSC-EVs are enriched with anti-inflammatory miRNAs, particularly miR-320a-3p, which appears to be unique to DPSC-EVs and regulates the NFκb pathway. Overall, our findings highlight the immunomodulatory properties of DPSC-EVs and provide vital clues that can stimulate future research into miRNA-based EV engineering as well as therapeutic approaches to inflammation control and disease treatment.

Crotonylation of NAE1 Modulates Cardiac Hypertrophy via Gelsolin Neddylation.

BACKGROUND: Cardiac hypertrophy and its associated remodeling are among the leading causes of heart failure. Lysine crotonylation is a recently discovered posttranslational modification whose role in cardiac hypertrophy remains largely unknown. NAE1 (NEDD8-activating enzyme E1 regulatory subunit) is mainly involved in the neddylation modification of protein targets. However, the function of crotonylated NAE1 has not been defined. This study aims to elucidate the effects and mechanisms of NAE1 crotonylation on cardiac hypertrophy. METHODS: Crotonylation levels were detected in both human and mouse subjects with cardiac hypertrophy through immunoprecipitation and Western blot assays. TMT-labeled quantitative lysine crotonylome analysis was performed to identify the crotonylated proteins in a mouse cardiac hypertrophic model induced by transverse aortic constriction. We generated NAE1 knock-in mice carrying a crotonylation-defective lysine to arginine K238R (lysine to arginine mutation at site 238) mutation (NAE1 K238R) and NAE1 knock-in mice expressing a crotonylation-mimicking lysine to glutamine K238Q (lysine to glutamine mutation at site 238) mutation (NAE1 K238Q) to assess the functional role of crotonylation of NAE1 at K238 in pathological cardiac hypertrophy. Furthermore, we combined coimmunoprecipitation, mass spectrometry, and dot blot analysis that was followed by multiple molecular biological methodologies to identify the target GSN (gelsolin) and corresponding molecular events contributing to the function of NAE1 K238 crotonylation. RESULTS: The crotonylation level of NAE1 was increased in mice and patients with cardiac hypertrophy. Quantitative crotonylomics analysis revealed that K238 was the main crotonylation site of NAE1. Loss of K238 crotonylation in NAE1 K238R knock-in mice attenuated cardiac hypertrophy and restored the heart function, while hypercrotonylation mimic in NAE1 K238Q knock-in mice significantly enhanced transverse aortic constriction-induced pathological hypertrophic response, leading to impaired cardiac structure and function. The recombinant adenoviral vector carrying NAE1 K238R mutant attenuated, while the K238Q mutant aggravated Ang II (angiotensin II)-induced hypertrophy. Mechanistically, we identified GSN as a direct target of NAE1. K238 crotonylation of NAE1 promoted GSN neddylation and, thus, enhanced its protein stability and expression. NAE1 crotonylation-dependent increase of GSN promoted actin-severing activity, which resulted in adverse cytoskeletal remodeling and progression of pathological hypertrophy. CONCLUSIONS: Our findings provide new insights into the previously unrecognized role of crotonylation on nonhistone proteins during cardiac hypertrophy. We found that K238 crotonylation of NAE1 plays an essential role in mediating cardiac hypertrophy through GSN neddylation, which provides potential novel therapeutic targets for pathological hypertrophy and cardiac remodeling.

Altimella gen. nov., a new genus of Cicurinidae (Arachnida, Araneae) from Xizang, China, with description of two new species.

Altimella Wang & Zhang, gen. nov., a new genus belonging to Cicurinidae, is established, and two new species are described, Altimellanedong Wang & Zhang, sp. nov. (♂♀, type species) and A.ngamring Wang & Zhang, sp. nov. (♂♀), from Xizang, China. Detailed descriptions of somatic features and genital characteristics, photos of the habitus, photos and drawings of the copulatory organs, and a distribution map are provided.

Study on the mechanisms and Pharmacodynamic substances of Lian-Gui-Ning-Xin-Tang on Arrhythmia Therapy based on Pharmacodynamic-Pharmacokinetic associations.

Background: The Chinese herbal compound Lian-Gui-Ning-Xin-Tang (LGNXT), composed of 9 herbs, has a significant antiarrhythmic effect. Previous studies have confirmed that preventing intracellular Ca2+ overload and maintaining intracellular Ca2+ homeostasis may be the important antiarrhythmic mechanisms of LGNXT. Recent studies are focused on elucidating the mechanisms and pharmacodynamic substances of LGNXT. Purpose: 1) To investigate the antiarrhythmic mechanisms of LGNXT; 2) to explore the association of pharmacodynamics (PD) and pharmacokinetics (PK) of the potential pharmacodynamic substances in LGNXT to further verify the mechanisms of action. Methods: First, pharmacodynamic studies were conducted to determine the effect of LGNXT in arrhythmia at the electrophysiological, molecular, and tissue levels, and the "effect-time" relationship of LGNXT was further proposed. Next, an HPLC-MS/MS method was established to identify the "dose-time" relationship of the 9 potential compounds. Combining the "effect-time" and "dose-time" curves, the active ingredients closely related to the inhibition of inflammation, oxidative stress, and energy metabolism were identified to further verify the mechanisms and pharmacodynamic substances of LGNXT. Results: Pretreatment with LGNXT could delay the occurrence of arrhythmias and reduce their duration and severity. LGNXT exerted antiarrhythmic effects by inhibiting MDA, LPO, IL-6, and cAMP; restoring Cx43 coupling function; and upregulating SOD, Ca2+-ATPase, and Na+-K+-ATPase levels. PK-PD association showed that nobiletin, methylophiopogonanone A, trigonelline, cinnamic acid, liquiritin, dehydropolisic acid, berberine, and puerarin were the main pharmacodynamic substances responsible for inhibiting the inflammatory response in arrhythmia. Methylophiopogonanone A, dehydropalingic acid, nobiletin, trigonelline, berberine, and puerarin in LGNXT exerted antiarrhythmic effects by inhibiting oxidative stress. Dehydropalingic acid, berberine, cinnamic acid, liquiritin, puerarin, trigonelline, methylophiopogonanone A, nobiletin, and tetrahydropalmatine exerted antiarrhythmic effects by inhibiting the energy-metabolism process. Conclusions: LGNXT had a positive intervention effect on arrhythmias, especially ventricular tachyarrhythmias, which could inhibit inflammation, oxidative stress, and energy metabolism; positively stabilize the structure, and remodify the function of myocardial cell membranes. Additionally, the PD-PK association study revealed that methylophiopogonanone A, berberine, trigonelline, liquiritin, puerarin, tetrahydropalmatine, nobiletin, dehydropachymic acid, and cinnamic acid directly targeted inflammation, oxidative stress, and energy metabolism, which could be considered the pharmacodynamic substances of LGNXT. Thus, the antiarrhythmic mechanisms of LGNXT were further elucidated.

Identification of novel drug targets for osteoarthritis by integrating genetics and proteomes from blood.

BACKGROUND: Osteoarthritis (OA) is a degenerative osteoarticular disease, involving genetic predisposition. How the risk variants confer the risk of OA through their effects on proteins remains largely unknown. Therefore, we aimed to discover new and effective drug targets for OA and its subtypes. METHODS: A proteome-wide association study (PWAS) was performed based on OA and its subtypes genome-wide association studies (GWAS) summary datasets and the protein quantitative trait loci (pQTL) data. Subsequently, Mendelian randomization (MR) and colocalization analysis was conducted to estimate the associations between protein and OA risk. The replication analysis was performed in an independent dataset of human plasma pQTL data. RESULTS: The abundance of seven proteins was causally related to OA, two proteins to knee OA and six proteins to hip OA, respectively. We replicated 2 of these proteins using an independent pQTL dataset. With the further support of colocalization, and higher ECM1 level was causally associated with a higher risk of OA and hip OA. Higher PCSK1 level was causally associated with a lower risk of OA. And higher levels of ITIH1, EFEMP1, and ERLEC1 were associated with decreased risk of hip OA. CONCLUSION: Our study provides new insights into the genetic component of protein abundance in OA and a promising therapeutic target for future drug development.

The mitochondrial stress signaling tunes immunity from a view of systemic tumor microenvironment and ecosystem.

Mitochondria play important roles in cell fate, calcium signaling, mitophagy, and the signaling through reactive oxygen species (ROS). Recently, mitochondria are considered as a signaling organelle in the cell and communicate with other organelles to constitute the mitochondrial information processing system (MIPS) that transduce input-to-output biological information. The success in immunotherapy, a concept of systemic therapy, has been proved to be dependent on paracrine interactions within the tumor microenvironment (TME) and distant organs including microbiota and immune components. We will adopt a broader view from the concept of TME to tumor micro- and macroenvironment (TM 2 E) or tumor-organ ecosystem (TOE). In this review, we will discuss the role of mitochondrial signaling by mitochondrial ROS, calcium flux, metabolites, mtDNA, vesicle transportation, and mitochondria-derived peptide in the TME and TOE, in particular immune regulation and effective cancer immunotherapy.

Intranasal esketamine versus esketamine-dexmedetomidine combination for premedication in pediatric patients undergoing strabismus surgery: a randomized controlled trial.

Background: Preoperative fear and anxiety are prevalent in children undergoing surgery. The combination of esketamine and dexmedetomidine has been proposed as a promising premedication for enhancing preoperative sedation and analgesia. This study compared the premedication efficacy of intranasal esketamine alone and esketamine-dexmedetomidine combination in pediatric patients undergoing strabismus surgery. Methods: One hundred and eighty preschool children aged 2-6 years scheduled for strabismus surgery were enrolled and randomly assigned to one of the three groups: intranasal premedication with esketamine 2 mg/kg (Group K), esketamine 1 mg/kg and dexmedetomidine 1 µg/kg (Group KD1), or esketamine 0.5 mg/kg and dexmedetomidine 2 µg/kg (Group KD2). The primary outcome was the level of sedation following the intervention, as measured by the modified Yale preoperative anxiety scale (mYPAS) and sedation scale (SS). Secondary outcomes included onset time of sedation, the successful rate of peripheral intravenous cannulation, parental separation anxiety scale (PSAS), mask acceptance scale (MAS), wake-up time, duration of stay in the post-anesthesia care unit (PACU), and premedication-related adverse effects. Results: After premedication, the mYPAS score gradually decreased in the three groups, with lower values in Group K than in Group KD1 and Group KD2 patients in 1, 5, and 10 min. SS in Group KD1 and Group KD2 steadily increased until 40 min after premedication, while SS in Group K increased in the first 5 min after premedication and maintained consistent levels during the remaining time. Sedation onset was substantially faster in Group K patients (11.4±7.8 min) than Group KD1 (18.1±7.5 min, P=0.006) and Group KD2 (18.4±6.8 min, P<0.001). PSAS, separation status, the successful rate of peripheral intravenous cannulation, and MAS were comparable among groups. There was no significant difference in terms of emergence time or duration of stay in the PACU among groups. More gastrointestinal events were observed in Group K (P<0.001). Conclusions: Intranasal premedication with 2 mg/kg esketamine produced a more rapid onset of sedation accompanied by more gastrointestinal reactions compared with a combination of esketamine and dexmedetomidine. Trial Registration: ClinicalTrials.gov identifier: NCT04757675.

The role of variation in phonological and semantic working memory capacities in sentence comprehension: neural evidence from healthy and brain-damaged individuals.

Research on the role of working memory (WM) in language processing has typically focused on WM for phonological information. However, considerable behavioral evidence supports the existence of a separate semantic WM system that plays a greater role in language processing. We review the neural evidence that supports the distinction between phonological and semantic WM capacities and discuss how individual differences in these capacities relate to sentence processing. In terms of neural substrates, findings from multivariate functional MRI for healthy participants and voxel-based lesion-symptom mapping for brain-damaged participants imply that the left supramarginal gyrus supports phonological WM, whereas the left inferior frontal gyrus (LIFG) and angular gyrus support semantic WM. In sentence comprehension, individual variation in semantic but not phonological WM related to performance in resolving semantic information and the LIFG region implicated in semantic WM showed fMRI activation during the resolution of semantic interference. Moreover, variation for brain-damaged participants in the integrity of a fiber tract supporting semantic WM had a greater relation to the processing of complex sentences than did the integrity of fiber tracts supporting phonological WM. Overall, the neural findings provide converging evidence regarding the distinction of these two capacities and the greater contribution of individual differences in semantic than phonological WM capacity to sentence processing.

Global, regional, and national burden of bladder cancer, 1990-2019: an age-period-cohort analysis based on the Global Burden of Disease 2019 study.

OBJECTIVES: Bladder cancer is a common malignancy worldwide, with substantial morbidity and mortality. This study aimed to assess the global, regional, and national burden of bladder cancer from 1990 to 2019 using data from the Global Burden of Disease (GBD) 2019 study and to analyze the trends using an age-period-cohort (APC) model. STUDY DESIGN: In this cross-sectional study, secondary analyses were conducted to assess the burden of bladder cancer using data from GBD 2019. METHODS: Bladder cancer prevalence, incidence, mortality, disability-adjusted life years (DALYs), and their age-standardized rates (ASRs) were obtained from the GBD 2019 study. The estimated annual percentage changes (EAPCs) were calculated to quantify the trends in ASRs. An APC analysis was performed to distinguish the effects of age, period, and cohort on the observed temporal trends. RESULTS: The global prevalence of bladder cancer increased substantially from 1990 to 2019, reaching 2,869,046.4 cases (95% UI: 2,614,200.3-3,114,474.4) in 2019. The age-standardized prevalence rate rose from 20.9 per 100,000 population in 1990 to 37.1 per 100,000 population in 2019, with an EAPC of 1.97 (95% CI: 1.93-2.01). The global burden of bladder cancer, as measured by DALYs, increased from 48.0 per 100,000 population in 1990 to 56.8 per 100,000 population in 2019, with an EAPC of 0.47 (95% CI: 0.4-0.53), demonstrating the growing impact of this disease on population health. CONCLUSIONS: This study demonstrates a significant increase in prevalence, incidence, mortality, and DALYs, with substantial variations across sociodemographic index (SDI) quintiles and GBD regions. The findings emphasize the need for concerted efforts at the global, regional, and national levels to reduce the burden of bladder cancer through primary prevention, early detection, and improved access to treatment services.