Latest advances and clinical application prospects of resveratrol therapy for neurocognitive disorders.

Neurocognitive disorders, such as Alzheimer's disease, vascular dementia, and postoperative cognitive dysfunction, are non-psychiatric brain syndromes in which a significant decline in cognitive function causes great trauma to the mental status of the patient. The lack of effective treatments for neurocognitive disorders imposes a considerable burden on society, including a substantial economic impact. Over the past few decades, the identification of resveratrol, a natural plant compound, has provided researchers with an opportunity to formulate novel strategies for the treatment of neurocognitive disorders. This is because resveratrol effectively protects the brain of those with neurocognitive disorders by targeting some mechanisms such as inflammation and oxidative stress. This article reviews the status of recent research investigating the use of resveratrol for the treatment of different neurocognitive disorders. By examining the possible mechanisms of action of resveratrol and the shared mechanisms of different neurocognitive disorders, treatments for neurocognitive disorders may be further clarified.

Effect of esketamine pretreatment on acute sepsis-associated encephalopathy.

PURPOSE: Esketamine, the S(+) enantiomer of ketamine, exhibits good anesthetic efficacy and controllability; however, its potential clinical applications, particularly in sepsis-associated encephalopathy (SAE), remain underexplored. SAE involves the development of diffuse brain dysfunction after sepsis, leading to markedly increased sepsis-related disability and mortality. In this study, we investigated the effects of esketamine pretreatment on acute SAE. METHODS: Mice were randomly divided into four groups: control (C, n = 22), acute SAE (L, n = 22), esketamine pretreatment + acute SAE (EL, n = 22), and nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor (ML385) + esketamine pretreatment + acute SAE (N + EL, n = 22). Acute SAE was established using intraperitoneal (i.p.) injection of lipopolysaccharide (LPS; 10 mg/kg), while controls received equal amounts of saline. The EL group received daily i.p. injections of esketamine (10 mg/kg) for 5 consecutive days, followed by LPS on day 6. The N + EL group received i.p. injections of ML385 (30 mg/kg) 1 h before esketamine pretreatment. The remainder of treatment followed the same protocol as the EL group. Behavioral tests were performed 24 h post-LPS injection, and whole blood and brain tissues were collected for further analysis. RESULTS: Esketamine improved sepsis symptoms, 7-day survival, and spatial cognitive impairment, without altering locomotor activity. Moreover, esketamine reversed the LPS-induced increase in serum S100 calcium-binding protein ß and neuron-specific enolase levels and reduced hippocampal neuroinflammation, oxidative stress, and neuronal apoptosis in the EL group. However, these neuroprotective effects of esketamine were reversed by ML385. CONCLUSION: The results of our study suggest that esketamine pretreatment mitigates acute SAE, highlighting the involvement of the Nrf2/heme oxygenase-1 pathway in mediating its neuroprotective effects.

Effects of xenon anesthesia on postoperative neurocognitive disorders: a systematic review and meta-analysis.

The latest clinical trials have reported conflicting outcomes regarding the effectiveness of xenon anesthesia in preventing postoperative neurocognitive dysfunction; thus, this study assessed the existing evidence. We searched the PubMed, Embase, Cochrane Library, and Web of Science databases from inception to April 9, 2023, for randomized controlled trials of xenon anesthesia in postoperative patients. We included English-language randomized controlled studies of adult patients undergoing surgery with xenon anesthesia that compared its effects to those of other anesthetics. Duplicate studies, pediatric studies, and ongoing clinical trials were excluded. Nine studies with 754 participants were identified. A forest plot revealed that the incidence of postoperative neurocognitive dysfunction did not differ between the xenon anesthesia and control groups (P = 0.43). Additionally, xenon anesthesia significantly shortened the emergence time for time to opening eyes (P < 0.001), time to extubation (P < 0.001), time to react on demand (P = 0.01), and time to time and spatial orientation (P = 0.04). However, the Aldrete score significantly increased with xenon anesthesia (P = 0.005). Postoperative complications did not differ between the anesthesia groups. Egger's test for bias showed no small-study effect, and a trim-and-fill analysis showed no apparent publication bias. In conclusion, xenon anesthesia probably did not affect the occurrence of postoperative neurocognitive dysfunction. However, xenon anesthesia may effectively shorten the emergence time of certain parameters without adverse effects.

Mitophagy-related genes could facilitate the development of septic shock during immune infiltration.

Septic shock often occurs following critically low blood pressure in patients with sepsis, and is accompanied by a high death rate. Although mitophagy is associated with infection and immune responses, its role in septic shock remains unknown. This study screened effective mitophagy-related genes (MRGs) for medical practice and depicted immune infiltration situations in patients with septic shock. Gene expression profiles of GSE131761 from the Gene Expression Omnibus database were compiled for differential analysis, weighted gene co-expression network analysis, and immune infiltration analysis, while other GSE series were used as validation datasets. A series of validation methods were used to verify the robustness of hub genes, while a nomogram and prognosis model were established for medical practice. Six genes were screened via combinations of differentially expressed genes, weighted gene co-expression network analysis, and MRGs. From this, 3 hub genes (MAP1LC3B, ULK1, and CDC37) were chosen for subsequent analysis based on different validation methods. Gene set enrichment analysis showed that leukocyte trans-endothelial migration and the p53 signaling pathway were abnormally activated during septic shock. Immune infiltration analysis indicated that the imbalance of neutrophils and CD4 naive T cells was significantly correlated with septic shock progression. A nomogram was generated based on MAP1LC3B, ULK1, and CDC37, as well as age. The stability of our model was confirmed using a calibration plot. Importantly, patients with septic shock with the 3 highly expressed hub genes displayed worse prognosis than did patients without septic shock. MAP1LC3B, ULK1, and CDC37 are considered hub MRGs in the development of septic shock and could represent promising diagnostic and prognostic biomarkers in blood tissue. The validated hub genes and immune infiltration pattern expand our knowledge on MRG functional mechanisms, which provides guidance and direction for the development of septic shock diagnostic and therapeutic markers.

Copper metabolism-related Genes in entorhinal cortex for Alzheimer's disease.

The pathological features of Alzheimer's disease are the formation of amyloid plaques and entanglement of nerve fibers. Studies have shown that Cu may be involved in the formation of amyloid plaques. However, their role has been controversial. The aim of this study was to explore the role of Cu in AD. We applied the "R" software for our differential analysis. Differentially expressed genes were screened using the limma package. Copper metabolism-related genes and the intersection set of differential genes with GSE5281 were searched; functional annotation was performed. The protein-protein interaction network was constructed using several modules to analyse the most significant hub genes. The hub genes were then qualified, and a database was used to screen for small-molecule AD drugs. We identified 87 DEGs. gene ontology analysis focused on homeostatic processes, response to toxic substances, positive regulation of transport, and secretion. The enriched molecular functions are mainly related to copper ion binding, molecular function regulators, protein-containing complex binding, identical protein binding and signalling receptor binding. The KEGG database is mainly involved in central carbon metabolism in various cancers, Parkinson's disease and melanoma. We identified five hub genes, FGF2, B2M, PTPRC, CD44 and SPP1, and identified the corresponding small molecule drugs. Our study identified key genes possibly related to energy metabolism in the pathological mechanism of AD and explored potential targets for AD treatment by establishing interaction networks.

Development of nomograms for predicting the survival of intestinal-type gastric adenocarcinoma patients after surgery.

Intestinal-type gastric adenocarcinoma (IGA) is a common phenotype of gastric cancer. Currently, few studies have constructed nomograms that may predict overall (OS) and cancer-specific survival (CSS) probability after surgery. This study is to establish novel nomograms for predicting the survival of IGA patients who received surgery. A total of 1814 IGA patients who received surgery between 2000 and 2018 were selected from Surveillance, Epidemiology, and End Results database and randomly assigned to the training and validating sets at a ratio of 7:3. Then univariate and multivariate cox regression analyses were performed to screen significant indictors for the construction of nomograms. The calibration curve, the area under the receiver operating characteristic (receiver operating characteristic, ROC) curve (the area under curve, AUC), C-index, net reclassification index (NRI), integrated discrimination improvement (IDI) and decision curve analysis (DCA) curves were applied to assess the performance of the model. The significant outcomes of multivariate analysis revealed that ten variables (age, sex, race, surgery type, summary stage, grade, AJCC TNM stage, radiotherapy, number of regional nodes examined, number of regional nodes positive) were demonstrated to construct the nomogram for OS and ten variables (age, sex, race, surgery type, summary stage, grade, AJCC TNM stage, chemotherapy, number of regional nodes examined, number of regional nodes positive) for CSS. The calibration and AUC uncovered their favorable predictive performance. Subsequently, C-index, NRI, IDI and DCA curves further validated the predicative superiority of nomograms over 7th AJCC Stage System. The validated nomogram provides more reliable OS and CSS predictions for postoperative IGA patients with good accuracy, which can help surgeons in treatment decision-making and prognosis evaluation.

A cutting-edge strategy for spinal cord injury treatment: resident cellular transdifferentiation.

Spinal cord injury causes varying degrees of motor and sensory function loss. However, there are no effective treatments for spinal cord repair following an injury. Moreover, significant preclinical advances in bioengineering and regenerative medicine have not yet been translated into effective clinical therapies. The spinal cord's poor regenerative capacity makes repairing damaged and lost neurons a critical treatment step. Reprogramming-based neuronal transdifferentiation has recently shown great potential in repair and plasticity, as it can convert mature somatic cells into functional neurons for spinal cord injury repair in vitro and in vivo, effectively halting the progression of spinal cord injury and promoting functional improvement. However, the mechanisms of the neuronal transdifferentiation and the induced neuronal subtypes are not yet well understood. This review analyzes the mechanisms of resident cellular transdifferentiation based on a review of the relevant recent literature, describes different molecular approaches to obtain different neuronal subtypes, discusses the current challenges and improvement methods, and provides new ideas for exploring therapeutic approaches for spinal cord injury.

Constructing and Validating a Network of Potential Olfactory Sheathing Cell Transplants Regulating Spinal Cord Injury Progression.

The pathology of spinal cord injury (SCI), including primary and secondary injuries, primarily involves hemorrhage, ischemia, edema, and inflammatory responses. Cell transplantation has been the most promising treatment for SCI in recent years; however, its specific molecular mechanism remains unclear. In this study, bioinformatics analysis verified by experiment was used to elucidate the hub genes associated with SCI and to discover the underlying molecular mechanisms of cell intervention. GSE46988 data were downloaded from the Gene Expression Omnibus dataset. In our study, differentially expressed genes (DEGs) were reanalyzed using the "R" software (R v4.2.1). Functional enrichment and protein-protein interaction network analyses were performed, and key modules and hub genes were identified. Network construction was performed for the hub genes and their associated miRNAs. Finally, a semi-quantitative analysis of hub genes and pathways was performed using quantitative real-time polymerase chain reaction. In total, 718 DEGs were identified, mainly enriched in immune and inflammation-related functions. We found that Cd4, Tp53, Rac2, and Akt3 differed between vehicle and transplanted groups, suggesting that these genes may play an essential role in the transplantation of olfactory ensheathing cells, while a toll-like receptor signaling pathway was significantly enriched in Gene set enrichment analysis, and then, the differences were statistically significant by experimentally verifying the expression of their associated molecules (Tlr4, Nf-κb, Ikkß, Cxcl2, and Tnf-α). In addition, we searched for upstream regulatory molecules of these four central genes and constructed a regulatory network. This study is the first to construct a regulatory network for olfactory ensheathing cell transplantation in treating SCI, providing a new idea for SCI cell therapy.

Tranexamic versus aminocaproic acids in patients with total hip arthroplasty: a retrospective study.

BACKGROUND: Recently, tranexamic acid (TXA) and epsilon aminocaproic acid (EACA) have been applied in total hip arthroplasty (THA). However, doubts in clinicians' minds about which medicine is more efficient and economical in THA need to be clarified. Therefore, this study compared the efficacy and cost of the intraoperative administration of TXA and EACA per surgery in decreasing perioperative blood transfusion rates in THA. METHODS:  This study enrolled patients who underwent THA between January 2019 to December 2020. A total of 295 patients were retrospectively divided to receive topical combined with intravenous TXA (n = 94), EACA (n = 97) or control (n = 104). The primary endpoints included transfusions, estimated perioperative blood loss, cost per patient and the drop in the haemoglobin and haematocrit levels. RESULTS: Patients who received EACA had greater total blood loss, blood transfusion rates, changes in HGB levels and mean cost of blood transfusion per patient (P < 0.05) compared with patients who received TXA. In addition, both TXA and EACA groups had significantly fewer perioperative blood loss, blood transfusion, operation time and changes in haemoglobin and haematocrit levels than the control group (P < 0.05). Cost savings in the TXA and EACA groups were 736.00 RMB and 408.00 RMB per patient, respectively. CONCLUSIONS: The application of perioperative antifibrinolytics notably reduces the need for perioperative blood transfusions. What's more, this study demonstrated that TXA is superior to EACA for decreasing blood loss and transfusion rates while at a lower cost per surgery. These results indicate that TXA may be the optimum antifibrinolytics for THA in Chinese area rather than EACA.

Recent progress on the role of non-coding RNA in postoperative cognitive dysfunction.

Postoperative cognitive dysfunction (POCD), especially in elderly patients, is a serious complication characterized by impairment of cognitive and sensory modalities after surgery. The pathogenesis of POCD mainly includes neuroinflammation, neuronal apoptosis, oxidative stress, accumulation of Aß, and tau hyperphosphorylation; however, the exact mechanism remains unclear. Non-coding RNA (ncRNA) may play an important role in POCD. Some evidence suggests that microRNA, long ncRNA, and circular RNA can regulate POCD-related processes, making them promising biomarkers in POCD diagnosis, treatment, and prognosis. This article reviews the crosstalk between ncRNAs and POCD, and systematically discusses the role of ncRNAs in the pathogenesis and diagnosis of POCD. Additionally, we explored the possible mechanisms of ncRNA-associated POCD, providing new knowledge for developing ncRNA-based treatments for POCD.

Recent advances in the development of transplanted colorectal cancer mouse models.

Despite progress in prevention and treatment, colorectal cancer (CRC) remains the third most common malignancy worldwide and the second most common cause of cancer death in 2020. To evaluate various characteristics of human CRC, a variety of mouse models have been established. Transplant mouse models have distinct advantages in studying the clinical behavior and therapeutic progress of CRC. Host, xenograft, and transplantation routes are the basis of transplant mouse models. As the effects of the tumor microenvironment and the systemic environment on cancer cells are gradually revealed, 3 key elements of transplanted CRC mouse models have been revolutionized. This has led to the development of humanized mice, patient-derived xenografts, and orthotopic transplants that reflect the human systemic environment, patient's tumor of origin, and tumor growth microenvironments in immunodeficient mice, respectively. These milestone events have allowed for great progress in tumor biology and the treatment of CRC. This article reviews the evolution of these events and points out their strengths and weaknesses as innovative and useful preclinical tools to study CRC progression and metastasis and to exploit novel treatment schedules by establishing a testing platform. This review article depicts the optimal transplanted CRC mouse models and emphasizes the significance of surgical models in the study of CRC behavior and treatment response.

Expression profile and prognostic significance of HOXB13 in rectal cancer.

BACKGROUND: This study aimed to investigate the expression pattern and prognostic significance of HOXB13 in rectal cancer. METHODS: HOXB13 expression in rectal cancer and normal adjacent tissues was detected by reverse transcriptase-polymerase chain reaction and immunohistochemistry, and its clinicopathological characteristics and prognosis were statistically tested. Furthermore, we evaluated the association between tumor immune infiltrating cells and HOXB13 using the tumor immune estimation resource (TIMER) database. The potential biological mechanism associated with HOXB13 overexpression was investigated by gene set enrichment analysis (GSEA). RESULTS: The expression of HOXB13 messenger RNA and protein in human rectal cancer tissues were significantly higher than those in the normal adjacent tissues (P < 0.05). HOXB13 expression was significantly correlated with depth of invasion, lymphatic invasion, lymph node metastasis, distant metastasis, and pathological tumor node metastasis stage (P < 0.05). Kaplan-Meier survival curves confirmed that HOXB13 overexpression was correlated negatively with overall survival and disease-free survival in rectal cancer (P < 0.05). Also, multivariate Cox regression analysis demonstrated that HOXB13 expression, age, and lymphatic invasion were independent prognostic factors in rectal cancer (P < 0.05). Plus, the results from the TIMER database indicated that HOXB13 expression has a significant association with several immune cell infiltrates. Finally, the GSEA results indicated that HOXB13 participated in the various immune-associated processes, including natural killer cell-mediated cytotoxicity and the T-cell receptor signaling pathway. CONCLUSION: Our study showed an essential role of HOXB13 in rectal cancer immunity and prognosis. Significantly, the overexpression of HOXB13 leads to the worse prognosis for patients with rectal cancer, which will contribute to understanding molecular mechanisms associated with tumor pathogenesis and prognosis in this disease.

TMPRSS4 overexpression promotes the metastasis of colorectal cancer and predicts poor prognosis of stage III-IV colorectal cancer.

PURPOSE: To study in detail the expression pattern and prognostic significance of TMPRSS4 in colorectal cancer. METHODS: The expression of TMPRSS4 protein was determined using Western blot in the colorectal cancer tissues and normal tissues. Immunohistochemistry was used to detect the TMPRSS4 expression in colorectal cancer tissues, and the clinicopathologic characteristics and prognostic significance were analyzed. RESULTS: TMPRSS4 overexpression was associated with tumor budding, lymphovascular invasion, perineural invasion, cancerous emboli, infiltration depth, lymph node metastasis, distant metastasis, and tumor node metastasis stage (P < 0.05 for all). Interestingly, TMPRSS4 expression in the tumor budding, tumor emboli, lymph node, and liver metastatic tumor samples was higher than in the paired primary tumors. In contrast, TMPRSS4 overexpression is inversely correlated with both the overall survival and the disease-free survival of the patients with colorectal cancer (P < 0.05 for both). Also, we found that TMPRSS4 is only of significance in predicting the prognosis of stage III and IV colorectal cancer, not stage I and II. CONCLUSIONS: TMPRSS4 was shown to be involved in the whole process of metastasis from tumor budding to lymph node and/or distant metastasis in colorectal cancer and predicted the unfavorable prognosis of stage III-IV, indicating that it is a novel target for the precise treatment of colorectal cancer with lymph node or distant organ metastasis.

Sophocarpine can enhance the inhibiting effect of oxaliplatin on colon cancer liver metastasis-in vitro and in vivo.

To determine whether sophocarpine (SC) can enhance the inhibiting effect of oxaliplatin on colorectal cancer (CRC) liver metastasis (CRCLM)-in vitro and in vivo. The inhibitory effect of SC and/or oxaliplatin on the proliferation, invasion, and migration of CRC cells was determined by CCK-8, MTT, wound healing migration, and transwell assay. Western blot and immunohistochemistry were used to evaluate the inhibitory effect of SC and/or oxaliplatin on the epithelial-mesenchymal transition (EMT) process. Nude mouse models of human CRCLM were established to test the anti-metastasis effect of SC and oxaliplatin in the single or combined form. SC exerted an inhibitory effect on the proliferation, invasion, and migration of CRC cells both in vitro and in vivo. The combination index of SC and oxaliplatin was 0.58. In addition, the inhibitory effect of SC in combination with oxaliplatin was found to be significantly stronger compared with that mediated by either SC or oxaliplatin alone, suggesting that SC can effectively enhance the inhibitory effect of oxaliplatin on CRCLM both in vitro and in vivo. SC was also revealed to reverse EMT process in cell lines and tissues, as reflected by the observed downregulation of N-cadherin and vimentin expression and the upregulation of E-cadherin expression. Taken together, data from the present study suggest that SC administration can inhibit CRC cell proliferation, invasion, migration, and EMT, while enhancing the inhibitory effects of oxaliplatin both in vitro and in vivo. These findings indicate (that) SC to be a promising anti-metastasis agent for CRCLM.

Preventive and therapeutic effect of intraportal oridonin on BALb/c nude mice hemispleen model of colon cancer liver metastasis.

BACKGROUND: This study is to investigate the preventive and therapeutic effect of intraportal oridonin on colorectal cancer liver metastasis (CRCLM). METHODS: The inhibitory effect of oridonin on HT29 cells was determined by CCK-8 and MTT assays. The preventive and therapeutic effect of intraportal oridonin on CRCLM were investigated by establishing BALb/c nude mice hemispleen models of colon cancer liver metastasis. The microscopic characteristics of tumor tissues were observed by hematoxylin-eosin staining, immunohistochemistry and TUNEL staining. On the other hand, liver function enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP), were detected to evaluate the hepatotoxicity of intraportal oridonin. The serum levels of tumor markers, including carcinoembryonic antigen (CEA) and α-fetoprotein (AFP), were used to investigate the intervention effect of intraportal oridonin on CRCLM. RESULTS: Oridonin exerted an inhibitory effect on the proliferation of HT29 cells in vitro. Intraportal oridonin was found to effectively prevent the occurrence and formation of CRCLM, whilst intraportal oridonin can also exert a therapeutic effect on CRCLM. Additionally, liver enzymes testing indicated that intraportal oridonin possesses non-hepatotoxicity, instead can effectively alleviate liver injury caused by tumor. Furthermore, intraportal oridonin was also revealed to decrease the serum levels of AFP and CEA. CONCLUSIONS: Intraportal oridonin can effectively inhibit the formation of liver metastatic tumor and exert a certain degree of preventive and therapeutic effect on CRCLM. These findings indicate intraportal oridonin to be a promising anti-metastasis agent for CRCLM.

HOXC9 overexpression is associated with gastric cancer progression and a prognostic marker for poor survival in gastric cancer patients.

BACKGROUND: As a member of the homeobox family, HOXC9 is overexpressed in several malignant tumors and may be regarded as a biomarker for prognostic evaluation. However, the expression pattern and prognostic significance of HOXC9 in gastric cancer have not been detailedly studied. METHODS: HOXC9 mRNA expression difference in normal tissues and gastric cancer tissues were investigated using RT-PCR, and immunohistochemistry was used to analyze HOXC9 protein expression in precancerous lesions and gastric cancer at different stages, and its clinicopathological characteristics and survival were statistically tested. RESULTS: Compared to the normal gastric mucosa tissues, the expression levels of HOXC9 mRNA in the human gastric cancer tissues were significantly higher. HOXC9 protein levels of gastric cancer were obviously higher than that in other noncancerous tissues (P < 0.001). Positive expression of HOXC9 was associated with tumor size (P = 0.036), lymphatic invasion (P = 0.001), depth of invasion (P < 0.001), lymph-node metastasis (P < 0.001), and higher stage disease (P < 0.001). Furthermore, Kaplan-Meier survival curves showed that HOXC9 expression is inversely correlated with both disease-specific and disease-free 5 year survival of patients with gastric cancer (P < 0.001 for both). Strikingly, our multivariate Cox regression analysis revealed that HOXC9 expression was an independent poor prognostic factor in gastric cancer (P < 0.05). CONCLUSIONS: HOXC9 expression was observed in a subset of patients with gastric cancer and was associated with an unfavorable prognosis. As well as being a new prognostic indicator, HOXC9 protein could be a useful marker for early diagnosis.