Repetitive traumatic brain injury-induced complement C1-related inflammation impairs long-term hippocampal neurogenesis.

JOURNAL/nrgr/04.03/01300535-202503000-00027/figure1/v/2024-06-17T092413Z/r/image-tiff Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus, leading to long-term cognitive impairment. However, the mechanism underlying this neurogenesis impairment remains unknown. In this study, we established a male mouse model of repetitive traumatic brain injury and performed long-term evaluation of neurogenesis of the hippocampal dentate gyrus after repetitive traumatic brain injury. Our results showed that repetitive traumatic brain injury inhibited neural stem cell proliferation and development, delayed neuronal maturation, and reduced the complexity of neuronal dendrites and spines. Mice with repetitive traumatic brain injuryalso showed deficits in spatial memory retrieval. Moreover, following repetitive traumatic brain injury, neuroinflammation was enhanced in the neurogenesis microenvironment where C1q levels were increased, C1q binding protein levels were decreased, and canonical Wnt/ß-catenin signaling was downregulated. An inhibitor of C1 reversed the long-term impairment of neurogenesis induced by repetitive traumatic brain injury and improved neurological function. These findings suggest that repetitive traumatic brain injury-induced C1-related inflammation impairs long-term neurogenesis in the dentate gyrus and contributes to spatial memory retrieval dysfunction.

Hydrogen sulfide enhances kiwifruit resistance to soft rot by regulating jasmonic acid signaling pathway.

As the third active gas signal molecule in plants, hydrogen sulfide (H2S) plays important roles in physiological metabolisms and biological process of fruits and vegetables during postharvest storage. In the present study, the effects of H2S on enhancing resistance against soft rot caused by Botryosphaeria dothidea and the involvement of jasmonic acid (JA) signaling pathway in kiwifruit during the storage were investigated. The results showed that 20 µL L-1 H2S fumigation restrained the disease incidence of B. dothidea-inoculated kiwifruit during storage, and delayed the decrease of firmness and the increase of soluble solids (SSC) content. H2S treatment increased the transcription levels of genes related to JA biosynthesis (AcLOX3, AcAOS, AcAOC2, and AcOPR) and signaling pathway (AcCOI1, AcJAZ5, AcMYC2, and AcERF1), as well as the JA accumulation. Meanwhile, H2S promoted the expression of defense-related genes (AcPPO, AcSOD, AcGLU, AcCHI, AcAPX, and AcCAT). Correlation analysis revealed that JA content was positively correlated with the expression levels of JA biosynthesis and defense-related genes. Overall, the results indicated that H2S could promote the increase of endogenous JA content and expression of defense-related genes by regulating the transcription levels of JA pathway-related genes, which contributed to the inhibition on the soft rot occurrence of kiwifruit.

Preparation of cylindrical Chitosan/ß-Cyclodextrin/MIL-68(Al) foam column for solid-phase extraction of sulfonamides in water, urine, and milk.

This study describes the preparation of a cylindrical polymer foam column termed Chitosan/ß-Cyclodextrin/MIL-68(Al) (CS/ß-CD/MIL-68(Al)). An ice template-freeze drying technique was employed to prepare the CS/ß-CD/MIL-68(Al) foam column by embedding MIL-68(Al) in a polymer matrix comprising cross-linked chitosan (CS) and ß-cyclodextrin (ß-CD). The cylindrical CS/ß-CD/MIL-68(Al) foam was subsequently inserted into a syringe to develop a solid phase extraction (SPE) device. Without the requirement for an external force, the sample solution passed easily through the SPE column thanks to the porous structure of the CS/ß-CD/MIL-68(Al) foam column. Moreover, the CS/ß-CD/MIL-68(Al) foam column was thought to be a superior absorbent for SPE since it included the adsorptive benefits of CS, ß-CD, and MIL-68(Al). The SPE was utilized in conjunction with high-performance liquid chromatography to analyze six sulfonamides found in milk, urine, and water. With matrix effects ranging from 80.49 % to 104.9 % with RSD values of 0.4-14.0 %, the method showed high recoveries ranging from 80.6 to 107.4 % for water samples, 93.4-105.2 % for urine, and 87.4-100.9 % for milk. It also demonstrated good linearity in the range of 10-258 ng·mL-1 with the limits of detection ranging from 1.88 to 2.58 ng·mL-1. The cylindrical CS/ß-CD/MIL-68(Al) foam column prepared in this work offered several advantages, including its simple fabrication, excellent water stability, absence of pollutants, biodegradability, and reusability. It is particularly well-suited for SPE. Furthermore, the developed SPE method, employing CS/ß-CD/MIL-68(Al) foam column, is straightforward and precise, and its benefits, including affordability, ease of preparation, lack of specialized equipment, and solvent economy, underline its broad applicability for the pretreatment of aqueous samples.

Identification of Differentially Expressed mRNAs and lncRNAs Contributes to Elucidation of Underlying Pathogenesis and Therapeutic Strategy of Recurrent Implantation Failure.

Recurrent implantation failure (RIF) is a complex and poorly understood clinical disorder characterized by failure to conceive after repeated embryo transfers. Endometrial receptivity (ER) is a prerequisite for implantation, and ER disorders are associated with RIF. However, little is known regarding the molecular mechanisms underlying ER in RIF. In the present study, RNA sequencing data from the mid-secretory endometrium of patients with and without RIF were analyzed to explore the potential long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) involved in RIF. The analysis revealed 213 and 1485 differentially expressed mRNAs and lncRNAs, respectively (fold change ≥ 2 and p < 0.05). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that these genes were mostly involved in processes related to immunity or inflammation. 5 key genes (TTR, ALB, TF, AFP, and CFTR) and a key module including 14 hub genes (AFP, ALB, APOA1, APOA2, APOB, APOH, FABP1, FGA, FGG, GC, ITIH2, SERPIND1, TF and TTR) were identified in the protein-protein interaction (PPI) network. The 5 key genes were used to further explore the lncRNA-miRNA-mRNA regulatory network. Finally, the drug ML-193 based on the 14 hub genes was identifed through the CMap. After ML-193 treatment, endometrial cell proliferation was increased, the hub genes were mostly down-regulated, and the ER marker HOXA10 was up-regulated. These results offer insights into the regulatory mechanisms of lncRNAs and mRNAs and suggest ML-193 as a therapeutic agent for RIF by enhancing ER.

The Synergistic Anti-tumor Effects of Evodiamine based on Animal Model Experiments: A Systematic Review and Meta-analysis.

BACKGROUND: Evodiamine (EVO) is an alkaloid extracted from the dried and nearly ripe fruits of Euodia rutaecarpa and used as an anti-cancer, anti-inflammatory and anti-obesity agent. However, robust evidence of preclinical experiments has been lacking so far. Therefore, the purpose of this article was to investigate the effect of EVO in combination with other treatments on tumors in animal experiments. METHODS: A systematic review and meta-analysis were conducted to assess the anti-tumor effect of evodiamine-combined therapy. The search engine and electronic databases included PubMed, Scopus, China Knowledge Resource Integrated Database (CNKI), and SinoMed. The research method was based on the PRISMA checklist. RESULTS: A total of 7 studies and 108 animals were included. As a result, EVO combined therapy was found to be more effective than EVO monotherapy. The SMD was -25.64(95% CI: -5.77 -3.13) in tumor growth. In tumor weight, the SMD was -8.91(95% CI: -16.37, -1.44). CONCLUSION: EVO has the potential to alleviate the toxicity of chemotherapeutic agents, which increases the translatability to the clinical situation.

First Report of Fruit Rot Disease on melon (Cucumis melo L.) Caused by Fusarium ipomoeae in China.

Fusarium rot on melon fruit has become an important postharvest disease for producers worldwide, typically involving multiple Fusarium pathogens (Khuna et al. 2022; Medeiros Araújo et al. 2021). In 2022, Fusarium fruit rot of muskmelon (Cucumis melo var. conomon) occurred sporadically in a field at Huainan Academy of Agricultural Sciences (32.658193º N, 117.064922º E) with an incidence of about 10%. Among these diseased muskmelons, a fruit exhibiting a white to yellowish colony athe intersection of the diseased and healthy tissues was collected and labeled TGGF22-17. The streak plate method was employed to isolate fungal spores on Bengal Red PDA (potato dextrose agar), which were then incubated at 25℃ in darkness. Following isolation and purification, a single-spore strain, TGGF22-17, was obtained and analyzed using morphological characters on PDA, synthetic nutrient agar (SNA) and carnation leaf agar (CLA) (Leslie and Summerell 2006), along with molecular identification. Colours were rated according to the color charts of Kornerup and Wanscher (1978). Based on the colony morphology on PDA, the isolate displayed a rosy buff or buff color with a white to buff margin. The colony margin was undulate, with the reverse transitioning from amber-yellow to honey-yellow. Aerial macroconidia on SNA were thin-walled, hyaline, mostly 3-5 septate, falcate, and measured 18.5-46.4 (x̄=34.2) × 2.9-4.8 (x̄ =3.9) µm in size (n =50). Sporodochial macroconidia on CLA were mostly five-septate with long apical and basal cells, exhibiting dorsiventral curvature. They were hyaline, with the apical cell hooked to tapering and the basal cell foot-shaped, measuring 46.5-89.6 (x̄ =72.3) × 3.5-5.0 (x̄ =4.3) µm in size (n = 100). Portions of three loci (TEF-1α, RPB1 and RPB2) were amplified and sequenced as described by Wang et al. (2019). Sequences were deposited in GenBank with accession number PP196583 to PP196585. The three gene sequences (TEF-1α, RPB1 and RPB2) of strain TGGF2022-17 shared 99.5% (629/632bp), 97.9% (1508/1540 bp) and 99.9% (1608/1609 bp) identity to the ex-type strain F. ipomoeae LC12165 respectively by pairwise DNA alignments on the FUSARIOID-ID database (https://www.fusarium.org). Phylogenetic analysis of the partial TEF-1α and RPB2 sequences with PhyloSuite (Zhang et al. 2020) showed the isolated fungus clustered with F. ipomoeae. Based on the morphological and phylogenetic analyses, TGGF22-17 was identified as F. ipomoeae. Pathogenicity tests were performed on healthy melons, which were surface-sterilized with 75% alcohol and wounded using a sterilized inoculation needle. A 4-mm diameter plug from a 7-day-old SNA culture of TGGF22-17 was aseptically inserted in the middle of the wound, sealed with plastic bag after absorbent cotton was included to maintain moisture. Five melons were each inoculated at three points. Noncolonized PDA agar plugs served as the negative control. The inoculated and uninoculated plugs were removed approximately 48 hours after inoculation. The melon inoculated with TGGF22-17 exhibited water-soaked black lesions 48h post-inoculation, resulting in a 100% infection rate (15/15). After 7 days, mycelium was obseved on the inoculated melons. No disease symptoms were observed on the uninoculated melons. To fulfill Koch's postulates, fungi were isolated from the inoculated fruit and confirmed as F. ipomoeae by morphological observation. Fusarium ipomoeae has been reported to cause fruit rot on winter squash (Cucurbita maxima) in Japan (Kitabayashi et al. 2023). To our knowledge, this is the first report of fruit rot on muskmelon caused by F. ipomoeae in China and this report will be valuable for monitoring and management of fruit rot disease on muskmelons.

Association between Pre-operative Body Mass Index and Surgical Infection in Perihilar Cholangiocarcinoma Patients Treated with Curative Resection: A Multi-center Study.

Background: The objective of this study was to investigate the association between pre-operative body mass index (BMI) and surgical infection in perihilar cholangiocarcinoma (pCCA) patients treated with curative resection. Methods: Consecutive pCCA patients were enrolled from four tertiary hospitals between 2008 and 2022. According to pre-operative BMI, the patients were divided into three groups: low BMI (≤18.4 kg/m2), normal BMI (18.5-24.9 kg/m2), and high BMI (≥25.0 kg/m2). The incidence of surgical infection among the three groups was compared. Multivariable logistic regression models were used to determine the independent risk factors associated with surgical infection. Results: A total of 371 patients were enrolled, including 283 patients (76.3%) in the normal BMI group, 30 patients (8.1%) in the low BMI group, and 58 patients (15.6%) in the high BMI group. The incidence of surgical infection was significantly higher in the patients in the low BMI and high BMI groups than in the normal BMI group. The multivariable logistic regression model showed that low BMI and high BMI were independently associated with the occurrence of surgical infection. Conclusions: The pCCA patients with a normal BMI treated with curative resection could have a lower risk of surgical infection than pCCA patients with an abnormal BMI.

Unveiling the therapeutic prospects of IFNW1 and IFNA21: insights into glioma pathogenesis and clinical significance.

Glioma, a type of brain tumor, poses significant challenges due to its heterogeneous nature and limited treatment options. Interferon-related genes (IRGs) have emerged as potential players in glioma pathogenesis, yet their expression patterns and clinical implications remain to be fully elucidated. We conducted a comprehensive analysis to investigate the expression patterns and functional enrichment of IRGs in glioma. This involved constructing protein-protein interaction networks, heatmap analysis, survival curve plotting, diagnostic and prognostic assessments, differential expression analysis across glioma subgroups, GSVA, immune infiltration analysis, and drug sensitivity analysis. Our analysis revealed distinct expression patterns and functional enrichment of IRGs in glioma. Notably, IFNW1 and IFNA21 were markedly downregulated in glioma tissues compared to normal tissues, and higher expression levels were associated with improved overall survival and disease-specific survival. Furthermore, these genes showed diagnostic capabilities in distinguishing glioma tissues from normal tissues and were significantly downregulated in higher-grade and more aggressive gliomas. Differential expression analysis across glioma subgroups highlighted the association of IFNW1 and IFNA21 expression with key pathways and biological processes, including metabolic reprogramming and immune regulation. Immune infiltration analysis revealed their influence on immune cell composition in the tumor microenvironment. Additionally, elevated expression levels were associated with increased resistance to chemotherapeutic agents. Our findings underscore the potential of IFNW1 and IFNA21 as diagnostic biomarkers and prognostic indicators in glioma. Their roles in modulating glioma progression, immune response, and drug sensitivity highlight their significance as potential therapeutic targets. These results contribute to a deeper understanding of glioma biology and may inform the development of personalized treatment strategies for glioma patients.

Research progress on Alpinia oxyphylla in the treatment of diabetic nephropathy.

Diabetic nephropathy (DN) constitutes a major microvascular complication of diabetes and is a primary cause of mortality in diabetic individuals. With the global rise in diabetes, DN has become an urgent health issue. Currently, there is no definitive cure for DN. Alpinia oxyphylla, a Chinese herbal medicine traditionally used, exhibits a wide range of pharmacological effects and is frequently used in the prevention and management of DN. This paper offers an extensive review of the biological mechanisms by which A. oxyphylla delivers therapeutic advantages in DN management. These mechanisms include activating podocyte autophagy, regulating non-coding RNA, modulating gut microbiota, alleviating lipotoxicity, counteracting oxidative stress, and diminishing inflammatory responses, underscoring the therapeutic potential of A. oxyphylla in DN treatment.

Novel mRNA adjuvant ImmunER enhances prostate cancer tumor-associated antigen mRNA therapy via augmenting T cell activity.

Prostate cancer (PCa) is characterized as a "cold tumor" with limited immune responses, rendering the tumor resistant to immune checkpoint inhibitors (ICI). Therapeutic messenger RNA (mRNA) vaccines have emerged as a promising strategy to overcome this challenge by enhancing immune reactivity and significantly boosting anti-tumor efficacy. In our study, we synthesized Tetra, an mRNA vaccine mixed with multiple tumor-associated antigens, and ImmunER, an immune-enhancing adjuvant, aiming to induce potent anti-tumor immunity. ImmunER exhibited the capacity to promote dendritic cells (DCs) maturation, enhance DCs migration, and improve antigen presentation at both cellular and animal levels. Moreover, Tetra, in combination with ImmunER, induced a transformation of bone marrow-derived dendritic cells (BMDCs) to cDC1-CCL22 and up-regulated the JAK-STAT1 pathway, promoting the release of IL-12, TNF-α, and other cytokines. This cascade led to enhanced proliferation and activation of T cells, resulting in effective killing of tumor cells. In vivo experiments further revealed that Tetra + ImmunER increased CD8+T cell infiltration and activation in RM-1-PSMA tumor tissues. In summary, our findings underscore the promising potential of the integrated Tetra and ImmunER mRNA-LNP therapy for robust anti-tumor immunity in PCa.

Uncovering the mechanism of Clostridium butyricum CBX 2021 to improve pig health based on in vivo and in vitro studies.

Introduction: As a symbiotic probiotic for the host, Clostridium butyricum (CB) has the potential to strengthen the body's immune system and improve intestinal health. However, the probiotic mechanism of CB is not completely understood. The Clostridium butyricum CBX 2021 strain isolated by our team from a health pig independently exhibits strong butyric acid production ability and stress resistance. Therefore, this study comprehensively investigated the efficacy of CBX 2021 in pigs and its mechanism of improving pig health. Methods: In this study, we systematically revealed the probiotic effect and potential mechanism of the strain by using various methods such as microbiome, metabolites and transcriptome through animal experiments in vivo and cell experiments in vitro. Results: Our in vivo study showed that CBX 2021 improved growth indicators such as daily weight gain in weaned piglets and also reduced diarrhea rates. Meanwhile, CBX 2021 significantly increased immunoglobulin levels in piglets, reduced contents of inflammatory factors and improved the intestinal barrier. Subsequently, 16S rRNA sequencing showed that CBX 2021 treatment implanted more butyric acid-producing bacteria (such as Faecalibacterium) in piglets and reduced the number of potentially pathogenic bacteria (like Rikenellaceae RC9_gut_group). With significant changes in the microbial community, CBX 2021 improved tryptophan metabolism and several alkaloids synthesis in piglets. Further in vitro experiments showed that CBX 2021 adhesion directly promoted the proliferation of a porcine intestinal epithelial cell line (IPEC-J2). Moreover, transcriptome analysis revealed that bacterial adhesion increased the expression of intracellular G protein-coupled receptors, inhibited the Notch signaling pathway, and led to a decrease in intracellular pro-inflammatory molecules. Discussion: These results suggest that CBX 2021 may accelerate piglet growth by optimizing the intestinal microbiota, improving metabolic function and enhancing intestinal health.

Catalytic Fast Pyrolysis of Tar-Rich Coal with a Bauxite Residue for Upgrading High-Value Products: Product Distribution and Kinetic Analysis.

Fast pyrolysis technology can reduce the secondary reactions, improve the volatile product yield, and reduce the semicoke yield. Still, the high proportion of heavy tar components affects the development of fast pyrolysis industrialization. Therefore, this paper put forward a catalytic upgrading method of coal based on the solid waste bauxite residue (BR) as a catalyst. This study investigated the impact of varying particle sizes of pulverized coal and the addition of the BR catalyst on the product distribution and kinetics of coal fast pyrolysis. The results found that the tar yield was the highest at 600 °C when the particle size of pulverized coal was 75-150 µm, which was 19.44%. In the range of 550-650 °C, the relative content of benzene and toluene xylene (BTX) in liquid products increased with the temperature. With the increase of the proportion of the BR catalyst, the yield of semicoke in coal pyrolysis products increased, the yield of the gas phase also increased, and the yield of the liquid phase decreased.

CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer.

Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.

Exploration and verification a 13-gene diagnostic framework for ulcerative colitis across multiple platforms via machine learning algorithms.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with intricate pathogenesis and varied presentation. Accurate diagnostic tools are imperative to detect and manage UC. This study sought to construct a robust diagnostic model using gene expression profiles and to identify key genes that differentiate UC patients from healthy controls. Gene expression profiles from eight cohorts, encompassing a total of 335 UC patients and 129 healthy controls, were analyzed. A total of 7530 gene sets were computed using the GSEA method. Subsequent batch correction, PCA plots, and intersection analysis identified crucial pathways and genes. Machine learning, incorporating 101 algorithm combinations, was employed to develop diagnostic models. Verification was done using four external cohorts, adding depth to the sample repertoire. Evaluation of immune cell infiltration was undertaken through single-sample GSEA. All statistical analyses were conducted using R (Version: 4.2.2), with significance set at a P value below 0.05. Employing the GSEA method, 7530 gene sets were computed. From this, 19 intersecting pathways were discerned to be consistently upregulated across all cohorts, which pertained to cell adhesion, development, metabolism, immune response, and protein regulation. This corresponded to 83 unique genes. Machine learning insights culminated in the LASSO regression model, which outperformed others with an average AUC of 0.942. This model's efficacy was further ratified across four external cohorts, with AUC values ranging from 0.694 to 0.873 and significant Kappa statistics indicating its predictive accuracy. The LASSO logistic regression model highlighted 13 genes, with LCN2, ASS1, and IRAK3 emerging as pivotal. Notably, LCN2 showcased significantly heightened expression in active UC patients compared to both non-active patients and healthy controls (P < 0.05). Investigations into the correlation between these genes and immune cell infiltration in UC highlighted activated dendritic cells, with statistically significant positive correlations noted for LCN2 and IRAK3 across multiple datasets. Through comprehensive gene expression analysis and machine learning, a potent LASSO-based diagnostic model for UC was developed. Genes such as LCN2, ASS1, and IRAK3 hold potential as both diagnostic markers and therapeutic targets, offering a promising direction for future UC research and clinical application.

Application of amphiregulin in IVM culture of immature human oocytes and pre-insemination culture for COCs in IVF cycles.

Background: Amphiregulin (AR) is a growth factor that resembles the epidermal growth factor (EGF) and serves various functions in different cells. However, no systematic studies or reports on the role of AR in human oocytes have currently been performed or reported. This study aimed to explore the role of AR in human immature oocytes during in vitro maturation (IVM) and in vitro fertilization (IVF) in achieving better embryonic development and to provide a basis for the development of a pre-insemination culture medium specific for cumulus oocyte complexes (COCs). Methods: First, we examined the concentration of AR in the follicular fluid (FF) of patients who underwent routine IVF and explored the correlation between AR levels and oocyte maturation and subsequent embryonic development. Second, AR was added to the IVM medium to culture immature oocytes and investigate whether AR could improve the effects of IVM. Finally, we pioneered the use of a fertilization medium supplemented with AR for the pre-insemination culture of COCs to explore whether the involvement of AR can promote the maturation and fertilization of IVF oocytes, as well as subsequent embryonic development. Results: A total of 609 FF samples were examined, and a positive correlation between AR levels and blastocyst formation was observed. In our IVM study, the development potential and IVM rate of immature oocytes, as well as the fertilization rate of IVM oocytes in the AR-added groups, were ameliorated significantly compared to the control group (All P < 0.05). Only the IVM-50 group had a significantly higher blastocyst formation rate than the control group (P < 0.05). In the final IVF study, the maturation, fertilization, high-quality embryo, blastocyst formation, and high-quality blastocyst rates of the AR-added group were significantly higher than those of the control group (All P < 0.05). Conclusion: AR levels in the FF positively correlated with blastocyst formation, and AR involvement in pre-insemination cultures of COCs can effectively improve laboratory outcomes in IVF. Furthermore, AR can directly promote the in vitro maturation and developmental potential of human immature oocytes at an optimal concentration of 50 ng/ml.

Pseudomeningocele Following Posterior Cranial Fossa Surgery Significantly Increases the Risk of Intracranial Infection: A 10-Year Retrospective Analysis.

Background: Posterior fossa craniotomy is commonly performed for various pathologies. However, intra-cranial infection following craniotomy causes morbidity. Pseudomeningocele is one of the main complications following posterior fossa operation. This study aimed to test the hypothesis that the risk of intra-cranial infection is increased in patients who undergo posterior fossa craniotomy with pseudomeningocele compared with those without pseudomeningocele. Methods: We retrospectively analyzed the data of patients undergoing posterior fossa craniotomy for the management of neurological pathologies at our institute from 2011 to 2020. A total of 308 craniotomies were included, and the primary outcome of interest was the occurrence of intra-cranial infection. Standard statistical methods were used to explore associations between several parameters, including pseudomeningocele, intra-cranial infection, and wound leak. Results: Of the 308 craniotomies, 41 (13.3%) developed intra-cranial infection and 59 (19.2%) involved pseudomeningocele. Of cases involving pseudomeningocele, 27 (45.8%) developed an intra-cranial infection compared with only 14 of 249 without pseudomeningocele (5.6%; p < 0.001). In the multi-variable analysis, pseudomeningocele was associated with intra-cranial infection (odds ratio [OR] 8.56; 95% confidence interval [CI] 3.145-23.299; p < 0.001) and wound leak (OR 91.339; 95% CI 10.437-799.364; p < 0.001). Conclusion: The findings indicate that patients undergoing posterior fossa craniotomy are at a greater risk of intra-cranial infection if there is pseudomeningocele after the operation.

Effects of additional physical exercise on the nutritional status and disease progression during the low-protein diet in Chronic Kidney Disease Patients: a systematic review and meta-analysis.

Low-protein diet (LPD) is the core of dietary and nutritional therapy for non-dialysis chronic kidney disease (CKD) patients. In addition, physical exercise could prevent and treat various illnesses and chronic diseases. The objective of the study was to search for and appraise evidence on the effect of additional physical exercise on patients' nutritional status and indicators of disease progression when compared with the LPD alone. PubMed Central, Embase, Cochrane, and Web of Knowledge for randomized controlled trials (published between January 1, 1956 and May 17, 2023) were searched. A total of 8698 identified studies, 9 were eligible and were included in our analysis (N = 250 participants). Compared with the LPD alone, additional physical exercise reduced serum creatinine by a mean of -0.21 mg/dL (95% CI -0.39 to -0.03) in CKD patients. Similarly, blood pressure decreased after physical exercise, with systolic blood pressure decreasing by -7.05 mm Hg (95% CI -13.13 to -0.96) and diastolic blood pressure decreasing by -5.31 mm Hg (95% CI -7.99 to -2.62). Subgroup analyses revealed that resistance exercise (RE) was effective in decreasing estimated glomerular filtration rate (eGFR) of -1.71 mL/min per 1.73 m² (95% CI -3.29 to -0.14). In addition, the VO2peak increasing by 2.41 mL/kg/min (95% CI 0.13 to 4.70) when physical exercise was continued for 24 weeks. The above results suggest that the LPD with additional physical exercise care is more beneficial for patients with CKD.

Elimination of GGTA1, CMAH, ß4GalNT2 and CIITA genes in pigs compromises human versus pig xenogeneic immune reactions.

BACKGROUND: Pig organ xenotransplantation is a potential solution for the severe organ shortage in clinic, while immunogenic genes need to be eliminated to improve the immune compatibility between humans and pigs. Current knockout strategies are mainly aimed at the genes causing hyperacute immune rejection (HAR) that occurs in the first few hours while adaptive immune reactions orchestrated by CD4 T cell thereafter also cause graft failure, in which process the MHC II molecule plays critical roles. METHODS: Thus, we generate a 4-gene (GGTA1, CMAH, ß4GalNT2, and CIITA) knockout pig by CRISPR/Cas9 and somatic cell nuclear transfer to compromise HAR and CD4 T cell reactions simultaneously. RESULTS: We successfully obtained 4KO piglets with deficiency in all alleles of genes, and at cellular and tissue levels. Additionally, the safety of our animals after gene editing was verified by using whole-genome sequencing and karyotyping. Piglets have survived for more than one year in the barrier, and also survived for more than 3 months in the conventional environment, suggesting that the piglets without MHC II can be raised in the barrier and then gradually mated in the conventional environment. CONCLUSIONS: 4KO piglets have lower immunogenicity, are safe in genomic level, and are easier to breed than the model with both MHC I and II deletion.

Discovery of 4-(isopentyloxy)-3-nitrobenzamide derivatives as xanthine oxidase inhibitors through a non-anthraquinone exploration.

In our previous study, we reported a series of N-(9,10-anthraquinone-2-carbonyl) amino acid derivatives as novel inhibitors of xanthine oxidase (XO). Recognizing the suboptimal drug-like properties associated with the anthraquinone moiety, we embarked on a nonanthraquinone medicinal chemistry exploration in the current investigation. Through systematic structure-activity relationship (SAR) studies, we identified a series of 4-(isopentyloxy)-3-nitrobenzamide derivatives exhibiting excellent in vitro potency against XO. The optimized compound, 4-isopentyloxy-N-(1H-pyrazol-3-yl)-3-nitrobenzamide (6k), demonstrated exceptional in vitro potency with an IC50 value of 0.13 µM. Compound 6k showed favorable drug-like characteristics with ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of 0.41 and 3.73, respectively. In comparison to the initial compound 1d, 6k exhibited a substantial 24-fold improvement in IC50, along with a 1.6-fold enhancement in LE and a 3.7-fold increase in LLE. Molecular modeling studies provided insights into the strong interactions of 6k with critical amino acid residues within the active site. Furthermore, in vivo hypouricemic investigations convincingly demonstrated that 6k significantly reduced serum uric acid levels in rats. The MTT results revealed that compound 6k is nontoxic to healthy cells. The gastric and intestinal stability assay demonstrated that compound 6k exhibits good stability in the gastric and intestinal environments. In conclusion, compound 6k emerges as a promising lead compound, showcasing both exceptional in vitro potency and favorable drug-like characteristics, thereby warranting further exploration.

Mesenteric lymph nodes: a critical site for the up-regulatory effect of hUC-MSCs on Treg cells by producing TGF-ß1 in colitis treatment.

BACKGROUND: Mesenchymal stem cells (MSCs) demonstrate a wide range of therapeutic capabilities in the treatment of inflammatory bowel disease (IBD). The intraperitoneal injection of MSCs has exhibited superior therapeutic efficacy on IBD than intravenous injection. Nevertheless, the precise in vivo distribution of MSCs and their biological consequences following intraperitoneal injection remain inadequately understood. Additional studies are required to explore the correlation between MSCs distribution and their biological effects. METHODS: First, the distribution of human umbilical cord MSCs (hUC-MSCs) and the numbers of Treg and Th17 cells in mesenteric lymph nodes (MLNs) were analyzed after intraperitoneal injection of hUC-MSCs. Subsequently, the investigation focused on the levels of transforming growth factor beta1 (TGF-ß1), a key cytokine to the biology of both Treg and Th17 cells, in tissues of mice with colitis, particularly in MLNs. The study also delved into the impact of hUC-MSCs therapy on Treg cell counts in MLNs, as well as the consequence of TGFB1 knockdown hUC-MSCs on the differentiation of Treg cells and the treatment of IBD. RESULTS: The therapeutic effectiveness of intraperitoneally administered hUC-MSCs in the treatment of colitis was found to be significant, which was closely related to their quick migration to MLNs and secretion of TGF-ß1. The abundance of hUC-MSCs in MLNs of colitis mice is much higher than that in other organs even the inflamed sites of colon. Intraperitoneal injection of hUC-MSCs led to a significant increase in the number of Treg cells and a decrease in Th17 cells especially in MLNs. Furthermore, the concentration of TGF-ß1, the key cytokine for Treg differentiation, were also found to be significantly elevated in MLNs after hUC-MSCs treatment. Knockdown of TGFB1 in hUC-MSCs resulted in a noticeable reduction of Treg cells in MLNs and the eventually failure of hUC-MSCs therapy in colitis. CONCLUSIONS: MLNs may be a critical site for the regulatory effect of hUC-MSCs on Treg/Th17 cells and the therapeutic effect on colitis. TGF-ß1 derived from hUC-MSCs promotes local Treg differentiation in MLNs. This study will provide new ideas for the development of MSC-based therapeutic strategies in IBD patients.