Anti-Inflammatory, Analgesic and Anti-Oxidant Effects of Shirakiopsis Indica (Willd). Fruit Extract: A Mangrove Species in the Field of Inflammation Research.

Background: Shirakiopsis indica (Willd)., commonly known as Sa-Mor-Ta-Lay in Thailand, is a mangrove plant belonging to the Euphorbiaceae family. As mangrove plants' medicinal potentials are less explored, this study sought to qualitatively and quantitatively verify the bioactive components of Shirakiopsis indica fruits methanolic extract (SIF-ME) at the side of its analgesic, anti-inflammatory and anti-oxidant effects followed by in-silico studies. Methods: The in-vivo assessments of analgesic activity involved the hot plate test, acetic acid-induced writhing test, and formalin-induced licking test. The anti-inflammatory efficacy was assessed through the human RBC membrane stabilization assay (HRBC), protein denaturation assay, and xylene-induced ear edema methods. Antioxidant potential was implemented by the DPPH scavenging method. Results: The SIF-ME consistently displayed significant anti-nociceptive activity in a dose-dependent pattern (p < 0.05). The maximum analgesic activity was found in the highest dose (200 mg/kg; p < 0.001) in a hot plate, acetic acid-induced writhing test 43.47%, and in formalin-induced licking test in both early phase (43.3%; p < 0.01) and late phase (61.84%; p < 0.001%). The extract provided optimal protection against hemolysis (83.41% decrease) at 1000 µg/mL and significantly inhibited protein denaturation (67.34-26.05%) at doses of 1000-62.5 µg/mL. At 200 mg/kg, the extract showed dose-dependent and substantial inhibition (54.07%; p < 0.01) of xylene-induced ear edema. The in-vitro DPPH (IC50 = 469.5 µg/mL) results showed remarkable scavenging activity and concentration-dependent reducing power. The extract demonstrates no acute oral toxicity, as indicated by an LD50 value exceeding 1000 mg/kg body weight. Gas Chromatography-Mass Spectrometry/Mass Spectrometry (GC-MS/MS) analysis was performed which yielded sixty bioactive compounds. In-silico and molecular docking studies revealed favorable pharmacological properties, including good binding affinities and ADME/T profiles. Conclusion: These results support the medicinal use of the plant, which makes it a potential source of analgesic, anti-inflammatory, and antioxidant candidates.

Unveiling the Therapeutic Potentials of Water Hyacinth (Eichhornia crassipes (Mart.) Solms) Flower against Oxidative Stress, Inflammation and Depressive Disorders: GC-MS/MS, In Vitro, In Vivo and In Silico Approaches.

Water hyacinth (Eichhornia crassipes (Mart.) Solms) is a highly invasive aquatic weed native to the Amazonia basin, known for its rapid propagation, adaptability and utilization in traditional medicine. The study aims to unveil the therapeutic potential of water hyacinth flowers methanolic extract (EC-CME) and its four kupchan fractions (EC-PESF, EC-DCMSF, EC-EASF, EC-ASF) through diversified chemical-pharmacological approaches. GC-MS/MS of EC-CME uncovered a rich tapestry of 72 phytochemical components. In vitro DPPH scavenging assay and total phenolic content determination assay deciphered promising antioxidant assays with remarkably low IC50 values of 0.353 and 0.485 µg/mL, respectively for EC-ESF and EC-ASF. Besides, different in vivo tests, including tail emersion, acetic acid-induced writhing, and thiopental-induced sleeping test of EC-CME, yielded a remarkable 8.61 ± 0.29 minutes of tail immersion time compared to the control's 2.05 ± 0.11 minutes at the highest dose (600 mg/kg). The best % inhibition of writhing was recorded as 47.96% accrued in 400 mg/kg dose, indicating robust pain-relieving properties. The onset and duration of sleep are significantly ameliorated for EC-CME, unveiling its antidepressant potential. Besides, molecular docking studies along with ADME/T analysis also validated the wet lab findings as well as their safety, efficacy and drug-likeliness profile.

Carvedilol to prevent hepatic decompensation of cirrhosis in patients with clinically significant portal hypertension stratified by new non-invasive model (CHESS2306).

Background & Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvedilol-treating cohort. Results: In the meta-analysis with six studies (n = 819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new "CSPH risk" model. In the HVPG cohort (n = 151), the new model accurately predicted CSPH with cutoff values of 0 and -0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n = 1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <-0.68 (low-risk), -0.68 to 0 (medium-risk), and >0 (high-risk). In the carvedilol-treated cohort, patients with high-risk CSPH treated with carvedilol (n = 81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n = 613 before propensity score matching [PSM], n = 162 after PSM). Conclusions: Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

MRI Radiomics Combined with Clinicopathological Factors for Predicting 3-Year Overall Survival of Hepatocellular Carcinoma After Hepatectomy.

Background: A limited number of studies have examined the use of radiomics to predict 3-year overall survival (OS) after hepatectomy in patients with hepatocellular carcinoma (HCC). This study develops 3-year OS prediction models for HCC patients after liver resection using MRI radiomics and clinicopathological factors. Materials and Methods: A retrospective analysis of 141 patients who underwent surgical resection of HCC was performed. Patients were randomized into two set: the training set (n=98) and the validation set (n=43) including the survival groups (n=111) and non-survival groups (n=30) based on 3-year survival after hepatectomy. Furthermore, x2 or Fisher's exact test, univariate and multivariate logistic regression analyses were conducted to determine independent clinicopathological risk factors associated with 3-year OS. 1688 quantitative imaging features were extracted from preoperative T2-weighted imaging (T2WI) and contrast-enhanced magnetic resonance imaging (CE-MRI) of arterial phase (AP), portal venous phases (PVP)and delay period (DP). The features were selected using the variance threshold method, the select K best method and the least absolute shrinkage and selection operator (LASSO) algorithm. By using Bernoulli Naive Bayes (BernoulliNB) and Multinomial Naive Bayes (MultinomialNB) classifiers, we constructed models based on the independent clinicopathological factors and Rad-scores. To determine the best model, receiver operating characteristics (ROC) and Delong's test were used. Moreover, calibration curves were used to determine the calibration ability of the model, while decision curve analysis (DCA) was implemented to evaluate its clinical benefit. Results: The fusion model showed excellent prediction precision with AUC of 0.910 and 0.846 in training and validation set and revealed significant diagnostic accuracy and value in the calibration curve and DCA analysis. Conclusion: Nomograms based on MRI radiomics and clinicopathological factors have significant predictive value for 3-year OS after hepatectomy and can be used for risk classification.

NIR-II Light-Actuated Nanomotors for Enhanced Photoimmunotherapy Toward Hepatocellular Carcinoma.

Light-propelled nanomotors, which can convert external light into mechanical motion, have shown considerable potential in the construction of a new generation of drug delivery systems. However, the therapeutic efficacy of light-driven nanomotors is always unsatisfactory due to the limited penetration depth of near-infrared-I (NIR-I) light and the inherent biocompatibility of the motor itself. Herein, an asymmetric nanomotor (Pd@ZIF-8/R848@M JNMs) with efficient motion capability is successfully constructed for enhanced photoimmunotherapy toward hepatocellular carcinoma. Under near-infrared-II (NIR-II) irradiation, Pd@ZIF-8/R848@M JNMs convert light energy into heat energy, exhibiting self-thermophoretic locomotion to penetrate deeper into tumor tissues to achieve photothermal therapy. At the same time, functionalized with an immune-activated agent Resiquimod (R848), our nanomotors could convert a "cold tumor" into a "hot tumor", transforming the immunosuppressive microenvironment into an immune-activated state, thus achieving immunotherapy. Dual photoimmunotherapy of the as-developed NIR-II light-driven Pd@ZIF-8/R848@M JNMs demonstrates considerable tumor inhibition effects, offering a promising therapeutic approach in the field of anticancer therapy.

Pyroptosis in Diabetic Peripheral Neuropathy and its Therapeutic Regulation.

Pyroptosis is a pro-inflammatory form of cell death resulting from the activation of gasdermins (GSDMs) pore-forming proteins and the release of several pro-inflammatory factors. However, inflammasomes are the intracellular protein complexes that cleave gasdermin D (GSDMD), leading to the formation of robust cell membrane pores and the initiation of pyroptosis. Inflammasome activation and gasdermin-mediated membrane pore formation are the important intrinsic processes in the classical pyroptotic signaling pathway. Overactivation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome triggers pyroptosis and amplifies inflammation. Current evidence suggests that the overactivation of inflammasomes and pyroptosis may further induce the progression of cancers, nerve injury, inflammatory disorders and metabolic dysfunctions. Current evidence also indicates that pyroptosis-dependent cell death accelerates the progression of diabetes and its frequent consequences including diabetic peripheral neuropathy (DPN). Pyroptosis-mediated inflammatory reaction further exacerbates DPN-mediated CNS injury. Accumulating evidence shows that several molecular signaling mechanisms trigger pyroptosis in insulin-producing cells, further leading to the development of DPN. Numerous studies have suggested that certain natural compounds or drugs may possess promising pharmacological properties by modulating inflammasomes and pyroptosis, thereby offering potential preventive and practical therapeutic approaches for the treatment and management of DPN. This review elaborates on the underlying molecular mechanisms of pyroptosis and explores possible therapeutic strategies for regulating pyroptosis-regulated cell death in the pharmacological treatment of DPN.

Recent advances in molecular mechanisms of skin wound healing and its treatments.

The skin, being a multifaceted organ, performs a pivotal function in the complicated wound-healing procedure, which encompasses the triggering of several cellular entities and signaling cascades. Aberrations in the typical healing process of wounds may result in atypical scar development and the establishment of a persistent condition, rendering patients more vulnerable to infections. Chronic burns and wounds have a detrimental effect on the overall quality of life of patients, resulting in higher levels of physical discomfort and socio-economic complexities. The occurrence and frequency of prolonged wounds are on the rise as a result of aging people, hence contributing to escalated expenditures within the healthcare system. The clinical evaluation and treatment of chronic wounds continue to pose challenges despite the advancement of different therapeutic approaches. This is mainly owing to the prolonged treatment duration and intricate processes involved in wound healing. Many conventional methods, such as the administration of growth factors, the use of wound dressings, and the application of skin grafts, are used to ease the process of wound healing across diverse wound types. Nevertheless, these therapeutic approaches may only be practical for some wounds, highlighting the need to advance alternative treatment modalities. Novel wound care technologies, such as nanotherapeutics, stem cell treatment, and 3D bioprinting, aim to improve therapeutic efficacy, prioritize skin regeneration, and minimize adverse effects. This review provides an updated overview of recent advancements in chronic wound healing and therapeutic management using innovative approaches.

Discovery of Small and Bifunctional Molecules Targeting PD-L1/CD73 for Cancer Dual Immunotherapy.

In this work, a series of bifunctional PD-L1/CD73 (cluster of differentiation 73) small-molecule inhibitors were designed and synthesized. Among them, CC-5 showed the strongest PD-L1 inhibitory effects with an IC50 of 6 nM and potent anti-CD73 activity with an IC50 of 0.773 µM. The high PD-L1/CD73 inhibitory activity of CC-5 was further confirmed by SPR assays with KD of 182 nM for human PD-L1 and 101 nM for CD73, respectively. Importantly, CC-5 significantly suppressed tumor growth in a CT26 and B16-F10 tumor model with TGI of 64.3% and 39.6%, respectively. Immunohistochemical (IHC) and flow cytometry analysis of tumor-infiltrating lymphocytes (TILs) indicated that CC-5 exerted anticancer effects via activating the tumor immune microenvironment. Collectively, CC-5 represents the first dual PD-L1/CD73 inhibitor worthy of further research as a bifunctional immunotherapeutic agent.

Discovery of Novel Heterotricyclic Compounds as DNA-Dependent Protein Kinase (DNA-PK) Inhibitors with Enhanced Chemosensitivity, Oral Bioavailability, and the Ability to Potentiate Cancer Immunotherapy.

In this work, a novel series of heterotricyclic DNA-PK inhibitors were rationally designed, synthesized, and assessed for their biological activity. In the DNA-PK biochemical assay, most compounds displayed potent enzymatic activity, with IC50 values between 0.11 and 71.5 nM. Among them, SK10 exhibited the most potent DNA-PK-inhibitory activity (IC50 = 0.11 nM). Studies of the mechanism of action indicated that SK10 could lower γH2A.X expression levels and demonstrate optimal synergistic antiproliferative activity against Jurkat cells (IC50 = 25 nM) when combined with doxorubicin. Importantly, in CT26 and B16-F10 tumor-bearing mouse models, the combination therapies of SK10 with chemotherapeutic drug doxorubicin, a PD-L1 antibody, and SWS1 (a potent PD-L1 small-molecule inhibitor) demonstrated superior synergistic anticancer and potential immunomodulatory effects. Furthermore, SK10 possessed favorable in vivo pharmacokinetic properties [e.g., oral bioavailability (F) = 31.8%]. Taken together, SK10 represents a novel heterotricyclic DNA-PK inhibitor with antitumor immune effects and favorable pharmacokinetics.

mTOR inhibitor reduces nontumour-related death in liver transplantation for hepatocellular carcinoma.

Sirolimus is a regularly applied immunosuppressant for patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC). Sirolimus not only significantly inhibits HCC recurrence but also protects renal function. However, the improvement effect of sirolimus on nontumour-related death in patients is still unknown. The aim of our study was to investigate the therapeutic effect of sirolimus on nontumour-related deaths. In this study, we retrospectively enrolled 403 LT patients with HCC from January 1, 2015, to December 31, 2018. The median follow-up time was 47.1 months. The patients were divided into the sirolimus group (N = 184) and the sirolimus-free group (N = 219). There were no significant differences between the sirolimus group and the sirolimus-free group in survival (P = 0.054). In transplant patients who exceeded the Milan or Hangzhou criteria, the sirolimus group achieved higher survival than the sirolimus-free group (P = 0.005; P = 0.02). Moreover, multivariate analysis showed that sirolimus strongly reduced the hazard ratio (HR) for nontumour-related death in LT patients who exceeded the Milan (HR: 0.42; 95% CI: 0.18-1; P = 0.05) or Hangzhou criteria (HR: 0.26; 95% CI: 0.08-0.89; P = 0.032). HCC recurrence increased the risk of nontumour-related death. In conclusion, sirolimus-based immunosuppression can significantly reduce nontumour-related death in LT patients who exceed the criteria for transplantation. In addition, this finding will further promote the application of sirolimus after liver transplantation for hepatocellular carcinoma.

Phyto-pharmacological evaluation and characterization of the methanolic extract of the Baccaurea motleyana Müll. Arg. seed: promising insights into its therapeutic uses.

Introduction: Plants and their extracts have been integral to the development of medicinal treatments throughout history, offering a vast array of compounds for innovative therapies. Baccaurea motleyana Müll. Arg., commonly known as Rambai, is an evergreen tree with economic importance in the Old-World Tropics. Method: The study investigates its phytochemical composition through Gas Chromatography-Mass Spectrometry (GC-MS) and evaluates its pharmacological properties, including antidiabetic, antidiarrheal, antimicrobial, and antidepressant effects. Result and Discussion: The GC-MS analysis revealed 15 bioactive compounds in the methanol extract, with Phenol, 3,5-bis(1,1-dimethylethyl)-, Methyl stearate, and Hexadecanoic acid, methyl ester being the predominant ones. The cytotoxicity assay demonstrated significant activity in the ethyl acetate fraction. Antimicrobial assays indicated mild to moderate antibacterial activity. In vivo studies on mice revealed significant hypoglycemic, antidiarrheal, and antidepressant properties. Molecular docking studies against EGFR, DHFR, GLUT-3, KOR, and MOA identified promising compounds with potential therapeutic effects. The identified compounds exhibited favorable ADME/T properties, emphasizing their potential for drug development. The study underscores the promising therapeutic potential of Baccaurea motleyana, showcasing its diverse bioactive compounds with significant medicinal properties. Conclusion: These findings lay the groundwork for future research, emphasizing the exploration of B. motleyana as a source of natural remedies for addressing prevalent health conditions.

The Mechanism of Pyroptosis and Its Application Prospect in Diabetic Wound Healing.

Pyroptosis defines a form of pro-inflammatory-dependent programmed cell death triggered by gasdermin proteins, which creates cytoplasmic pores and promotes the activation and accumulation of immune cells by releasing several pro-inflammatory mediators and immunogenic substances upon cell rupture. Pyroptosis comprises canonical (mediated by Caspase-1) and non-canonical (mediated by Caspase-4/5/11) molecular signaling pathways. Numerous studies have explored the contributory roles of inflammasome and pyroptosis in the progression of multiple pathological conditions such as tumors, nerve injury, inflammatory diseases and metabolic disorders. Accumulating evidence indicates that the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome results in the activation of pyroptosis and inflammation. Current evidence suggests that pyroptosis-dependent cell death plays a progressive role in the development of diabetic complications including diabetic wound healing (DWH) and diabetic foot ulcers (DFUs). This review presents a brief overview of the molecular mechanisms underlying pyroptosis and addresses the current research on pyroptosis-dependent signaling pathways in the context of DWH. In this review, we also present some prospective therapeutic compounds/agents that can target pyroptotic signaling pathways, which may serve as new strategies for the effective treatment and management of diabetic wounds.

Polyphenols Targeting NF-κB Pathway in Neurological Disorders: What We Know So Far?

Polyphenolic compounds have shown promising neuroprotective properties, making them a valuable resource for identifying prospective drug candidates to treat several neurological disorders (NDs). Numerous studies have reported that polyphenols can disrupt the nuclear factor kappa B(NF-κB) pathway by inhibiting the phosphorylation or ubiquitination of signaling molecules, which further prevents the degradation of IκB. Additionally, they prevent NF-κB translocation to the nucleus and pro-inflammatory cytokine production. Polyphenols such as curcumin, resveratrol, and pterostilbene had significant inhibitory effects on NF-κB, making them promising candidates for treating NDs. Recent experimental findings suggest that polyphenols possess a wide range of pharmacological properties. Notably, much attention has been directed towards their potential therapeutic effects in NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), cerebral ischemia, anxiety, depression, autism, and spinal cord injury (SCI). Much preclinical data supporting the neurotherapeutic benefits of polyphenols has been developed. Nevertheless, this study has described the significance of polyphenols as potential neurotherapeutic agents, specifically emphasizing their impact on the NF-κB pathway. This article offers a comprehensive analysis of the involvement of polyphenols in NDs, including both preclinical and clinical perspectives.

A novel nomogram for prognosis stratification in salvage liver transplantation: a national-wide study with propensity score matching analysis in China.

Background: Salvage liver transplantation (SLT) has been reported to be an efficient treatment option for patients with recurrent hepatocellular carcinoma (HCC) after liver resection (LR). However, for recipients who underwent liver transplantation (LT) due to recurrent HCC after LR in China, the selection criteria are not well established. Methods: In this study, data from the China Liver Transplant Registry (CLTR) of 4,244 LT performed from January 2015 to December 2019 were examined, including 3,498 primary liver transplantation (PLT) and 746 SLT recipients. Propensity score matching (PSM) analysis was used to minimize between-group imbalances. The overall survival (OS) and disease-free survival (DFS) between PLT and SLT in recipients fulfilling the Milan or Hangzhou criteria were compared based on the multivariate analysis, nomograms were plotted to further classify the SLT group into low- and high-risk groups. Results: In this study, the 1-, 3- and 5-year OS and DFS of SLT recipients fulfilling Milan criteria (OS, P=0.01; DFS, P<0.001) or Hangzhou criteria (OS, P=0.03; DFS, P=0.003) were significantly reduced when compared to that of PLT group after PSM analysis. Independent risk factors, including preoperative transarterial chemoembolization (TACE), alpha fetoprotein (AFP) level, tumor maximum size and tumor total diameter were selected to draw a prognostic nomogram. The low-risk SLT recipients (1-year, 95.34%; 3-year, 84.26%; 5-year, 77.20%) showed a comparable OS with PLT recipients fulfilling Hangzhou criteria (P=0.107). Conclusions: An optimal nomogram model for prognosis stratification and clinical decision guidance of SLT was established. The low-risk SLT recipients based on the nomograms showed comparable survival with those fulfilling Hangzhou criteria in PLT group.

Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C.

Malignant hyperthermia (MH) is an inherited skeletal muscle disorder caused primarily by a genetic mutation, usually in the calcium channel gene of the muscle. This mutation can lead to muscle hypersensitivity to volatile anesthetics (such as sevoflurane) and the depolarizing muscle relaxant succinylcholine, resulting in hyperthermia, muscle stiffness, metabolic disturbances, and other severe physiological reactions. This condition may prove fatal unless it is recognized in its early stages and treatment is administered promptly and aggressively. We report a 13-year-old adolescent who underwent laparoscopic appendectomy and developed MH after the use of inhalational anesthetics, manifested by unremitting hyperthermia with a maximum temperature of 44.2°C, muscle rigidity, tachycardia, hypercapnia; and malignant arrhythmias, cardiogenic shock, hyperkalemia, metabolic, and respiratory acidosis. After early and timely recognition, multidisciplinary management and administration of dantrolene, the case was successfully treated. Exome sequencing revealed a point mutation (amino acid change) on the RYR1 gene: c.12700G>C(p.Val4234Leu). Due to the lack of ready-made dantrolene in our hospital, the patient in this case received dantrolene treatment only 6 h after the first observation of high body temperature. We review the development of the disease and summarize the success of treatment and what can be done to improve the chances of saving the patient's life if dantrolene is not available in time.

Bladder microenvironment actuated proteomotors with ammonia amplification for enhanced cancer treatment.

Enzyme-driven micro/nanomotors consuming in situ chemical fuels have attracted lots of attention for biomedical applications. However, motor systems composed by organism-derived organics that maximize the therapeutic efficacy of enzymatic products remain challenging. Herein, swimming proteomotors based on biocompatible urease and human serum albumin are constructed for enhanced antitumor therapy via active motion and ammonia amplification. By decomposing urea into carbon dioxide and ammonia, the designed proteomotors are endowed with self-propulsive capability, which leads to improved internalization and enhanced penetration in vitro. As a glutamine synthetase inhibitor, the loaded l-methionine sulfoximine further prevents the conversion of toxic ammonia into non-toxic glutamine in both tumor and stromal cells, resulting in local ammonia amplification. After intravesical instillation, the proteomotors achieve longer bladder retention and thus significantly inhibit the growth of orthotopic bladder tumor in vivo without adverse effects. We envision that the as-developed swimming proteomotors with amplification of the product toxicity may be a potential platform for active cancer treatment.

Systemic analysis identifying PVT1/DUSP13 axis for microvascular invasion in hepatocellular carcinoma.

BACKGROUND: Microvascular invasion (MVI) is an independent detrimental risk factor for tumor recurrence and poor survival in hepatocellular carcinoma (HCC). Competitive endogenous RNA (ceRNA) networks play a pivotal role in the modulation of carcinogenesis and progression among diverse tumor types. However, whether the ceRNA mechanisms are engaged in promoting the MVI process in patients with HCC remains unknown. METHODS: A ceRNA regulatory network was constructed based on RNA-seq data of patients with HCC from The Cancer Genome Atlas (TCGA) database. In total, 10 hub genes of the ceRNA network were identified using four algorithms: "MCC," "Degree," "Betweenness," and "Stress." Transcriptional expressions were verified by in situ hybridization using clinical samples. Interactions between ceRNA modules were validated by luciferase reporting assay. Logistic regression analysis, correlation analysis, enrichment analysis, promoter region analysis, methylation analysis, and immune infiltration analysis were performed to further investigate the molecular mechanisms and clinical transformation value. RESULTS: The ceRNA regulatory network featuring a tumor invasion phenotype consisting of 3 long noncoding RNAs, 3 microRNAs, and 93 mRNAs was constructed using transcriptional data from the TCGA database. Systemic analysis and experimentally validation identified a ceRNA network (PVT1/miR-1258/DUSP13 axis) characterized by lipid regulatory potential, immune properties, and abnormal methylation states in patients with HCC and MVI. Meanwhile, 28 transcriptional factors were identified as potential promotors of PVT1 with 3 transcriptional factors MXD3, ZNF580, and KDM1A promising as therapeutic targets in patients with HCC and MVI. Furthermore, miR-1258 was an independent predictor for MVI in patients with HCC. CONCLUSION: The PVT1/DUSP13 axis is significantly associated with MVI progression in HCC patients. This study provides new insight into mechanisms related to lipids, immune phenotypes, and abnormal epigenetics in oncology research.

Knockdown of PKMYT1 is associated with autophagy inhibition and apoptosis induction and suppresses tumor progression in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a cancerous tumor that ranks as the third leading cause of cancer death across the globe. Protein kinase membrane-associated tyrosine/threonine kinase 1 (PKMYT1) is overexpressed in many cancer types, including HCC, but the potential mechanism and biological function of PKMYT1 are not fully understood. MATERIALS AND METHODS: The expression level of PKMYT1 was detected in human HCC tissues and adjacent tissues. We then established HCC cell lines with PKMYT1 knockdown and observed proliferation, migration, autophagy, apoptosis in cell lines and tumor growth in a nude mouse model. To investigate the underlying mechanism by which PKMYT1 regulates autophagy and apoptosis, RNA sequencing was performed in HCC-LM3 cells with and without PKMYT1 knockdown. RESULTS: Here, we observed that human HCC tissues had higher expression of PKMYT1 than adjacent tissues. Overexpression of PKMYT1 was closely associated with poor prognosis in HCC patients. PKMYT1 knockdown inhibited the proliferative potential and migration of HCC cell lines. We also found that downregulation of PKMYT1 inhibited autophagy and induced apoptosis. RNA sequencing analysis showed that the MAPK and PI3K-AKT pathways, which have been reported to affect autophagy and apoptosis, may be regulated after PKMYT1 knockdown by KEGG pathway enrichment analysis. Furthermore, we identified that knockdown of PKMYT1 attenuated the phosphorylation levels of p38 MAPK, ERK and PI3K/Akt/mTOR, which might mediate autophagy inhibition and apoptosis induction via these signaling pathways to inhibit the development of HCC. CONCLUSION: Our study suggests that PKMYT1 functions as an oncogene and may be a new target for HCC treatment.

Advances in FGFs for diabetes care applications.

BACKGROUND: Diabetes mellitus (DM) is an endocrine and metabolic disease caused by a variety of pathogenic factors, including genetic factors, environmental factors and behavior. In recent decades, the number of cases and the prevalence of diabetes have steadily increased, and it has become one of the most threatening diseases to human health in the world. Currently, insulin is the most effective and direct way to control hyperglycemia for diabetes treatment at a low cost. However, hypoglycemia is often a common complication of insulin treatment. Moreover, with the extension of treatment time, insulin resistance, considered the typical adverse symptom, can appear. Therefore, it is urgent to develop new targets and more effective and safer drugs for diabetes treatment to avoid adverse reactions and the insulin tolerance of traditional hypoglycemic drugs. SCOPE OF REVIEW: In recent years, it has been found that some fibroblast growth factors (FGFs), including FGF1, FGF19 and FGF21, can safely and effectively reduce hyperglycemia and have the potential to be developed as new drugs for the treatment of diabetes. FGF23 is also closely related to diabetes and its complications, which provides a new approach for regulating blood glucose and solving the problem of insulin tolerance. MAJOR CONCLUSIONS: This article reviews the research progress on the physiology and pharmacology of fibroblast growth factor in the treatment of diabetes. We focus on the application of FGFs in diabetes care and prevention.

Construction of polysaccharide scaffold-based perfusion bioreactor supporting liver cell aggregates for drug screening.

Rebuilding a suitable microenvironment of liver cells is the key challenge to enhancing the expression of hepatic functions for drug screening in vitro. To improve the microenvironment by providing the specific adhesive ligands for hepatocytes in the three-dimensional dynamic culture, a perfusion bioreactor with a pectin/alginate blend porous scaffold was constructed in this study. The galactosyl component in the main chain of pectin was able to be specifically recognized by the asialoglycoprotein receptor on the surface of hepatocytes, and subsequently promoted the adhesion and aggregation of hepatocytes co-cultured with hepatic non-parenchymal cells. The bioreactor was optimized for 4 h of dynamic inoculation followed by perfusion at a flow rate of 2 mL/min, which provided adequate oxygen supply and good mass transfer to the liver cells. During dynamic cultured in the bioreactor for 14 days, more multicellular aggregates were formed and were evenly distributed in the pectin/alginate blend scaffolds. The expressions of intercellular interaction and hepatic functions of the hepatocytes in aggregates were significantly enhanced in the three-dimensional dynamic group. Furthermore, the bioreactor not only markedly upregulated the cell polarity markers expression of hepatocytes but also enhanced their metabolic capacity to acetaminophen, isoniazid, and tolbutamide, which exhibited a significant concentration-dependent manner. Therefore, the pectin/alginate blend scaffold-based perfusion bioreactor appeared to be a promising candidate in the field of drug development and liver regeneration research.