Does a high peritoneal cancer index lead to a worse prognosis of patients with advanced ovarian cancer?: a systematic review and meta-analysis based on the latest evidence.

Background: The newest clinical evidence that the relationship between the peritoneal cancer index (PCI) and the postoperative prognosis of advanced ovarian cancer patients remains controversial, and there are no large-sample and multicenter studies to clarify this matter. Therefore, in this paper, we used meta-analysis to systematically assess the postoperative prognostic value of PCI in subjects with advanced ovarian cancer to provide individualized treatment plans and thus improve the prognosis of patients. Methods: Literature on the correlation between PCI and the postoperative prognosis in subjects with advanced OC undergoing cytoreductive surgery (CRS) was searched in the Cochrane Library, Pubmed, Embase, and Web of Science from the database inception to April 20, 2023. The search was updated on February 28, 2024. We only included late-stage (FIGO stage: III-IV) patients who did not undergo neoadjuvant chemotherapy (NACT) or hyperthermic intraperitoneal chemotherapy (HIPEC). Afterwards, literature screening and data extraction were conducted using Endnote20 software. The literature quality was assessed using the Newcastle-Ottawa Scale (NOS). Lastly, statistical analysis was performed with STATA 15.0 software. Results: Five studies with 774 patients were included. The result indicated that patients with high PCI had a worse prognosis than those with low PCI. The combined hazard ratio was 2.79 [95%CI: (2.04, 3.82), p<0.001] for overall survival (OS) in patients with high PCI. Further subgroup analysis by the FIGO staging revealed that in stage III [HR: 2.61, 95%CI: (2.00, 3.40), p<0.001] and stage III-IV patients [HR: 2.69, 95%CI: (1.66, 4.36), p<0.001], a high PCI score was significantly associated with a worse prognosis. The PCI score had a greater impact on the OS of patients with higher stages. The combined hazard ratio was 1.89 [95%CI: (1.51, 2.36), p<0.001] for progression-free survival (PFS) in patients with high PCI. Conclusion: PCI may be used as a postoperative prognosis indicator in patients with advanced OC on primary debulking surgery. High PCI indicates a worse prognosis. However, further research is warranted to confirm these findings. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023424010.

Heparin-binding epidermal growth factor-like growth factor improves erectile function in streptozotocin-induced diabetic mice.

BACKGROUND: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) serves as a pro-angiogenic factor; however, there is to our knowledge currently no reported research on the relationship between HB-EGF and diabetic erectile dysfunction (ED). AIM: In this study we aimed to determine whether HB-EGF can improve the erectile function of streptozotocin-induced diabetic mice and to explore the related mechanisms. METHODS: Eight-week-old male C57BL/6 mice were used for diabetes induction. Diabetes mellitus (DM) was induced by low-dose injections of streptozotocin (50 mg/kg) for 5 consecutive days. Eight weeks after streptozotocin injections, DM was determined by measuring blood glucose and body weight. Diabetic mice were treated with two intracavernous administrations of phosphate-buffered saline (20 µL) or various doses of HB-EGF (days -3 and 0; 1, 5, and 10 µg in 20 µL of phosphate-buffered saline). The angiogenesis effect of HB-EGF was confirmed by tube formation and migration assays in mouse cavernous endothelial cells and mouse cavernous pericytes under high-glucose conditions. Erectile function was measured by electrical stimulation of the cavernous nerve, as well as histological examination and Western blot analysis for mechanism assessment. OUTCOMES: In vitro angiogenesis, cell proliferation, in vivo intracavernous pressure, neurovascular regeneration, cavernous permeability, and survival signaling were the outcomes measured. RESULTS: Expression of HB-EGF was reduced under diabetic conditions. Exogenous HB-EGF induced angiogenesis in mouse cavernous endothelial cells and mouse cavernous pericytes under high-glucose conditions. Erectile function was decreased in the DM group, whereas administration of HB-EGF resulted in a significant improvement of erectile function (91% of the age-matched control group) in association with increased neurovascular content, including cavernous endothelial cells, pericytes, and neuronal cells. Histological and Western blot analyses revealed a significant increase in the permeability of the corpus cavernosum in DM mice, which was attenuated by HB-EGF treatment. The protein expression of phospho-Akt Ser473 and phosphorylated endothelial nitric oxide synthase Ser1177 increased after HB-EGF treatment. CLINICAL IMPLICATIONS: The use of HB-EGF may be an effective strategy to treat ED associated with DM or other neurovascular diseases. STRENGTHS AND LIMITATIONS: Similarly to other pro-angiogenic factors, HB-EGF has dual roles in vascular and neuronal development. Our study focused on broadly evaluating the role of HB-EGF in diabetic ED. In view of the properties of HB-EGF as an angiogenic factor, its dose concentration should be strictly controlled to avoid potential side effects. CONCLUSION: In the diabetic ED mouse model in this study erectile function was improved by HB-EGF, which may provide new treatment strategies for patients with ED who do not respond to phosphodiesterase 5 Inhibitors.

Exploring the role of Chinese herbal medicine in the long-term management of postoperative ovarian endometriotic cysts: a systematic review and meta-analysis.

Background: Ovarian endometriotic cysts (OEC) represent the primary manifestation of endometriosis, constituting a hormonally dependent inflammatory disorder in gynecology. It significantly affects the quality of life and reproductive health of women. It is worth noting that traditional Chinese medicine (TCM), especially Chinese herbal medicine (CHM), has been widely applied in mainland China due to its unique therapeutic system and commendable clinical efficacy, bringing new hope for preventing and managing OEC. Objective: This study aims to evaluate the efficacy and safety of CHM in the management of postoperative OEC. Simultaneously, it seeks to explore the medication laws, therapeutic principles, and specific treatment mechanisms of CHM. Methods: Eight electronic databases were searched from their inception to 01 November 2023. Randomized controlled trials (RCTs) assessing the therapeutic effects and safety of CHM for postoperative OEC were included. The risk of bias for each trial was assessed using the Cochrane Collaboration's tool. The certainty of the evidence was evaluated using the GRADE profiler 3.2. Additionally, we extracted formulation from the included studies, conducting a thorough analysis. Results: (ⅰ) Twenty-two RCTs involving 1938 patients were included. In terms of the primary efficacy outcome, the CHM group demonstrated a potentially lower recurrence rate compared to both control (odds ratio (OR) = 0.25; 95% confidence intervals (CI): 0.10-0.64) and conventional western medicine (CWM) (OR = 0.26; 95% CI: 0.11-0.65) groups. Furthermore, the joint application of CHM and CWM resulted in a significant reduction in the recurrence rate (OR = 0.26; 95% CI: 0.17-0.40). (ⅱ) Regarding secondary efficacy outcomes, (a) Total clinical efficacy rate: CHM showcased an augmentation in clinical effectiveness compared to both the control (OR = 4.23; 95% CI: 1.12-15.99) and CWM (OR = 2.94; 95% CI: 1.34-6.43) groups. The combined administration of CHM and CWM substantially enhanced overall clinical effectiveness (OR = 3.44; 95% CI: 2.37-5.00). (b) VAS Score: CHM exhibited the capacity to diminish the VAS score in comparison to surgery alone (Mean difference (MD) = -0.86; 95% CI: -1.01 to -0.71). Nevertheless, no substantial advantage was observed compared to CWM alone (MD = -0.16; 95% CI: -0.49 to 0.17). The integration of CHM with CWM effectively ameliorated pain symptoms (MD = -0.87; 95% CI: -1.10 to -0.65). (c) Serum Level of Cancer antigen 125 (CA125): the CHM group potentially exhibited lower CA125 levels in comparison to CWM alone (MD = -11.08; 95% CI: -21.75 to -0.42). The combined intervention of CHM and CWM significantly decreased CA125 levels (MD = -5.31; 95% CI: -7.27 to -3.36). (d) Pregnancy Rate: CHM exhibited superiority in enhancing the pregnancy rate compared to surgery (OR = 3.95; 95% CI: 1.60-9.74) or CWM alone (OR = 3.31; 95% CI: 1.40-7.83). The combined utilization of CHM and CWM demonstrated the potential to enhance pregnancy rates compared to CWM (OR = 2.99; 95% CI: 1.28-6.98). Concerning safety outcome indicators, CHM effectively decreased the overall incidence of adverse events and, to a certain extent, alleviated perimenopausal symptoms as well as liver function impairment. (ⅲ) Most of CHMs were originated from classical Chinese herbal formulas. Prunus persica (L.) Batsch (Taoren), Angelica sinensis (Oliv.) Diels (Danggui), Salvia miltiorrhiza Bunge (Danshen), Paeonia lactiflora Pall. (Chishao), and Corydalis yanhusuo W.T.Wang (Yanhusuo) were most frequently used CHM. Conclusion: CHM may be a viable choice in the long-term management of postoperative OEC, with the potential to enhance clinical efficacy while decreasing recurrence and adverse effects.

A literature review on signaling pathways of cervical cancer cell death-apoptosis induced by Traditional Chinese Medicine.

ETHNOPHARMACOLOGICAL RELEVANCE: Cervical cancer (CC) is a potentially lethal disorder that can have serious consequences for a woman's health. Because early symptoms are typically only present in the middle to late stages of the disease, clinical diagnosis and treatment can be challenging. Traditional Chinese medicine (TCM) has been shown to have unique benefits in terms of alleviating cancer clinical symptoms, lowering the risk of recurrence after surgery, and reducing toxic side effects and medication resistance after radiation therapy. It has also been shown to improve the quality of life for patients. Because of its improved anti-tumor effectiveness and biosafety, it could be considered an alternative therapy option. This study examines how TCM causes apoptosis in CC cells via signal transduction, including the active components and medicinal tonics. It also intends to provide a reliable clinical basis and protocol selection for the TCM therapy of CC. METHODS: The following search terms were employed in PubMed, Web of Science, Embase, CNKI, Wanfang, VIP, SinoMed, and other scientific databases to retrieve pertinent literature on "cervical cancer," "apoptosis," "signaling pathway," "traditional Chinese medicine," "herbal monomers," "herbal components," "herbal extracts," and "herbal formulas." RESULTS: It has been demonstrated that herbal medicines can induce apoptosis in cells of the cervix, a type of cancer, by influencing the signaling pathways involved. CONCLUSION: A comprehensive literature search was conducted, and 148 papers from the period between January 2017 and December 2023 were identified as eligible for inclusion. After a meticulous process of screening, elimination and summary, generalization, and analysis, it was found that TCM can regulate multiple intracellular signaling pathways and related molecular targets, such as STAT3, PI3K/AKT, Wnt/ß-catenin, MAPK, NF-κB, p53, HIF-1α, Fas/FasL and so forth. This regulatory capacity was observed to induce apoptosis in cervical cancer cells. The study of the mechanism of TCM against cervical cancer and the screening of new drug targets is of great significance for future research in this field. The results of this study will provide ideas and references for the future development of Chinese medicine in the diagnosis and treatment of cervical cancer.

Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis.

Semaglutide, a glucagon-like peptide-1 receptor agonist, is clinically used as a glucose-lowering and weight loss medication due to its effects on energy metabolism. In heart failure, energy production is impaired due to altered mitochondrial function and increased glycolysis. However, the impact of semaglutide on cardiomyocyte metabolism under pressure overload remains unclear. Here we demonstrate that semaglutide improves cardiac function and reduces hypertrophy and fibrosis in a mouse model of pressure overload-induced heart failure. Semaglutide preserves mitochondrial structure and function under chronic stress. Metabolomics reveals that semaglutide reduces mitochondrial damage, lipid accumulation, and ATP deficiency by promoting pyruvate entry into the tricarboxylic acid cycle and increasing fatty acid oxidation. Transcriptional analysis shows that semaglutide regulates myocardial energy metabolism through the Creb5/NR4a1 axis in the PI3K/AKT pathway, reducing NR4a1 expression and its translocation to mitochondria. NR4a1 knockdown ameliorates mitochondrial dysfunction and abnormal glucose and lipid metabolism in the heart. These findings suggest that semaglutide may be a therapeutic agent for improving cardiac remodeling by modulating energy metabolism.

CTA-Based Radiomics and Area Change Rate Predict Infrarenal Abdominal Aortic Aneurysms Patients Events: A Multicenter Study.

RATIONALE AND OBJECTIVES: Clinical assessment of abdominal aortic aneurysm (AAA) intervention and rupture risk relies primarily on maximum diameter, but studies have shown that sole dependence on diameter has limitations. CTA-based radiomics, aneurysm and lumen area change rates (AACR, LACR) are measured to predict potential AAA events. MATERIALS AND METHODS: Between January 2017 and November 2022, 260 AAA patients from four centers who underwent two preoperative CTA examinations were included in this retrospective study. The endpoint event is defined as AAA rupture or repair. Patients were categorized into event and no-event groups based on the occurrence of endpoint event during follow-up. AACR and LACR were assessed using baseline and follow-up CTA, with radiomics features extracted from the baseline images. C-statistics and the Kaplan-Meier analysis were used to evaluate the predictive performance. RESULTS: A total of 193 eligible infrarenal AAA patients were included, 176 (91.2%) were man and 17 (8.8%) were woman. The median follow-up was 33.4 (14.2, 57.4) months. Seven models were constructed, comprising the aneurysm-based Radscore model, lumen-based Radscore model, intraluminal thrombus (ILT)-based Radscore model, AACR model, LACR model, clinical model (including high-density lipoprotein, D-dimer, and baseline aneurysm diameter), and a merged model. On the external validation set, the C-index of seven models were 0.713 (0.574-0.853), 0.642 (0.499-0.786), 0.727 (0.600-0.854), 0.619 (0.484-0.753), 0.680 (0.530-0.830), 0.690 (0.557-0.824) and 0.760 (0.651-0.869), in that order. In the Kaplan-Meier analysis, the merged model was best-divided patients into high/low-risk groups with Log-rank p < 0.0001. The AARC and LARC between non-event and event groups have significant differences (AACR: 1.4 cm2/y vs. 2.3 cm2/y, p < 0.0001; LACR: 0.3 cm2/y vs. 1.1 cm2/y, p < 0.0001). CONCLUSION: CTA-based radiomics, AACR and LACR have good predictive value for outcome event in infrarenal AAA patients.

Exploring the causal role of multiple metabolites on ovarian cancer: a two sample Mendelian randomization study.

BACKGROUND: The mechanisms and risk factors underlying ovarian cancer (OC) remain under investigation, making the identification of new prognostic biomarkers and improved predictive factors critically important. Recently, circulating metabolites have shown potential in predicting survival outcomes and may be associated with the pathogenesis of OC. However, research into their genetic determinants is limited, and there are some inadequacies in understanding the distinct subtypes of OC. In this context, we conducted a Mendelian randomization study aiming to provide evidence for the relationship between genetically determined metabolites (GDMs) and the risk of OC and its subtypes. METHODS: In this study, we consolidated genetic statistical data of GDMs with OC and its subtypes through a genome-wide association study (GWAS) and conducted a two-sample Mendelian randomization (MR) analysis. The inverse variance weighted (IVW) method served as the primary approach, with MR-Egger and weighted median methods employed for cross-validation to determine whether a causal relationship exists between the metabolites and OC risk. Moreover, a range of sensitivity analyses were conducted to validate the robustness of the results. MR-Egger intercept, and Cochran's Q statistical analysis were used to evaluate possible heterogeneity and pleiotropy. False discovery rate (FDR) correction was applied to validate the findings. We also conducted a reverse MR analysis to validate whether the observed blood metabolite levels were influenced by OC risk. Additionally, metabolic pathway analysis was carried out using the MetaboAnalyst 5.0 software. RESULTS: In MR analysis, we discovered 18 suggestive causal associations involving 14 known metabolites, 8 metabolites as potential risk factors, and 6 as potential cancer risk reducers. In addition, three significant pathways, "caffeine metabolism," "arginine biosynthesis," and "citrate cycle (TCA cycle)" were associated with the development of mucinous ovarian cancer (MOC). The pathways "caffeine metabolism" and "alpha-linolenic acid metabolism" were associated with the onset of endometrioid ovarian cancer (OCED). CONCLUSIONS: Our MR analysis revealed both protective and risk-associated metabolites, providing insights into the potential causal relationships between GDMs and the metabolic pathways related to OC and its subtypes. The metabolites that drive OC could be potential candidates for biomarkers.

LAMB3 Promotes Intestinal Inflammation Through SERPINA3 and Is Directly Transcriptionally Regulated by P65 in Inflammatory Bowel Disease.

BACKGROUND: Various extracellular matrix (ECM) reshaping events are involved in inflammatory bowel disease (IBD). LAMB3 is a vital subunit of laminin-332, an important ECM component. Data on the biological function of LAMB3 in intestinal inflammation are lacking. Our aim is to discuss the effect of LAMB3 in IBD. METHODS: LAMB3 expression was assessed in cultured intestinal epithelial cells, inflamed mucosal tissues of patients and mouse colitis models. RNA sequencing, quantitative real-time polymerase chain reaction and Western blotting were used to detect the LAMB3 expression distribution and potential downstream target genes. Dual-luciferase assays and chromatin immunoprecipitation-quantitative polymerase chain reaction were used to determine whether P65 could transcriptionally activate LAMB3 under tumor necrosis factor α stimulation. RESULTS: LAMB3 expression was increased in inflammatory states in intestinal epithelial cells and colonoids and was associated with adverse clinical outcomes in Crohn's disease. Knockdown of LAMB3 inhibited the expression of proinflammatory cytokines. Mechanistically, LAMB3 expression was directly transcriptionally activated by P65 and was inhibited by nuclear factor kappa B inhibitors under tumor necrosis factor α stimulation. Furthermore, RNA sequencing and replenishment experiments revealed that LAMB3 upregulated SERPINA3 to promote intestinal inflammation via the integrin α3ß1/FAK pathway. CONCLUSION: We propose that LAMB3 could serve as a potential therapeutic target of IBD and a predictor of intestinal stenosis of Crohn's disease. Our findings demonstrate the important role of ECM in the progression of IBD and offer an experimental basis for the treatment and prognosis of IBD.

Research progress on the mechanism of glycolysis in ovarian cancer.

Glycolysis is the preferred energy metabolism pathway in cancer cells even when the oxygen content is sufficient. Through glycolysis, cancer cells convert glucose into pyruvic acid and then lactate to rapidly produce energy and promote cancer progression. Changes in glycolysis activity play a crucial role in the biosynthesis and energy requirements of cancer cells needed to maintain growth and metastasis. This review focuses on ovarian cancer and the significance of key rate-limiting enzymes (hexokinase, phosphofructokinase, and pyruvate kinase, related signaling pathways (PI3K-AKT, Wnt, MAPK, AMPK), transcription regulators (HIF-1a), and non-coding RNA in the glycolytic pathway. Understanding the relationship between glycolysis and these different mechanisms may provide new opportunities for the future treatment of ovarian cancer.

Bibliometric analysis of global research trends in adeno-associated virus vector for gene therapy (1991-2022).

Background: Gene therapy involves introducing and editing foreign genes in the body to treat and prevent genetic diseases. Adeno-associated virus (AAV) vector has become a widely used tool in gene therapy due to its high safety and transfection efficiency. Methods: This study employs bibliometric analysis to explore the foundation and current state of AAV vector application in gene therapy research. A total of 6,069 publications from 1991 to 2022 were analyzed, retrieved from the Science Citation Index Expanded (SCI-E) within the Web of Science Core Collection (WoSCC) of Clarivate Analytics. Institutions, authors, journals, references, and keywords were analyzed and visualized by using VOSviewer and CiteSpace. The R language and Microsoft Excel 365 were used for statistical analyses. Results: The global literature on AAV vector and gene therapy exhibited consistent growth, with the United States leading in productivity, contributing 3,868 papers and obtaining the highest H-index. Noteworthy authors like Wilson JM, Samulski RJ, Hauswirth WW, and Mingozzi F were among the top 10 most productive and co-cited authors. The journal "Human Gene Therapy" published the most papers (n = 485) on AAV vector and gene therapy. Current research focuses on "gene editing," "gene structure," "CRISPR," and "AAV gene therapy for specific hereditary diseases." Conclusion: The application of AAV vector in gene therapy has shown continuous growth, fostering international cooperation among countries and institutions. The intersection of gene editing, gene structure, CRISPR, and AAV gene therapy for specific hereditary diseases and AAV vector represents a prominent and prioritized focus in contemporary gene therapy research. This study provides valuable insights into the trends and characteristics of AAV gene therapy research, facilitating further advancements in the field.

Chirality detection of biological molecule through spin selectivity effect.

The ability to accurately monitor chiral biological molecules is of great significance for their potential applications in disease diagnosis and virus detection. As the existing chiral detection technologies are mainly relying on an optical method by using left/right circularly polarized light, the universality is low and the operation is complicated. Moreover, large quantity of chiral molecules is required, causing low detection efficiency. Here, a self-assembled monolayer of polypeptides has been fabricated to realize trace detection of chirality based on spin selectivity of photon-electron interaction. We have utilized Kerr technique to detect the rotation angle by the molecular monolayer, which indicates the chirality of polypeptides. The chiral structure of a biological molecule could result in spin-selectivity of electrons and thus influence the interaction between electron spin and light polarization. A Kerr rotation angle of ∼3° has been obviously observed, equivalent to the magneto-optic Kerr effect without magnetic material or magnetic field. Furthermore, we have provided a novel solution to achieve chirality discrimination and amplification simultaneously through an optical fiber. The proposed design is applicable for chiral detection via increasing their differential output signal, which clearly demonstrates a useful strategy toward chirality characterization of biological molecules.

Triad3A-Mediated K48-Linked ubiquitination and degradation of TLR9 impairs mitochondrial bioenergetics and exacerbates diabetic cardiomyopathy.

INTRODUCTION: Targeted protein degradation represents a promising therapeutic approach, while diabetic cardiomyopathy (DCM) arises as a consequence of aberrant insulin secretion and impaired glucose and lipid metabolism in the heart.. OBJECTIVES: Considering that the Toll-like receptor 9 (TLR9) signaling pathway plays a pivotal role in regulating energy metabolism, safeguarding cardiomyocytes, and influencing glucose uptake, the primary objective of this study was to investigate the impact of TLR9 on diabetic cardiomyopathy (DCM) and elucidate its underlying mechanism. METHODS: Mouse model of DCM was established using intraperitoneal injection of STZ, and mice were transfected with adeno-associated virus serotype 9-TLR9 (AAV9-TLR9) to assess the role of TLR9 in DCM. To explore the mechanism of TLR9 in regulating DCM disease progression, we conducted interactome analysis and employed multiple molecular approaches. RESULTS: Our study revealed a significant correlation between TLR9 expression and mouse DCM. TLR9 overexpression markedly mitigated cardiac dysfunction, myocardial fibrosis, oxidative stress, and apoptosis in DCM, while inflammation levels remained relatively unaffected. Mechanistically, TLR9 overexpression positively modulated mitochondrial bioenergetics and activated the AMPK-PGC1a signaling pathway. Furthermore, we identified Triad3A as an interacting protein that facilitated TLR9's proteasomal degradation through K48-linked ubiquitination. Inhibiting Triad3A expression improved cardiac function and pathological changes in DCM by enhancing TLR9 activity. CONCLUSIONS: The findings of this study highlight the critical role of TLR9 in maintaining cardiac function and mitigating pathological alterations in diabetic cardiomyopathy. Triad3A-mediated regulation of TLR9 expression and function has significant implications for understanding the pathogenesis of DCM. Targeting TLR9 and its interactions with Triad3A may hold promise for the development of novel therapeutic strategies for diabetic cardiomyopathy. Further research is warranted to fully explore the therapeutic potential of TLR9 modulation in the context of cardiovascular diseases.

Icariin as a potential anticancer agent: a review of its biological effects on various cancers.

Numerous chemical compounds used in cancer treatment have been isolated from natural herbs to address the ever-increasing cancer incidence worldwide. Therein is icariin, which has been extensively studied for its therapeutic potential due to its anti-inflammatory, antioxidant, antidepressant, and aphrodisiac properties. However, there is a lack of comprehensive and detailed review of studies on icariin in cancer treatment. Given this, this study reviews and examines the relevant literature on the chemopreventive and therapeutic potentials of icariin in cancer treatment and describes its mechanism of action. The review shows that icariin has the property of inhibiting cancer progression and reversing drug resistance. Therefore, icariin may be a valuable potential agent for the prevention and treatment of various cancers due to its natural origin, safety, and low cost compared to conventional anticancer drugs, while further research on this natural agent is needed.

Heme-binding protein 1 delivered via pericyte-derived extracellular vesicles improves neurovascular regeneration in a mouse model of cavernous nerve injury.

As a peripheral nerve injury disease, cavernous nerve injury (CNI) caused by prostate cancer surgery and other pelvic surgery causes organic damage to cavernous blood vessels and nerves, thereby significantly attenuating the response to phosphodiesterase-5 inhibitors. Here, we investigated the role of heme-binding protein 1 (Hebp1) in erectile function using a mouse model of bilateral CNI, which is known to promote angiogenesis and improve erection in diabetic mice. We found a potent neurovascular regenerative effect of Hebp1 in CNI mice, demonstrating that exogenously delivered Hebp1 improved erectile function by promoting the survival of cavernous endothelial-mural cells and neurons. We further found that endogenous Hebp1 delivered by mouse cavernous pericyte (MCP)-derived extracellular vesicles promoted neurovascular regeneration in CNI mice. Moreover, Hebp1 achieved these effects by reducing vascular permeability through regulation of claudin family proteins. Our findings provide new insights into Hebp1 as a neurovascular regeneration factor and demonstrate its potential therapeutic application to various peripheral nerve injuries.

Therapeutic effects of shikonin on adjuvant-induced arthritis in rats and cellular inflammation, migration and invasion of rheumatoid fibroblast-like synoviocytes via blocking the activation of Wnt/ß-catenin pathway.

BACKGROUND: Shikonin (SKN), the main bioactive component isolated from Lithospermum erythrorhizon Sieb et Zucc, has multiple activities including anti-rheumatic effect, but its specific roles and the precise mechanisms in regulating biological properties of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) are unclear and need further clarification. PURPOSE: This study explored the therapeutic roles of SKN on rat adjuvant-induced arthritis (AIA) and cellular inflammation, migration and invasion of TNF-α-induced RA FLS (MH7A cells), and further demonstrated the involved mechanisms. METHODS: SKN was intraperitoneally given to AIA rats and its therapeutic role was valued. The effects of SKN in vivo and in vitro on the production of pro-inflammatory factors were examined by ELISA and western blot. Wound-healing, transwell and phalloidin staining assay were carried out to evaluate the effects of SKN on TNF-α-induced migration and invasion in RA FLS. The involvement of Wnt/ß-catenin pathway was checked by immunohistochemistry or immunofluorescence assay for ß-catenin and western blot for pathway-related proteins. RESULTS: SKN treatment in AIA rats reduced paw swelling, arthritis index and pathological damage of ankle joints, indicating its anti-arthritic effect in vivo. SKN had anti-inflammatory roles in vivo and in vitro, evidenced by inhibiting the production of pro-inflammatory factors (like IL-1ß, IL-6, IL-8, TNF-α, MMP-2 and MMP-9) in sera and synovium of AIA rats, and in TNF-α-induced MH7A cells. Gelatin zymography result revealed the suppression of SKN on TNF-α-induced MMP-2 activity in vitro. Moreover, SKN inhibited TNF-α-induced migration, invasion and cytoskeletal reorganization in MH7A cells. Mechanistically, SKN suppressed the activation of Wnt/ß-catenin signaling in AIA rat synovium and in TNF-α-induced MH7A cells, indicated by the reduced protein levels of Wnt1, p-GSK-3ß (Ser9) and ß-catenin, the raised protein level of GSK-3ß and the decreased nuclear translocation of ß-catenin. Interestingly, the combination of LiCl (Wnt/ß-catenin agonist) canceled the therapeutic functions of SKN on cellular inflammation, migration and invasion in TNF-α-induced MH7A cells, whereas XAV939 (Wnt/ß-catenin inhibitor) enhanced the therapeutic roles of SKN. CONCLUSION: SKN showed therapeutic effects on rat AIA and cellular inflammation, migration and invasion of TNF-α-stimulated RA FLS via interrupting Wnt/ß-catenin pathway.

Reprogramming efficiency and pluripotency of mule iPSCs over its parents†.

The mule is the interspecific hybrid of horse and donkey and has hybrid vigor in muscular endurance, disease resistance, and longevity over its parents. Here, we examined adult fibroblasts of mule (MAFs) compared with the cells from their parents (donkey adult fibroblasts and horse adult fibroblasts) (each species has repeated three independent individuals) in proliferation, apoptosis, and glycolysis and found significant differences. We subsequently derived mule, donkey, and horse doxycycline (Dox)-independent induced pluripotent stem cells (miPSCs, diPSCs, and hiPSCs) from three independent individuals of each species and found that the reprogramming efficiency of MAFs was significantly higher than that of cells of donkey and horse. miPSCs, diPSCs, and hiPSCs all expressed the high levels of crucial endogenous pluripotency genes such as POU class 5 homeobox 1 (POU5F1, OCT4), SRY-box 2 (SOX2), and Nanog homeobox (NANOG) and propagated robustly in single-cell passaging. miPSCs exhibited faster proliferation and higher pluripotency and differentiation than diPSCs and hiPSCs, which were reflected in co-cultures and separate-cultures, teratoma formation, and chimera contribution. The establishment of miPSCs provides a unique research material for the investigation of "heterosis" and perhaps is more significant to study hybrid gamete formation.

PCSK6 attenuates cardiac dysfunction in doxorubicin-induced cardiotoxicity by regulating autophagy.

Doxorubicin (DOX) is a chemotherapeutic drug widely used in the field of cancer, but its side effects on the heart hinder its clinical application. In cardiac injury caused by DOX, apoptosis and oxidative stress are both involved in cardiac damage, and autophagy is also one of the key responses. Both apoptosis and oxidative stress interact with autophagy. Proper promotion of autophagy effectively protects the myocardium and blocks cardiac injury. DOX mainly acts downstream of the autophagic flow and hinders the degradation process of autophagolysosomes, resulting in abnormal accumulation of autophagolysosomes in cells, which can prevent the timely removal of harmful substances and disrupt the normal function of cells. Proprotein convertase subtilisin/kexin type 6 (PCSK6) is involved in the occurrence and development of various cardiovascular diseases, blood pressure regulation and the inflammatory response, but its role in DOX is still unclear. Here, we constructed cardiac PCSK6-overexpressing mice by injecting AAV9-PCSK6. Both in vivo and in vitro experiments confirmed that overexpression of PCSK6 effectively protected cardiac function, inhibited apoptosis and oxidative stress. We focused on the effect of PCSK6 overexpression on autophagy. We have detected an increase in autophagosomes production and a decrease in autophagolysosomes accumulation. This suggests that PCSK6 promotes the level of autophagy, while possibly acting on the sites where DOX inhibits degradation, so that the autophagic flux inhibited by DOX is restored and the degradation process of autophagolysosomes is restored. The effect of PCSK6 was dependent on FOXO3a, which promoted the nuclear translocation of Forkhead box O3 (FOXO3a), and Sirtuin 1 (SIRT1) regulated the expression of FOXO3a. When SIRT1 was inhibited, the protective effect of PCSK6 was diminished. In conclusion, overexpression of PCSK6 exerts a protective effect through SIRT1/FOXO3a in cardiac injury induced by DOX, suggesting that PCSK6 may be a therapeutic target for DOX cardiomyopathy.

Patient-derived spheroids and patient-derived organoids simulate evolutions of lung cancer.

Cancer cells harbor many genetic mutations and gene expression profiles different from normal cells. Patient-derived cancer cells (PDCC) are preferred materials in cancer study. We established patient-derived spheroids (PDSs) and patient-derived organoids (PDOs) from PDCCs isolated from the malignant pleural effusion in 8 patients. The morphologies suggested that PDSs may be a model of local cancer extensions, while PDOs may be a model of distant cancer metastases. The gene expression profiles differed between PDSs and PDOs: Gene sets related to inflammatory responses and EMT were antithetically regulated in PDSs or in PDOs. PDSs demonstrated an attenuation of the pathways that contribute to the enhancement of transforming growth factor beta (TGF-ß) induced epithelial mesenchymal transition (EMT), while PDOs demonstrated an attenuation of it. Taken together, PDSs and PDOs have differences in both the interaction to the immune systems and to the stroma. PDSs and PDOs will provide a model system that enable intimate investigation of the behavior of cancer cells in the body.

Comparison of The Toronto IBD Global Endoscopic Reporting (TIGER) score, Mayo endoscopic score (MES), and ulcerative colitis endoscopic index of severity (UCEIS) in predicting the need for ileal pouch-anal anastomosis in patients with ulcerative colitis.

BACKGROUND: Total proctocolectomy (TPC) with ileal pouch-anal anastomosis (IPAA) has been accepted as a radical surgery for refractory ulcerative colitis (UC). We aimed to assess the predictive value of several novel and widely used endoscopic core systems, The Toronto IBD Global Endoscopic Reporting (TIGER) score, Mayo endoscopic score (MES), and ulcerative colitis endoscopic index of severity (UCEIS) in guiding the need for IPAA. METHODS: Data on patients with UC from June 1986 and June 2022 at our institute were collected. The endoscopic evaluation was recorded according to the first colonoscopy after hospitalization. Primary outcome was the need for IPAA during admission and follow-up. RESULTS: A total of 313 patients with a median follow-up time and a median TIGER score of 12.0 years (interquartile range (IQR): 6.0-17.0) and 212.0 (IQR: 7.0-327.0) were enrolled. IPAA was conducted in 110 (35.1%) patients, which significantly improved the long-term quality of life. TIGER score had the biggest area under the receiver-operating characteristic curve of 0.810 with a sensitivity of 75.0% and specificity of 87.1% at the cut-off value of 315 (p < 0.001). TIGER score ≥ 315 was an independent risk factor with the highest odds ratio for the need for IPAA and associated with the shortest IPAA-free survival time compared with UCEIS and MES. CONCLUSION: TIGER score was superior to UCEIS and MES in predicting the need for IPAA. For colorectal surgeons, three or more segments with moderate-to-severe endoscopic activity should be considered as a threshold value for decision-making for IPAA.

MRI-based radiomics nomogram for differentiation of solitary metastasis and solitary primary tumor in the spine.

BACKGROUND: Differentiating between solitary spinal metastasis (SSM) and solitary primary spinal tumor (SPST) is essential for treatment decisions and prognosis. The aim of this study was to develop and validate an MRI-based radiomics nomogram for discriminating SSM from SPST. METHODS: One hundred and thirty-five patients with solitary spinal tumors were retrospectively studied and the data set was divided into two groups: a training set (n = 98) and a validation set (n = 37). Demographics and MRI characteristic features were evaluated to build a clinical factors model. Radiomics features were extracted from sagittal T1-weighted and fat-saturated T2-weighted images, and a radiomics signature model was constructed. A radiomics nomogram was established by combining radiomics features and significant clinical factors. The diagnostic performance of the three models was evaluated using receiver operator characteristic (ROC) curves on the training and validation sets. The Hosmer-Lemeshow test was performed to assess the calibration capability of radiomics nomogram, and we used decision curve analysis (DCA) to estimate the clinical usefulness. RESULTS: The age, signal, and boundaries were used to construct the clinical factors model. Twenty-six features from MR images were used to build the radiomics signature. The radiomics nomogram achieved good performance for differentiating SSM from SPST with an area under the curve (AUC) of 0.980 in the training set and an AUC of 0.924 in the validation set. The Hosmer-Lemeshow test and decision curve analysis demonstrated the radiomics nomogram outperformed the clinical factors model. CONCLUSIONS: A radiomics nomogram as a noninvasive diagnostic method, which combines radiomics features and clinical factors, is helpful in distinguishing between SSM and SPST.