Traditional Chinese Medicine in Regulating Tumor Microenvironment.

Tumor microenvironment (TME) is a complex and integrated system containing a variety of tumor-infiltrating immune cells and stromal cells. They are closely connected with cancer cells and influence the development and progression of cancer. Traditional Chinese medicine (TCM) is an important complementary therapy for cancer treatment in China. It mainly eliminates cancer cells by regulating TME. The aim of this review is to systematically summarize the crosstalk between tumor cells and TME, and to summarize the research progress of TCM in regulating TME. The review is of great significance in revealing the therapeutic mechanism of action of TCM, and provides an opportunity for the combined application of TCM and immunotherapy in cancer treatment.

The global patent landscape of emerging infectious disease monkeypox.

BACKGROUND: Monkeypox is an emerging infectious disease with confirmed cases and deaths in several parts of the world. In light of this crisis, this study aims to analyze the global knowledge pattern of monkeypox-related patents and explore current trends and future technical directions in the medical development of monkeypox to inform research and policy. METHODS: A comprehensive study of 1,791 monkeypox-related patents worldwide was conducted using the Derwent patent database by descriptive statistics, social network method and linear regression analysis. RESULTS: Since the 21st century, the number of monkeypox-related patents has increased rapidly, accompanied by increases in collaboration between commercial and academic patentees. Enterprises contributed the most in patent quantity, whereas the initial milestone patent was filed by academia. The core developments of technology related to the monkeypox include biological and chemical medicine. The innovations of vaccines and virus testing lack sufficient patent support in portfolios. CONCLUSIONS: Monkeypox-related therapeutic innovation is geographically limited with strong international intellectual property right barriers though it has increased rapidly in recent years. The transparent licensing of patent knowledge is driven by the merger and acquisition model, and the venture capital, intellectual property and contract research organization model. Currently, the patent thicket phenomenon in the monkeypox field may slow the progress of efforts to combat monkeypox. Enterprises should pay more attention to the sharing of technical knowledge, make full use of drug repurposing strategies, and promote innovation of monkeypox-related technology in hotspots of antivirals (such as tecovirimat, cidofovir, brincidofovir), vaccines (JYNNEOS, ACAM2000), herbal medicine and gene therapy.

The Role of Zuo Jin Wan in Modulating the Tumor Microenvironment of Colorectal Cancer.

INTRODUCTION: Traditional Chinese medicine (TCM) can modulate the immune function of tumor patients in various ways. Zuojin Wan (ZJW, a 6:1 ratio of Huanglian and Wuzhuyu) can modulate the microenvironment of ulcerative colitis, but its role in regulating the CRC microenvironment remains unclear. Exploring the role of ZJW in CRC immunomodulation may improve the antitumor effect of existing immunotherapeutic strategies. MATERIAL AND METHODS: The active compounds of each herb in ZJW were obtained from the HIT2.0 database with literature evidence. Single-cell RNA sequencing data of CRC were obtained from published studies (PMID: 32451460, 32103181, and 32561858). Pathway enrichment was analyzed using the reactome database, and intergenic correlation analysis was performed using the corrplot R software package. ZJW-regulated gene expression was verified by RT-qPCR. RESULTS: Huanglian and Wuzhu contain 19 and 4 compounds, respectively. Huang Lian targets 146 proteins, and Wu Zhu Yu targets 28 proteins based on evidence from the literature. ZJW regulates a range of biological processes associated with immune function, including cytokine signaling and Toll-Like Receptor 4 (TLR4) cascade. ZJW regulates malignant CRC cells, immune cells (including T-cells, B-cells, mast cells, NK/NKT cells, and myeloid cells), and other non-immune cells (including endothelial cells, enteric glial cells, and pericytes). We confirmed that ZJW significantly downregulated the expression of TIMP1 and MTDH. CONCLUSIONS: ZJW regulates a range of cells in the CRC microenvironment, including malignant CRC, immune cells, and stromal cells. In CRC cell lines, downregulation of TIMP1 and MTDH by ZJW may play an important role in the immunomodulation in CRC.

Effect of Two Particle Sizes of Nano Zinc Oxide on Growth Performance, Immune Function, Digestive Tract Morphology, and Intestinal Microbiota Composition in Broilers.

The effects of dietary supplementation with two particle sizes of nano zinc oxide (ZnO) on growth performance, immune function, intestinal morphology, and the gut microbiome were determined in a 42-day broiler chicken feeding experiment. A total of 75 one-day-old Arbor Acres broilers were randomized and divided into three groups with five replicates of five chicks each, including the conventional ZnO group (NC), the nano-ZnO group with an average particle size of 82 nm (ZNPL), and the nano-ZnO group with an average particle size of 21 nm (ZNPS). Each group was supplemented with 40 mg/kg of ZnO or nano-ZnO. Our results revealed that birds in the ZNPS group had a higher average daily gain and a lower feed-to-gain ratio than those in the NC group. ZNPS significantly increased the thymus index and spleen index, as well as the levels of serum metallothionein (MT), superoxide dismutase (SOD), and lysozyme (LZM). The ZNPS treatments reduced interleukin (IL)-1ß and tumor necrosis factor-alpha (TNF-α) levels and increased IL-2 and interferon (IFN)-γ levels compared to that in the NC group. Additionally, compared with the birds in the NC group, those in the nano-ZnO group had a higher villus height to crypt depth ratio of the duodenum, jejunum, and ileum. Bacteroides increased in the ZNPS group at the genus level. Further, unidentified_Lachnospiraceae, Blautia, Lachnoclostridium, unidentified_Erysipelotrichaceae, and Intestinimonas were significantly increased in the ZNPL group. In conclusion, nano-ZnO improved the growth performance, promoted the development of immune organs, increased nonspecific immunity, improved the villus height to crypt depth ratio of the small intestine, and enriched the abundance of beneficial bacteria. Notably, the smaller particle size (21 nm) of nano-ZnO exhibited a more potent effect.

Ultrasensitive electrochemical sensing platform for miRNA-21 detection based on manganese dioxide-gold nanoparticle nanoconjugates coupled with hybridization chain reaction and horseradish peroxidase signal amplification.

In this study, an ultrasensitive electrochemical miRNA-21 biosensor is described. Manganese dioxide-gold nanoparticle (MnO2-Au NP) nanoconjugates were employed as sensing base materials, miRNA-21 was selected as a model analyte, and hybridization chain reaction (HCR) was employed to form long DNA concatemers using two different oligonucleotides with a complementary sequence. Thus, lots of biotin were loaded on DNA concatemers and one of them was labelled with biotin at its 3' terminal. The biosensor was designed as follows: a sulfhydryl-hairpin probe (HP) was first dropped on the surface of the glassy carbon electrode (GCE) modified with MnO2-Au NP nanoconjugates (HP/MnO2-AuNPs/GCE). After it was treated with MCH, the modified electrode was hybridized with miRNA-21, resulting in the loop of HP being opened to form a vertical structure. Subsequently, the modified electrode (miRNA-21/HP/MCH/MnO2-AuNPs/GCE) was incubated with DNA concatemers to form a sandwich structure of HP-miRNA-21-DNA concatemers on the modified electrode surface. Finally, the streptavidin-HRP conjugates were linked to the sandwich structure by specific recognition interaction between biotin and avidin. Differential pulse voltammetry (DPV) was used to measure the electrochemical response of the biosensor in the phosphate-buffered solution (0.10 M PBS, pH 7.0) containing 2.0 mM hydroquinone (HQ) and 1.8 mM H2O2. As a result, a larger reductive signal was obtained at a potential of -0.17 V (vs. SCE). Various experimental conditions were optimized, including solution pH, incubation time, and the amount of DNA concatemers. Under optimal conditions, the biosensor showed good sensing performance, such as a wide linear response range (0.1 fM and 100 nM) and low detection limit (0.063 fM, at S/N = 3). Meanwhile, the biosensor can discriminate single base matched miRNA-21, indicating that the biosensor had good selectivity.

Genetically encoded sensors for measuring histamine release both in vitro and in vivo.

Histamine (HA) is a key biogenic monoamine involved in a wide range of physiological and pathological processes in both the central and peripheral nervous systems. Because the ability to directly measure extracellular HA in real time will provide important insights into the functional role of HA in complex circuits under a variety of conditions, we developed a series of genetically encoded G-protein-coupled receptor-activation-based (GRAB) HA (GRABHA) sensors with good photostability, sub-second kinetics, nanomolar affinity, and high specificity. Using these GRABHA sensors, we measured electrical-stimulation-evoked HA release in acute brain slices with high spatiotemporal resolution. Moreover, we recorded HA release in the preoptic area of the hypothalamus and prefrontal cortex during the sleep-wake cycle in freely moving mice, finding distinct patterns of HA dynamics between these specific brain regions. Thus, GRABHA sensors are robust tools for measuring extracellular HA transmission in both physiological and pathological processes.

Providing holistic care to children with cerebral palsy treated with transnasal neural stem cell transplantation.

Objective: Holistic care is a key element in nursing care. Aiming at the heterogeneous disease of cerebral palsy, researchers focused on children with cerebral palsy who received transnasal transplantation of neural stem cells as a specific group. Based on establishing a multidisciplinary team, comprehensive care is carried out for this type of patient during the perioperative period to improve the effectiveness and safety of clinical research and increase the comfort of children. Methods: Between January 2018 and June 2023, 22 children with cerebral palsy underwent three transnasal transplants of neural stem cells. Results: No adverse reactions related to immune rejection were observed in the 22 children during hospitalization and follow-up. All children tolerated the treatment well, and the treatment was superior. One child developed nausea and vomiting after sedation; three had a small amount of bleeding of nasal mucosa after transplantation. Two children had a low fever (≤38.5°C), and one had a change in the type and frequency of complex partial seizures. Moreover, 3 children experienced patch shedding within 4 h of patch implantation into the nasal cavity. Conclusion: The project team adopted nasal stem cell transplantation technology. Based on the characteristics of transnasal transplantation of neural stem cells in the treatment of neurological diseases in children, a comprehensive and novel holistic care plan is proposed. It is of great significance to guide caregivers of children to complete proper care, further improve the safety and effectiveness of treatment, and reduce the occurrence of complications.

Danshensu prevents thrombosis by inhibiting platelet activation via SIRT1/ROS/mtDNA pathways without increasing bleeding risk.

BACKGROUND: Coronary thrombosis and its correlated disorders are main healthcare problems globally. The therapeutic effects of current treatments involving antiplatelet drugs are not fully satisfactory. Danshensu (DSS) is an important monomer obtained from Salvia miltiorrhiza roots that have been widely employed for vascular diseases in medicinal practices. Nonetheless, the underlying mechanisms of DSS are not fully unraveled. PURPOSE: The objective of this study was to penetrate the antithrombotic and antiplatelet mechanisms of DSS. METHODS: Network pharmacology assay was used to forecast the cellular mechanisms of DSS for treating thrombosis. The work focused the impacts of DSS on platelet activation by analyzing aggregation and adhesion in vitro. Flow cytometry, western blotting, CM-H2DCFDA staining and mitochondrial function assays were performed to reveal the molecular mechanisms. The model of common carotid artery thrombus induced by ferric chloride was established. The wet weight of thrombus was measured, and the thrombosis was observed by hematoxylin and eosin (H&E) staining, in order to support the inhibitory effect of DSS on thrombosis. RESULTS: Data mining found the antithrombotic effect of DSS is related to platelet activation and the core target is silent information regulator 1 (SIRT1). We confirmed that DSS dose-dependently inhibited platelet activation in vitro. DSS was further demonstrated to induce the expression of SIRT1 and decreased reactive oxygen species (ROS) burden and thereby prevented mitochondrial dysfunction. Mitochondrial function tests further indicated that DSS prevented mitochondrial DNA (mtDNA) release, which induced activation of platelet in a dendritic cell specific intercellular-adhesion-molecule-3 grabbing non-integrin (DC-SIGN)-dependent manner. In carotid artery injury model induced by ferric chloride, DSS inhibited the development of carotid arterial thrombosis. More encouragingly, in tail bleeding time assay, DSS did not augment bleeding risk. CONCLUSION: These findings indicated that DSS effectively inhibited platelet activation by depressing the collection of ROS and the release of platelet mtDNA without arousing hemorrhage risk. DSS might represent a promising candidate drug for thrombosis and cardiovascular disease therapeutics.

Shuxuetong injection and its peptides enhance angiogenesis after hindlimb ischemia by activating the MYPT1/LIMK1/Cofilin pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Shuxuetong (SXT) injection is formulated by leech and earthworm, has been widely used in the treatment of thrombotic cardiovascular and cerebrovascular diseases with remarkable clinical efficacy. AIM OF THE STUDY: The purpose of this study is to investigate the protective mechanism of SXT injection on the mice model of hindlimb ischemia, and to evaluate the angiogenic effects of SXT injection and its main active substances. MATERIALS AND METHODS: Hindlimb ischemia was induced by left femoral artery ligation. After operation, the mice were injected with saline, 10 mg/kg/d cilostazol, 37.5 mg/kg/d SXT injection, 75 mg/kg/d SXT injection and 150 mg/kg/d SXT injection via tail vein for 4 weeks. Ischemia severity was assessed using laser Doppler perfusion imaging system. Tissue recovery and capillary density were evaluated by histological and immunofluorescent staining. Vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor (PDGF-BB) expression were measured by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) analyses. Human umbilical vein endothelial cells (HUVECs) proliferation was measured using a BrdU kit and the viability of HUVECs was performed by MTT assay. Migration of HUVECs was performed by the wound healing method and a modified transwell assay. Capillary tube formation by HUVECs was examined by using Matrigel assay. Western blotting was used to detect the expressions of p-Cofilin, p-MYPT1, and p-LIMK1. RESULTS: SXT injection treatment significantly restored the blood flow and reduced tissue injury in mouse gastrocnemius muscle. SXT injection treatment increased capillary density and promoted angiogenesis in hindlimb ischemia. Moreover, SXT injection enhanced the expression of VEGF-A and PDGF-BB at both mRNA and protein levels in ischemic tissue of mice. SXT injection and its main active peptides dramatically increased the migration and capillary tube formation of HUVECs. SXT injection and its peptides enhanced protein expressions of the phosphorylation of MYPT1, Cofilin, and LIMK1. DSYVGDEAQSKR, YNELRVAPEEHP, and IQFLPEGSPVTM may act as the active components of SXT injection. CONCLUSION: SXT injection promoted angiogenesis and improved function recovery in hindlimb ischemia mice by regulation of VEGF-A/PDGF-BB. Moreover, SXT injection and its active peptides induced cell migration and tube formation in HUVECs through activating the MYPT1/LIMK1/Cofilin pathway. This study provided experimental basis for SXT injection in the treatment of ischemic diseases and revealed the effective substance of SXT injection in regulating angiogenesis, providing better evidence for the clinical application of SXT injection.

Naoxintong capsule limits myocardial infarct expansion by inhibiting platelet activation through the ERK5 pathway.

BACKGROUND: In the clinic, Naoxintong capsule (NXT) has been applied in two level prevention of ischemic disease. However, its mechanism of action requires further study. PURPOSE: This study investigated whether NXT could affect platelet function and activation under ischemic pathological conditions. MATERIALS AND METHODS: Wistar rats were divided into six groups, sham, saline, NXT (250, 500, 1000 mg/kg), and aspirin group (10 mg/kg). For the pre-treatment assays, MI model was established after pre-administration of saline, NXT-L, NXT-M, NXT-H, and aspirin respectively for 14 days, and after surgery, there were no continuous treatments. For the post-treatment assay, rats were orally administered for 3 days after MI. FeCl3-induced thrombosis model was applied to determine the thrombus wet weight. Bleeding time was used to assess the ability of the platelets to develop a hemostatic plug. RESULTS: NXT decreased infarct size, decreased LDH, CK, and CK-MB values, and improved cardiac function. NXT inhibited platelets activation through reducing CD62P-positive platelets and inhibited infarct expansion by decreasing the number of CD45-positive cells and the amount of MMP9 secreted into the heart tissue. Mechanistically, NXT inhibited platelets activation through decreasing ROS levels, decreasing ERK5 phosphorylation, and increasing RAC1 phosphorylation in MI rats. Pre-treatment with NXT decreased thrombus formation and had normal bleeding times. CONCLUSION: NXT showed obviously preventive effects, which was associated with negative control of platelet activation. The above results provide a basis for clinically expanding application of NXT.

ß-patchoulene protects against non-alcoholic steatohepatitis via interrupting the vicious circle among oxidative stress, histanoxia and lipid accumulation in rats.

Non-alcoholic steatohepatitis (NASH), an extreme progressive subtype of metabolic associated fatty liver disease, is well characterized by hepatic steatosis, injury and inflammation. It causes irreversible hepatic damage and there are no approved interventions for it. ß-PAE, a representatively pharmacological active substance isolated from Pogostemon cablin, has been indicated to alleviate hepatic steatosis and injury through modulating lipid metabolism in rats with simple steatosis. However, its protection against NASH remains unclear. Here, this study explored the potential effect of ß-PAE against high-fat diet-induced NASH in rats. The results displayed that ß-PAE significantly reduced the gains of body weight and epididymal adipose tissue, liver index and attenuated liver histological damages in NASH rats. It also markedly alleviated hepatic inflammation by inhibiting NLRP3 inflammasome activation. In NASH, the active NLRP3 inflammasome is caused by hepatic lipid abnormal accumulation-induced oxidative stress. Excessive oxidative stress results in hepatic histanoxia, which exacerbates lipid metabolism disorders by elevating CD36 to suppress AMPK signalling pathways. Moreover, the lipid accumulation led by lipid metabolism dysfunction intensifies oxidative stress. A vicious circle is formed among oxidative stress, histanoxia and lipid accumulation, eventually, but ß-PAE effectively interrupted it. Interestingly, soluble CD36 (sCD36) was tightly associated not only with hepatic steatosis and injury but also with inflammation. Collectively, ß-PAE exerted a positive effect against NASH by interrupting the vicious circle among oxidative stress, histanoxia and lipid accumulation, and sCD36 may be a promising non-invasive tool for NASH diagnosis.

Systematic Literature Review and Meta-Analysis of Response to First-Line Therapies for Advanced/Metastatic Urothelial Cancer Patients Who Are Cisplatin Ineligible.

OBJECTIVE: The purpose of this systematic literature review (SLR) and meta-analysis was to compile the response of historic treatment options in first-line settings for patient populations who are cisplatin ineligible. MATERIALS AND METHODS: SLR was conducted to compile objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) of historic therapies for this population based on stringent criteria. Clinical trials published in English from January 1991 to June 2016 were identified by searching the PubMed (Medline), Cochrane, and Embase databases. RESULTS: Eighteen studies (21 arms; N=810) were identified and used for this meta-analysis. For all treatments included in these studies, the pooled ORR was 0.36 (95% confidence interval [CI], 0.30-0.42). The ORR for the carboplatin+gemcitabine arms (6 arms; N=259), which is the National Comprehensive Cancer Network's recommended first-line treatment (before approval of atezolizumab and pembrolizumab) for this population was 0.36 (95% CI, 0.30-0.42), the median DOR (4 arms) was 7.00 months (95% CI, 4.34-11.29), and the median OS was 8.39 months (95% CI, 7.05-9.98). CONCLUSIONS: The results of this SLR clearly demonstrate the paucity of clinical studies that assess therapeutic intervention in truly cisplatin-ineligible advanced/metastatic urothelial carcinoma subjects and highlight the development of novel therapies that can create real improvement in long-term outcomes. The recent approval of 2 checkpoint inhibitors, atezolizumab and pembrolizumab, were added in the National Comprehensive Cancer Network guidance as recommended first-line treatment for cisplatin-ineligible patients with advanced/metastatic urothelial carcinoma and has provided alternatives for this patient population.

FoxO Transcription Factors Are Critical Regulators of Diabetes-Related Muscle Atrophy.

Insulin deficiency and uncontrolled diabetes lead to a catabolic state with decreased muscle strength, contributing to disease-related morbidity. FoxO transcription factors are suppressed by insulin and thus are key mediators of insulin action. To study their role in diabetic muscle wasting, we created mice with muscle-specific triple knockout of FoxO1/3/4 and induced diabetes in these M-FoxO-TKO mice with streptozotocin (STZ). Muscle mass and myofiber area were decreased 20-30% in STZ-Diabetes mice due to increased ubiquitin-proteasome degradation and autophagy alterations, characterized by increased LC3-containing vesicles, and elevated levels of phosphorylated ULK1 and LC3-II. Both the muscle loss and markers of increased degradation/autophagy were completely prevented in STZ FoxO-TKO mice. Transcriptomic analyses revealed FoxO-dependent increases in ubiquitin-mediated proteolysis pathways in STZ-Diabetes, including regulation of Fbxo32 (Atrogin1), Trim63 (MuRF1), Bnip3L, and Gabarapl. These same genes were increased 1.4- to 3.3-fold in muscle from humans with type 1 diabetes after short-term insulin deprivation. Thus, FoxO-regulated genes play a rate-limiting role in increased protein degradation and muscle atrophy in insulin-deficient diabetes.

Psychological Disorders and Psychosocial Resources of Patients with Newly Diagnosed Bladder and Kidney Cancer: A Cross-Sectional Study.

PURPOSE: Psychological disorders have been proven to be associated with poor physiological, psychological and immune outcomes in cancer patients. However, despite of many challenges of the changed self-image/body image and the altered sexual/urinary function, relatively little is known about psychological disorders of patients with newly diagnosed bladder and kidney cancer. We aimed to investigate the prevalence of depression, anxiety, post-traumatic stress disorder (PTSD) and the associated psychosocial factors among bladder/kidney cancer patients. METHODS: A cross-sectional study was conducted of consecutive inpatients with bladder/kidney cancer in the First Affiliated Hospital of China Medical University in Liaoning Province, northeast China. A total of 489 early-stage cancer patients eligible for this study completed questionnaires on demographic and clinical variables, depression, anxiety, PTSD, perceived social support and positive psychological variables (hope, optimism and resilience) anonymously during October 2013 and August 2014. Hierarchical regression analysis was used to examine the relationships between psychosocial resources and psychological disorders, while controlling for possible covariates. RESULTS: The prevalence of depression, anxiety and PTSD was 77.5%, 69.3% and 25.2%, respectively, while 24.9% of patients had psychological co-morbidity. Psychosocial resources together explained more than one-third of the variance on psychological disorders. Under standardized estimate (ß) sequence, patient's perception of social support from family was significantly associated with depression, anxiety and PTSD (p < 0.01). Optimism and resilience showed integrated and independent effects on psychological disorders, and hope represented the significant association with PTSD only (p < 0.01). CONCLUSIONS: The high prevalence of psychological disorders in newly diagnosed patients with early-stage bladder/kidney cancer should receive more attention in Chinese medical settings. Additionally, in consideration of the different protective effects of psychosocial resources, the present study demonstrated that one complete psychological intervention integrating the associated psychosocial factors are necessary to ameliorate psychological disorders so as to provide patients with a more holistic cancer care.