Lone-Star retractor perineal exposure method for laparoscopic abdominal perineal resection of rectal cancer.

BACKGROUND: The abdominal perineal resection (APR), historically referred to as Mile's procedure, stands as a time-honored surgical intervention for rectal cancer management. Advancements in surgical techniques and the advent of neoadjuvant therapies have significantly improved the rate of sphincter preservation among patients afflicted with rectal cancer, including those with ultralow rectal cancer. Despite these improvements, APR maintains its irreplaceable role in the clinical landscape, particularly for cases involving low rectal cancer with encroachment on the external anal sphincter or levator ani muscles. Optimal perineal exposure stands as a pivotal phase in APR, given that the precision of this maneuver is directly correlated with both the safety of the surgery and the patient's subsequent long-term prognosis. AIM: To evaluate the value of Lone-Star retractor (LSR) perineal exposure method in the treatment for laparoscopic APR of rectal cancer. METHODS: We reviewed the records of 38 patients with rectal cancer at Anqing Municipal Hospital from January 2020 to December 2023, including 20 patients who underwent the APR procedure with a LSR perineal exposure method (LSR group) and 18 patients who underwent the APR procedure with a conventional perineal exposure method (control group). In the LSR group, following incision of the skin and subcutaneous tissue, the LSR was placed and dynamically adjusted according to the surgical plane to fully expose the perineal operative field. RESULTS: A total of 38 patients underwent laparoscopic APR, none of whom were found to have distant metastasis upon intraoperative exploration. Perineal blood loss, the postoperative hospital stays and the wound pain scores in the LSR group were significantly lower than those in the control group. A single surgeon completed the perineal operation significantly more often in the LSR group than in the control group (P < 0.05). The incidence of infection via the perineal incision in the LSR group was significantly lower than that in the control group (P < 0.05). No cases of distant metastasis or local recurrence were found among the patients at the postoperative follow-up. CONCLUSION: The application of the LSR technique might be helpful for performing perineal exposure during APR for rectal cancer and could reduce the incidence of perineal complications, shorten the postoperative hospital stay, improve postoperative pain, and allow one surgeon to perform the perineal operation.

A MOFs/MIPs@GAs Ternary Composite Catalytic System with Graphene Oxide Aerogels as the Multifunctional Skeleton for High-Efficiency Detoxification of Organophosphate Nerve Agents in Pure Water.

Organophosphate nerve agents (OPs) are widely used as pesticides and chemical agents and pose a threat to human health and life. At present, most personal protective equipment usually only serves as physical protection and does not have an effect of chemical detoxification. In this work, ultra lightweight graphene oxide aerogels (GAs) have been used as a multifunctional skeleton to integrate the metal-organic frameworks (MOFs) and molecularly imprinted polymers (MIPs) together for obtaining a high-performance hybrid material (MOFs/MIPs@GAs) on hydrolysis detoxification of OPs. As a porous three-dimensional material full of carboxyl groups, GAs can not only support excellent mass transfer performance but also provide a proper pH self-buffering catalytic reaction external environment for hydrolyzing OPs. The obtained MOFs/MIPs@GAs can catalyze dimethyl-4-nitrophenyl phosphate (DMNP) hydrolysis detoxification rapidly in pure water (kobs = 0.2227 min-1, t1/2 = 3.11 min). This ternary hybrid material with exceptional performance and practical applicability has vast application prospects for the development of protective equipment.

Recent advances in the natural product analogues for the treatment of neurodegenerative diseases.

Neurodegenerative diseases (NDs) represent a hallmark of numerous incapacitating and untreatable conditions, the incidence of which is escalating swiftly, exemplified by Alzheimer's disease and Parkinson's disease. There is an urgent necessity to create pharmaceuticals that exhibit high efficacy and minimal toxicity in order to address these debilitating diseases. The structural complexity and diversity of natural products confer upon them a broad spectrum of biological activities, thereby significantly contributing to the history of drug discovery. Nevertheless, natural products present challenges in drug discovery, including time-consuming separation processes, low content, low bioavailability, and other related issues. To address these challenges, numerous analogs of natural products have been synthesized. This methodology enables the rapid synthesis of analogs of natural products with the potential to serve as lead compounds for drug development, thereby paving the way for the discovery of novel pharmaceuticals. This paper provides a summary of 127 synthetic analogues featuring various natural product structures, including flavonoids, alkaloids, coumarins, phenylpropanoids, terpenoids, polyphenols, and amides. The compounds are categorized based on their efficacy in treating various diseases. Furthermore, this article delves into the structure-activity relationship (SAR) of certain analogues, offering a thorough point of reference for the systematic development of pharmaceuticals aimed at addressing neurodegenerative conditions.

CircRNA-Phf21a_0002 promotes pyroptosis to aggravate hepatic ischemia/ reperfusion injury by sponging let-7b-5p.

Hepatic ischemia‒reperfusion injury is a common injury in liver surgery and liver transplantation that can lead to liver function damage, including oxidative stress, apoptosis, autophagy and inflammatory reactions. Pyroptosis is a type of inflammatory programmed cell death that has been implicated in ischemia‒reperfusion injury-associated inflammatory reactions. Although circular RNAs can regulate cell death in hepatic ischemia‒reperfusion injury, their relationship with pyroptosis remains unclear. Therefore, this study aimed to investigate the effect of circular RNA on pyroptosis in hepatic ischemia‒reperfusion injury. We constructed a mouse hepatic ischemia‒reperfusion injury model for circular RNA sequencing and obtained 40 circular RNAs with significant differential expression, of which 39 were upregulated and 1 was downregulated. Subsequently, the endogenous competitive RNA network was constructed using TarBase, miRTarBase, TargetScan, RNAhybrid, and miRanda. Gene Set Enrichment Analysis, Kyoto Encyclopedia of Genes and Genomes and Gene Ontology functional analyses of downstream target genes revealed that circRNA-Phf21a_0002 might affect pyroptosis by regulating the mTOR signaling pathway and Bach1 by sponging let-7b-5p. The overexpression plasmid upregulated the expression of circRNA-Phf21a_0002 in a hypoxia/reoxygenation model, which aggravated pyroptosis in AML12 cells and apoptosis and necrosis of hepatocytes. Next, we investigated the underlying mechanism and found that circRNA-Phf21a_0002 enabled the expression of Bach1 through sponging of let-7b-5p. The aggravation of pyroptosis via overexpression of circRNA-Phf21a_0002 was reversed by let-7b-5p mimics in hypoxia/reoxygenation-subjected AML12 cells. Collectively, our study clarifies that circRNA-Phf21a_0002 aggravates the pyroptosis of hepatocytes related to ischemia-reperfusion by sponging let-7b-5p. These findings provide new molecular mechanisms and novel biomarkers for follow-up treatment.

Inferring Characteristics of the Tumor Immune Microenvironment of Patients with HNSCC from Single-Cell Transcriptomics of Peripheral Blood.

In this study, we explore the possibility of inferring characteristics of the tumor immune microenvironment from the blood. Specifically, we investigate two datasets of patients with head and neck squamous cell carcinoma with matched single-cell RNA sequencing (scRNA-seq) from peripheral blood mononuclear cells (PBMCs) and tumor tissues. Our analysis shows that the immune cell fractions and gene expression profiles of various immune cells within the tumor microenvironment can be inferred from the matched PBMC scRNA-seq data. We find that the established exhausted T-cell signature can be predicted from the blood and serve as a valuable prognostic blood biomarker of immunotherapy response. Additionally, our study reveals that the inferred ratio between tumor memory B- and regulatory T-cell fractions is predictive of immunotherapy response and is superior to the well-established cytolytic and exhausted T-cell signatures. These results highlight the promising potential of PBMC scRNA-seq in cancer immunotherapy and warrant, and will hopefully facilitate, further investigations on a larger scale. The code for predicting tumor immune microenvironment from PBMC scRNA-seq, TIMEP, is provided, offering other researchers the opportunity to investigate its prospective applications in various other indications. SIGNIFICANCE: Our work offers a new and promising paradigm in liquid biopsies to unlock the power of blood single-cell transcriptomics in cancer immunotherapy.

Solid pseudopapillary neoplasm of the pancreas with hepatic metastases: problems and strategies.

Background: Solid pseudopapillary neoplasms of the pancreas with hepatic metastases are infrequent and difficult to diagnose, and treatment is uncertain. Methods: A retrospective analysis of clinical data from patients with pancreatic solid pseudopapillary neoplasm (SPN) hepatic metastases who underwent surgery at the First Hospital of Jilin University from January 2005 to December 2021 was conducted. A total of 287 patients with SPN were included in the study, of which 8 (3%) developed liver metastases, all of whom were treated surgically and recovered well after surgery. The clinical presentation, imaging features, surgical treatment, histopathological examination, and postoperative follow-up data (mean 70 months; range 28-138 months) of the patients were recorded and analyzed. Clinical response strategies can be derived by reviewing previous studies on hepatic metastases of SPNs. Results: For resectable hepatic metastases from pancreatic solid pseudopapillary neoplasms, early surgery with total resection of the primary tumor and metastasis has shown great efficiency and is associated with patient good prognosis. In patients presenting unresectable hepatic metastases, aggressive tumor reduction surgery resulted in the alleviation of clinical symptoms and reduction of tumor burden while potentially achieving long-term survival. Conclusion: For hepatic metastases of SPNs, a preoperative liver tissue biopsy is beneficial for a definitive diagnosis. Surgery demonstrates excellent therapeutic efficacy and is considered the preferred curative treatment approach. This paper presents clinical experiences with SPN-related hepatic metastases at the Affiliated Hospital of Jilin University, which can be used to guide patient counseling in clinical practice.

CGPA: multi-context insights from the cancer gene prognosis atlas.

Cancer transcriptomic data are used extensively to interrogate the prognostic value of targeted genes, yet basic scientists and clinicians have predominantly relied on univariable survival analysis for this purpose. This method often fails to capture the full prognostic potential and contextual relevance of the genes under study, inadvertently omitting a group of genes we term univariable missed-opportunity prognostic (UMOP) genes. Recognizing the complexity of revealing multifaceted prognostic implications, especially when extending the analysis to include various covariates and thresholds, we present the Cancer Gene Prognosis Atlas (CGPA). This platform greatly enhances gene-centric biomarker research across cancer types by offering an interactive and user-friendly interface for highly customized, in-depth prognostic analysis. CGPA notably supports data-driven exploration of gene pairs and gene-hallmark relationships, elucidating key composite biological mechanisms like synthetic lethality and immunosuppression. It further expands its capabilities to assess multi-gene panels using both public and user-provided data, facilitating a seamless mechanism-to-machine analysis. Additionally, CGPA features a designated portal for discovering prognostic gene modules using curated cancer immunotherapy data. Ultimately, CGPA's comprehensive, accessible tools allow cancer researchers, including those without statistical expertise, to precisely investigate the prognostic landscape of genes, customizing the model to fit specific research hypotheses and enhancing biomarker discovery and validation through a synergy of mechanistic and data-driven strategies.

Mendelian randomization study reveals causal effects of specific gut microbiota on the risk of interstitial cystitis/bladder pain syndrome (IC/BPS).

Evidence from previous studies have demonstrated that gut microbiota are closely associated with occurrence of interstitial cystitis/bladder pain syndrome (IC/BPS), yet the causal link between the two is not well known. In this study, we performed a two-sample Mendelian randomization (MR) analysis to determine the possible causal association between gut microbiota with IC/BPS. Gut microbiota summary level data were derived from the genome-wide association study (GWAS) conducted by MiBioGen and the IC/BPS GWAS summary level data were obtained from the GWAS Catalog. Next, we performed an MR study to investigate the causal link between gut microbiota and IC/BPS. The primary method for causal analysis was the inverse variance weighted (IVW), and the MR results were validated through multiple sensitivity analyses. A positive association was found between IC/BPS and eight gut microbial taxa, including genus Bacteroides, genus Haemophilus, genus Veillonella, genus Coprococcus1, genus Butyricimonas, family Bacteroidaceae, family Christensenellaceae, and order Lactobacillales. Sensitivity analysis revealed lack of significant pleiotropy or heterogeneity in the obtained results. This MR analysis reveals that a causal association exists between some gut microbiota with IC/BPS. This finding may is expected to guide future research and development of IC/BPS preventions and treatments based on the bladder-gut axis. However, given the clinical complexity and diagnostic challenges of IC/BPS, along with the limitations of using large-scale GWAS summary data for analysis, our MR results require further validation through additional research.

Pectolinarigenin targeting FGFR3 alleviates osteoarthritis progression by regulating the NF-κB/NLRP3 inflammasome pyroptotic pathway.

OBJECTIVE: Osteoarthritis (OA) is a chronic degenerative disease characterized by cartilage degeneration, involving inflammation, pyroptosis, and degeneration of the extracellular matrix (ECM). Pectolinarigenin (PEC) is a natural flavonoid with antioxidant, anti-inflammatory and anti-tumor properties. This study aims to explore the potential of PEC in ameliorating OA progression and its underlying mechanisms. METHODS: Chondrocytes were exposed to 10 ng/mL IL-1ß to simulate OA-like changes. The effect of PEC on IL-1ß-treated chondrocytes was assessed using ELISA, western blot, and immunofluorescence. The mRNA sequencing (mRNA-seq) was employed to explore the possible targets of PEC in delaying OA progression. The OA mouse model was induced through anterior cruciate ligament transection (ACLT) and divided into sham, ACLT, ACLT+5 mg/kg PEC, and ACLT+10 mg/kg PEC groups. Micro-computed tomography and histological analysis were conducted to confirm the beneficial effects of PEC on OA in vivo. RESULTS: PEC mitigated chondrocyte pyroptosis, as evidenced by reduced levels of pyroptosis-related proteins. Additionally, PEC attenuated IL-1ß-mediated chondrocyte ECM degradation and inflammation. Mechanistically, mRNA-seq showed that FGFR3 was a downstream target of PEC. FGFR3 silencing reversed the beneficial effects of PEC on IL-1ß-exposed chondrocytes. PEC exerted anti-pyroptotic, anti-ECM degradative, and anti-inflammatory effects through upregulating FGFR3 to inhibit the NF-κB/NLRP3 pyroptosis-related pathway. Consistently, in vivo experiments demonstrated the chondroprotective effects of PEC in OA mice. CONCLUSION: PEC alleviate OA progression by FGFR3/NF-κB/NLRP3 pathway mediated chondrocyte pyroptosis, ECM degradation and inflammation, suggesting the potential of PEC as a therapeutic agent for OA.

Inhibition of Dorsal Root Ganglia Transient Receptor Potential Ankyrin 1 Upregulation Contributes to the Protective Effect of Morphine Against Gastric Mucosal Damage Induced by Water-Immersion Restraint Stress.

The pathogenesis mechanism of acute gastric mucosal lesions (AGML) is still unclear; further exploration is urgently needed to find a new therapeutic target. This study aimed to investigate whether morphine might regulate the expression and function of transient receptor potential ankyrin 1 (TRPA1) through a cyclic adenosine monophosphate/protein kinase A (cAMP/PKA)-dependent pathway, thereby alleviating gastric mucosal lesions caused by water-immersion restraint stress (WIRS). Rats were administered with intrathecal morphine, TRPA1 antagonist (HC-030031), µ-opioid receptor antagonist, or protein kinase A inhibitor (H-89), respectively, before WIRS. After 6 hours of WIRS, microscopic lesions, hematoxylin and eosin staining, and transmission electron microscopy were applied to assess the damage of the gastric mucosa. Real-time polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay were conducted to detect the levels of TRPA1 and substance P (SP) in the dorsal root ganglia (DRG) and gastric tissues. In addition, immunofluorescence was used to explore the possible co-expression of TRPA1 and µ-opioid receptors in the DRG. The results indicated that WIRS upregulated TRPA1 and SP in gastric mucosa, and HC-030031 or H-89 could alleviate gastric mucosal lesions caused by WIRS (P < .0001). Morphine was found to suppress both WIRS-induced gastric mucosal lesions (P < .0001) and the upregulation of TRPA1 (P = .0086) and SP (P = .0013). Both TRPA1 and SP play important roles in the pathogenesis of WIRS-induced AGML. Exogenous gastroprotective strategies reduce elevated levels of TRPA1 via the cAMP/PKA-dependent pathway. Inhibition of TRPA1 upregulation in the DRG is critical for intrathecal morphine preconditioning-induced gastric protection.

CA IX-targeted Ag2S quantum dots bioprobe for NIR-II imaging-guided hypoxia tumor chemo-photothermal therapy.

Hypoxia is the common characteristic of almost all solid tumors, which prevents therapeutic drugs from reaching the tumors. Therefore, the development of new targeted agents for the accurate diagnosis of hypoxia tumors is widely concerned. As carbonic anhydrase IX (CA IX) is abundantly distributed on the hypoxia tumor cells, it is considered as a potential tumor biomarker. 4-(2-Aminoethyl)benzenesulfonamide (ABS) as a CA IX inhibitor has inherent inhibitory activity and good targeting effect. In this study, Ag2S quantum dots (QDs) were used as the carrier to prepare a novel diagnostic and therapeutic bioprobe (Ag2S@polyethylene glycol (PEG)-ABS) through ligand exchange and amide condensation reaction. Ag2S@PEG-ABS can selectively target tumors by surface-modified ABS and achieve accurate tumor imaging by the near infrared-II (NIR-II) fluorescence characteristics of Ag2S QDs. PEG modification of Ag2S QDs greatly improves its water solubility and stability, and therefore achieves high photothermal stability and high photothermal conversion efficiency (PCE) of 45.17%. Under laser irradiation, Ag2S@PEG-ABS has powerful photothermal and inherent antitumor combinations on colon cancer cells (CT-26) in vitro. It also has been proved that Ag2S@PEG-ABS can realize the effective treatment of hypoxia tumors in vivo and show good biocompatibility. Therefore, it is a new efficient integrated platform for the diagnosis and treatment of hypoxia tumors.

Co-Transplantation-Based Human-Mouse Chimeric Brain Models to Study Human Glial-Glial and Glial-Neuronal Interactions.

Human-mouse chimeric brain models, generated by transplanting human induced pluripotent stem cell (hiPSC)-derived neural cells, are valuable for studying the development and function of human neural cells in vivo. Understanding glial-glial and glial-neuronal interactions is essential for unraveling the complexities of brain function and developing treatments for neurological disorders. To explore these interactions between human neural cells within an intact brain environment, we employe a co-transplantation strategy involving the engraftment of hiPSC-derived neural progenitor cells along with primitive macrophage progenitors into the neonatal mouse brain. This approach creates human-mouse chimeric brains containing human microglia, macroglia (astroglia and oligodendroglia), and neurons. Using super-resolution imaging and 3D reconstruction techniques, we examine the dynamics between human neurons and glia, unveiling human microglia engulfing immature human neurons, microglia pruning synapses of human neurons, and significant interactions between human oligodendrocytes and neurons. Single-cell RNA sequencing analysis of the chimeric brain uncovers a close recapitulation of the human glial progenitor cell population, along with a dynamic stage in astroglial development that mirrors the processes found in the human brain. Furthermore, cell-cell communication analysis highlights significant neuronal-glial and glial-glial interactions, especially the interaction between adhesion molecules neurexins and neuroligins. This innovative co-transplantation model opens up new avenues for exploring the complex pathophysiological mechanisms underlying human neurological diseases. It holds particular promise for studying disorders where glial-neuronal interactions and non-cell-autonomous effects play crucial roles.

A brief review of current treatment options for osteoarthritis including disease-modifying osteoarthritis drugs (DMOADs) and novel therapeutics.

Osteoarthritis (OA) is a chronic disorder caused by degenerative changes in articular cartilage, which are mainly manifests as degeneration of cartilage, subchondral bone remodeling, as well as synovial inflammation. Over the next few decades, OA and its burden will continue to increase worldwide, posing a major public health challenge for the foreseeable future. Treatment for OA includes non-pharmacological, pharmacological, and surgical treatments. Existing conservative treatments and joint surgery can only alleviate the symptoms and cannot be cured, so new therapies for OA are urgently needed. Since advances in the understanding of OA pathophysiology, researchers have identified some potential therapeutic targets against degeneration of cartilage, subchondral bone remodeling and synovial inflammation, enabling development of the disease-modifying OA drugs (DMOADs). Additionally, a number of new technologies are also being investigated for treating OA, such as RNA interference (RNAi), CRISPR/Cas9 and PROTAC. The goal of this review is to describe the current development status of DMOADs and to discuss the potential of emerging therapeutic approaches for treating OA, thus providing a reference for OA treatments.

A deep-learning framework to predict cancer treatment response from histopathology images through imputed transcriptomics.

Advances in artificial intelligence have paved the way for leveraging hematoxylin and eosin-stained tumor slides for precision oncology. We present ENLIGHT-DeepPT, an indirect two-step approach consisting of (1) DeepPT, a deep-learning framework that predicts genome-wide tumor mRNA expression from slides, and (2) ENLIGHT, which predicts response to targeted and immune therapies from the inferred expression values. We show that DeepPT successfully predicts transcriptomics in all 16 The Cancer Genome Atlas cohorts tested and generalizes well to two independent datasets. ENLIGHT-DeepPT successfully predicts true responders in five independent patient cohorts involving four different treatments spanning six cancer types, with an overall odds ratio of 2.28 and a 39.5% increased response rate among predicted responders versus the baseline rate. Notably, its prediction accuracy, obtained without any training on the treatment data, is comparable to that achieved by directly predicting the response from the images, which requires specific training on the treatment evaluation cohorts.

Comparison of the treatment strategies for symptomatic chronic internal carotid artery occlusion.

OBJECTIVE: The best management of symptomatic chronic internal carotid artery occlusion (CICAO) has been controversial. This systematic review and meta-analysis were to compare the outcomes of different treatment strategies for symptomatic CICAO. METHODS: Two independent researchers conducted a search of articles on the treatment of CICAO published between January 2000 and October 2023 in PubMed, Web of Science, Embase, and The Cochrane Library. Twenty-two articles were eligible for meta-analysis using a random effects model to combine and analyze the data for the pooled rates of stroke and death, and the rates of procedural success and significant restenosis/occlusion. RESULTS: A total of 1193 patients from 22 publications were included in this study. Six of them had bilateral internal carotid artery occlusion. The 30-day stroke and death rates were 1.1% (95% confidence interval [CI], 0%-4.4%) in the best medical treatment (BMT) group, 4.1% (95% CI, 0.7%-9.3%; I2 = 71.4%) in the extracranial-intracranial (EC-IC) bypass group, 4.4% (95% CI, 2.4%-6.8%; I2 = 0%) in the carotid artery stenting (CAS) group, and 1.2% (95% CI, 0%-3.4%; I2 = 0%) in the combined carotid endarterectomy (CEA) and stenting (CEA + CAS) group. During follow-up of 16.5 (±16.3) months, the stroke and death rates were 19.5%, 1.2%, 6.6%, and 2.4% in the BMT, EC-IC, CAS, and CEA + CAS groups respectively. The surgical success rate was 99.7% (95% CI, 98.5%-100%; I2 = 0%) in the EC-IC group, 70.1% (95% CI, 62.3%-77.5%; I2 = 64%) in the CAS group, and 86.4% (95% CI, 78.8%-92.7%; I2 = 60%) in the CEA + CAS group. The rate of post-procedural significant restenosis or occlusion was 3.6% in the EC-IC group, 18.7% in the CAS group, and 5.7% in the CEA + CSA group. The surgical success rate was negatively associated by the length of internal carotid artery (ICA) occlusion. Surgical success rate was significantly higher in the patients with occlusive lesion within C1 to C4 segments, compared with those with occlusion distal to C4 segment (odds ratio, 11.3; 95% CI, 5.0-25.53; P < .001). A proximal stump of ICA is a favorable sign for CAS. The success rate of CAS was significantly higher in the patients with an ICA stump than that in the patients without (odds ratio, 11.36; 95% CI, 4.84-26.64; P < .01). However, the success rate of CEA + CAS was not affected by the proximal ICA stump. CONCLUSIONS: For the management of symptomatic CICAO, BMT alone is associated with the highest risk of mid- and long-term stroke and death. EC-IC bypass surgery and CEA + CAS should be considered as the choice of treatment based on operator's expertise and patient's anatomy. CAS may be employed as an alternative option in high surgical risk patients, especially when proximal ICA stump exists.

Pim-1 kinase protects the liver from ischemia reperfusion injury by regulating dynamics-related protein 1.

Hepatic ischemia-reperfusion (IR) injury significantly impacts liver transplantation success, yet current treatments remain inadequate. This study explores the role of Proto-oncogene serine/threonine-protein kinase (Pim-1) in liver IR, an area previously unexplored. Utilizing a mouse liver IR in vivo model and a MIHA cell hypoxia-reoxygenation in vitro model, we observed that Pim-1 expression increases following IR, inversely correlating with serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Increased Pim-1 expression stabilizes mitochondrial membranes by modifying Drp1 phosphorylation, reducing mitochondrial fission and apoptosis, thereby mitigating liver damage. Additionally, we discovered that elevated Pim-1 expression is dependent on the trimethylation of histone H3 lysine 9 during liver IR. These findings underscore the importance and potential clinical application of targeting Pim-1 in treating hepatic IR, presenting a novel therapeutic avenue.

Ultrasound-Mediated Lysozyme Microbubbles Targeting NOX4 Knockdown Alleviate Cisplatin-Exposed Cochlear Hair Cell Ototoxicity.

The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) protein plays an essential role in the cisplatin (CDDP)-induced generation of reactive oxygen species (ROS). In this study, we evaluated the suitability of ultrasound-mediated lysozyme microbubble (USMB) cavitation to enhance NOX4 siRNA transfection in vitro and ex vivo. Lysozyme-shelled microbubbles (LyzMBs) were constructed and designed for siNOX4 loading as siNOX4/LyzMBs. We investigated different siNOX4-based cell transfection approaches, including naked siNOX4, LyzMB-mixed siNOX4, and siNOX4-loaded LyzMBs, and compared their silencing effects in CDDP-treated HEI-OC1 cells and mouse organ of Corti explants. Transfection efficiencies were evaluated by quantifying the cellular uptake of cyanine 3 (Cy3) fluorescein-labeled siRNA. In vitro experiments showed that the high transfection efficacy (48.18%) of siNOX4 to HEI-OC1 cells mediated by US and siNOX4-loaded LyzMBs significantly inhibited CDDP-induced ROS generation to almost the basal level. The ex vivo CDDP-treated organ of Corti explants of mice showed an even more robust silencing effect of the NOX4 gene in the siNOX4/LyzMB groups treated with US sonication than without US sonication, with a marked abolition of CDDP-induced ROS generation and cytotoxicity. Loading of siNOX4 on LyzMBs can stabilize siNOX4 and prevent its degradation, thereby enhancing the transfection and silencing effects when combined with US sonication. This USMB-derived therapy modality for alleviating CDDP-induced ototoxicity may be suitable for future clinical applications.

Berberine alleviates ovarian tissue damage in mice with hepatolenticular degeneration by suppressing ferroptosis and endoplasmic reticulum stress.

OBJECTIVE: Hepatolenticular degeneration (HLD) is an autosomal recessive disorder that manifests as multiorgan damage due to impaired copper (Cu) metabolism. Female patients with HLD often experience reproductive impairments. This study investigated the protective effect of berberine against ovarian damage in toxic-milk (TX) mice, a murine model for HLD. METHODS: Mice were categorized into control group, HLD TX group (HLD group), penicillamine (Cu chelator)-treated TX group and berberine-treated TX group. Body weight, ovary weight and the number of ovulated eggs were recorded. Follicular morphology and cellular ultrastructure were examined. Total iron, ferrous iron (Fe2+) and trivalent iron (Fe3+) levels, as well as malondialdehyde (MDA), glutathione (GSH) and oxidized glutathione (GSSG), were measured in the ovaries. Western blot analysis was used to analyze the expression of proteins related to ferroptosis and endoplasmic reticulum (ER) stress. RESULTS: Ovarian tissue damage was evident in the HLD group, with a significant increase in ferroptosis and ER stress compared to the control group. This damage was inhibited by treatment with penicillamine, a Cu chelator. Compared with the HLD group, berberine increased the number of ovulations, and improved ovarian morphology and ultrastructure. Further, we found that berberine reduced total iron, Fe2+, MDA and GSSG levels, elevated GSH levels, decreased the expression of the ferroptosis marker protein prostaglandin-endoperoxide synthase 2 (PTGS2), and increased glutathione peroxidase 4 (GPX4) expression. Furthermore, berberine inhibited the expression of ER stress-associated proteins mediated by the protein kinase RNA-like ER kinase (PERK) pathway. CONCLUSION: Ferroptosis and ER stress are involved in Cu-induced ovarian damage in TX mice. Berberine ameliorates ovarian damage in HLD TX mice by inhibiting ferroptosis and ER stress. Please cite this article as: Liu QZ, Han H, Fang XR, Wang LY, Zhao D, Yin MZ, Zhang N, Jiang PY, Ji ZH, Wu LM. Berberine alleviates ovarian tissue damage in mice with hepatolenticular degeneration by suppressing ferroptosis and endoplasmic reticulum stress. J Integr Med. 2024; 22(4): 494-503.

Identification and Characterization of Metastasis-Initiating Cells in ESCC in a Multi-Timepoint Pulmonary Metastasis Mouse Model.

Metastasis is the biggest obstacle to esophageal squamous cell carcinoma (ESCC) treatment. Single-cell RNA sequencing analyses are applied to investigate lung metastatic ESCC cells isolated from pulmonary metastasis mouse model at multiple timepoints to characterize early metastatic microenvironment. A small population of parental KYSE30 cell line (Cluster S) resembling metastasis-initiating cells (MICs) is identified because they survive and colonize at lung metastatic sites. Differential expression profile comparisons between Cluster S and other subpopulations identified a panel of 7 metastasis-initiating signature genes (MIS), including CD44 and TACSTD2, to represent MICs in ESCC. Functional studies demonstrated MICs (CD44high) exhibited significantly enhanced cell survival (resistances to oxidative stress and apoptosis), migration, invasion, stemness, and in vivo lung metastasis capabilities, while bioinformatics analyses revealed enhanced organ development, stress responses, and neuron development, potentially remodel early metastasis microenvironment. Meanwhile, early metastasizing cells demonstrate quasi-epithelial-mesenchymal phenotype to support both invasion and anchorage. Multiplex immunohistochemistry (mIHC) staining of 4 MISs (CD44, S100A14, RHOD, and TACSTD2) in ESCC clinical samples demonstrated differential MIS expression scores (dMISs) predict lymph node metastasis, overall survival, and risk of carcinothrombosis.

Non-Clinical Safety Evaluation of Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells in Cynomolgus Monkeys.

Purpose: In recent years, exosomes have been proved to be used to treat many diseases. However, due to the lack of uniform quality control standards for exosomes, the safety of exosomes is still a problem to be solved, especially now more and more exosomes are used in clinical trials, and its non-clinical safety evaluation is particularly important. However, there is no safety evaluation standard for exosomes at present. Therefore, this study will refer to the evaluation criteria of therapeutic biological products, adopt non-human primates to evaluate the non-clinical safety of human umbilical cord mesenchymal stem cell exosomes from the general pharmacology and immunotoxicity, aiming at establishing a safety evaluation system of exosomes and providing reference for the clinical application of exosomes in the future. Methods: 3.85 × 1012 exosomes derived from human umbilical cord mesenchymal stem cells were injected into cynomolgus monkeys intravenously. The changes of general clinical conditions, hematology, immunoglobulin, Th1/Th2 cytokines, T lymphocytes and B lymphocytes, and immune organs were observed before and within 14 days after injection. Results: The results showed that exosomes did not have obvious pathological effects on the general clinical conditions, blood, coagulation function, organ coefficient, immunoglobulin, Th1/Th2 cytokines, lymphocytes, major organs, and major immune organs (spleen, thymus, bone marrow) of cynomolgus monkeys. However, the number of granulocyte-macrophage colonies in exosomes group was significantly higher than that in control group. Conclusion: To sum up, the general pharmacological results and immunotoxicity results showed that the injection of 3.85 × 1012 exosomes may have no obvious adverse reactions to cynomolgus monkeys. This dose of exosomes is relatively safe for treatment, which provides basis research for non-clinical safety evaluation of exosomes and provides reliable research basis for future clinical application of exosomes.