Biomarkers for diagnosis and therapeutic options in hepatocellular carcinoma.

Liver cancer is a global health challenge, causing a significant social-economic burden. Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, which is highly heterogeneous in terms of molecular and cellular signatures. Early-stage or small tumors are typically treated with surgery or ablation. Currently, chemotherapies and immunotherapies are the best treatments for unresectable tumors or advanced HCC. However, drug response and acquired resistance are not predictable with the existing systematic guidelines regarding mutation patterns and molecular biomarkers, resulting in sub-optimal treatment outcomes for many patients with atypical molecular profiles. With advanced technological platforms, valuable information such as tumor genetic alterations, epigenetic data, and tumor microenvironments can be obtained from liquid biopsy. The inter- and intra-tumoral heterogeneity of HCC are illustrated, and these collective data provide solid evidence in the decision-making process of treatment regimens. This article reviews the current understanding of HCC detection methods and aims to update the development of HCC surveillance using liquid biopsy. Recent critical findings on the molecular basis, epigenetic profiles, circulating tumor cells, circulating DNAs, and omics studies are elaborated for HCC diagnosis. Besides, biomarkers related to the choice of therapeutic options are discussed. Some notable recent clinical trials working on targeted therapies are also highlighted. Insights are provided to translate the knowledge into potential biomarkers for detection and diagnosis, prognosis, treatment response, and drug resistance indicators in clinical practice.

Traditional Chinese medicine for the treatment of cancers of hepatobiliary system: from clinical evidence to drug discovery.

Hepatic, biliary, and pancreatic cancer pose significant challenges in the field of digestive system diseases due to their highly malignant nature. Traditional Chinese medicine (TCM) has gained attention as a potential therapeutic approach with long-standing use in China and well-recognized clinical benefits. In this review, we systematically summarized the clinical applications of TCM that have shown promising results in clinical trials in treating hepatic, biliary, and pancreatic cancer. We highlighted several commonly used TCM therapeutics with validated efficacy through rigorous clinical trials, including Huaier Granule, Huachansu, and Icaritin. The active compounds and their potential targets have been thoroughly elucidated to offer valuable insights into the potential of TCM for anti-cancer drug discovery. We emphasized the importance of further research to bridge the gap between TCM and modern oncology, facilitating the development of evidence-based TCM treatment for these challenging malignancies.

Loss of lncRNA LINC01056 leads to sorafenib resistance in HCC.

BACKGROUND AND AIMS: Sorafenib is a major nonsurgical option for patients with advanced hepatocellular carcinoma (HCC); however, its clinical efficacy is largely undermined by the acquisition of resistance. The aim of this study was to identify the key lncRNA involved in the regulation of the sorafenib response in HCC. MATERIALS AND METHODS: A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) single-guide RNA (sgRNA) synergistic activation mediator (SAM)-pooled lncRNA library was applied to screen for the key lncRNA regulated by sorafenib treatment. The role of the identified lncRNA in mediating the sorafenib response in HCC was examined in vitro and in vivo. The underlying mechanism was delineated by proteomic analysis. The clinical significance of the expression of the identified lncRNA was evaluated by multiplex immunostaining on a human HCC microtissue array. RESULTS: CRISPR/Cas9 lncRNA library screening revealed that Linc01056 was among the most downregulated lncRNAs in sorafenib-resistant HCC cells. Knockdown of Linc01056 reduced the sensitivity of HCC cells to sorafenib, suppressing apoptosis in vitro and promoting tumour growth in mice in vivo. Proteomic analysis revealed that Linc01056 knockdown in sorafenib-treated HCC cells induced genes related to fatty acid oxidation (FAO) while repressing glycolysis-associated genes, leading to a metabolic switch favouring higher intracellular energy production. FAO inhibition in HCC cells with Linc01056 knockdown significantly restored sensitivity to sorafenib. Mechanistically, we determined that PPARα is the critical molecule governing the metabolic switch upon Linc01056 knockdown in HCC cells and indeed, PPARα inhibition restored the sorafenib response in HCC cells in vitro and HCC tumours in vivo. Clinically, Linc01056 expression predicted optimal overall and progression-free survival outcomes in HCC patients and predicted a better sorafenib response. Linc01056 expression indicated a low FAO level in HCC. CONCLUSION: Our study identified Linc01056 as a critical epigenetic regulator and potential therapeutic target in the regulation of the sorafenib response in HCC.

Unravelling the role of natural and synthetic products as DNA topoisomerase inhibitors in hepatocellular carcinoma.

Topoisomerase is a ubiquitous enzyme in the control of DNA chain topology. There have been extensive research on topoisomerase inhibitors derived from natural sources, which act as partial inducers of tumor cell apoptosis. However, their specific efficacy in treating hepatocellular carcinoma is relatively unexplored. Hence, this comprehensive review focuses on the structural characteristics and anti-cancer properties of topoisomerase inhibitors in hepatocellular carcinoma. Furthermore, this review is also elucidating the mechanism of action, structure-activity relationships, therapeutic limitations, stage of clinical trials of described classes of natural bioactive compounds as well as their potential application in cancer chemotherapies. This broad understanding of topoisomerase medical biology will provide indispensable framework for enhancing the efficiency of rational anti-hepatocellular carcinoma drug discovery.

CRISPR/Cas9 screens unravel miR-3689a-3p regulating sorafenib resistance in hepatocellular carcinoma via suppressing CCS/SOD1-dependent mitochondrial oxidative stress.

AIMS: Therapeutic outcome of sorafenib in hepatocellular carcinoma (HCC) is undermined by the development of drug resistance. This study aimed to identify the critical microRNA (miRNA) which is responsible for sorafenib resistance at the genomic level. METHODS: CRISPR/Cas9 screen followed by gain- and loss-of-function assays both in vitro and in vivo were applied to identify the role of miR-3689a-3p in mediating sorafenib response in HCC. The upstream and downstream molecules of miR-3689a-3p and their mechanism of action were investigated. RESULTS: CRISPR/Cas9 screening identified miR-3689a-3p was the most up-regulated miRNA in sorafenib sensitive HCC. Knockdown of miR-3689a-3p significantly increased sorafenib resistance, while its overexpression sensitized HCC response to sorafenib treatment. Proteomic analysis revealed that the effect of miR-3689a-3p was related to the copper-dependent mitochondrial superoxide dismutase type 1 (SOD1) activity. Mechanistically, miR-3689a-3p targeted the 3'UTR of the intracellular copper chaperone for superoxide dismutase (CCS) and suppressed its expression. As a result, miR-3689a-3p disrupted the intracellular copper trafficking and reduced SOD1-mediated scavenge of mitochondrial oxidative stress that eventually caused HCC cell death in response to sorafenib treatment. CCS overexpression blunted sorafenib response in HCC. Clinically, miR-3689a-3p was down-regulated in HCC and predicted favorable prognosis for HCC patients. CONCLUSION: Our findings provide comprehensive evidence for miR-3689a-3p as a positive regulator and potential druggable target for improving sorafenib treatment in HCC.

The tumor microenvironment in the postsurgical liver: Mechanisms and potential targets of postoperative recurrence in human hepatocellular carcinoma.

Surgery remains to be the mainstay of treatment for hepatocellular carcinoma (HCC). Nonetheless, its therapeutic efficacy is significantly impaired by postoperative recurrence, which occurs in more than half of cases as a result of intrahepatic metastasis or de novo tumorigenesis. For decades, most therapeutic strategies on inhibiting postoperative HCC recurrence have been focused on the residual tumor cells but satisfying therapeutic outcomes are barely observed in the clinic. In recent years, a better understanding of tumor biology allows us to shift our focus from tumor cells toward the postoperative tumor microenvironment (TME), which is gradually identified to play a pivotal role in tumor recurrence. In this review, we describe various surgical stress and surgical perturbation on postoperative TME. Besides, we discuss how such alternations in TME give rise to postoperative recurrence of HCC. Based on its clinical significance, we additionally highlight the potential of the postoperative TME as a target for postoperative adjuvant therapeutics.

Minocycline, a classic antibiotic, exerts psychotropic effects by normalizing microglial neuroinflammation-evoked tryptophan-kynurenine pathway dysregulation in chronically stressed male mice.

The dysregulation of tryptophan-kynurenine pathway (TKP) is extensively involved in the pathophysiology of Alzheimer's disease, depression, and neurodegenerative disorders. Minocycline, a classic antibiotic, may exert psychotropic effects associated with the modulation of TKP. In this study, we examined the effects of minocycline in improving behaviour and modulating TKP components in chronically stressed male mice. Following repeated treatment with 22.5 mg/kg and 45 mg/kg minocycline for 27 days, the stressed mice particularly with higher dose displayed significant improvement on cognitive impairment, depression- and anxiety-like behaviour. Minocycline suppressed stress-induced overexpression of pro-inflammatory cytokines and restored anti-inflammatory cytokines. Chronic stress dramatically suppressed blood and prefrontal cortical levels of the primary substrate tryptophan (TRP), the neuroprotective metabolite kynurenic acid (KYNA), and KYNA/KYN ratio, but increased the intermediate kynurenine (KYN), 3-hydroxykynurenine (3-HK), KYN/TRP ratio, and the neurotoxic metabolite quinolinic acid (QUIN). Minocycline partially or completely reversed changes in these components. Minocycline also inhibited stress-induced overexpression of QUIN-related enzymes, indoleamine 2, 3-dioxygenase 1(iDO-1), kynureninase (KYNU), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilate 3,4-dioxygenase (3-HAO), but rescued the decreased expression of kynurenine aminotransferase (KAT) in brain regions. Behavioral improvements were correlated with multiple TKP metabolites and enzymes. These results suggest that the psychotropic effects of minocycline are mainly associated with the restoration of biodistribution of the primary substrate in the brain and normalization of neuroinflammation-evoked TKP dysregulation.

Effects and mechanisms of tea on obesity.

Obesity has become a global health concern. It increases the risk of several diseases, such as type 2 diabetes mellitus, nonalcoholic fatty liver disease, and certain cancers, which threatens human health and increases social economic burden. As one of the most consumed beverages, tea contains various phytochemicals with potent bioactive properties and health-promoting effects, such as antioxidant, immune-regulation, cardiovascular protection and anticancer. Tea and its components are also considered as potential candidates for anti-obesity. Epidemiological studies indicate that regular consumption of tea is beneficial for reducing body fat. In addition, the experimental studies demonstrate that the potential anti-obesity mechanisms of tea are mainly involved in increasing energy expenditure and lipid catabolism, decreasing nutrient digestion and absorption as well as lipid synthesis, and regulating adipocytes, neuroendocrine system and gut microbiota. Moreover, most of clinical studies illustrate that the intake of green tea could reduce body weight and alleviate the obesity. In this review, we focus on the effect of tea and its components on obesity from epidemiological, experimental, and clinical studies, and discuss their potential mechanisms.

Efficacy and safety of herbal medicines intervention for cachexia associated with cancer: A systematic review and meta-analysis.

As a worldwide public health issue, cancer-induced cachexia can result in decreasing physical function and survival rate. However, the therapeutic effects of conventional approaches, including pharmacotherapy, exercise and nutritional intervention, are far from satisfactory. Herbal medicines (HMs), especially Traditional Chinese Medicine (TCM), are reported to effectively treat cachexia for centuries. The inclusion criteria of all participants in this study pointed to the diagnosis of cachexia, the trial group used herbal medicine (HM) in complementary and alternative medicine, etc. Twelve databases, including EMbase, PubMed, Web of science, Cochrane CENTRAL, CINAHL, CINAHLPlus, PsycINFO, AMED, China Biology Medicine disc (CBM), China National Knowledge Infrastructure (CNKI), Wanfang and Chongqing VIP (CQVIP) were retrieved from inception to March 28, 2022. We conducted the meta-analysis utilizing RevMan 5.3. A trial sequential analysis (TSA) was conducted to assess the adequacy of the sample size for the outcomes. We have registered the protocol and the registration number was CRD42022336446. A total of 66 studies were included, containing 3654 patients diagnosed with cancer cachexia, of which 1833 patients were assigned to the trial group and 1821 patients were treated in the control group. Outcomes cover the primary indicator KPS (RR = 1.84, 95%CI = [1.61, 2.09], p < 0.00001), and other outcomes including adverse events rate (RR = 0.37, 95%CI = [0.23, 0.58], p < 0.0001), albumin (MD = 2.14, 95%CI = [1.56, 2.71], p < 0.00001), haemoglobin (MD = 4.88, 95%CI = [3.26, 6.50], p < 0.00001), TCM syndrome effect (MD = 1.47, 95%CI = [1.31, 1.65], p < 0.00001), effect of weight (RR = 1.62, 95%CI = [1.34, 1.95], p < 0.00001), effect of appetite (RR = 1.23, 95%CI = [1.13, 1.34], p < 0.00001), FAACT (RR = 7.81, 95%CI = [6.12, 9.50], p < 0.00001), PG-SGA (MD = -2.16, 95%CI = [-2.65, -1.67], p < 0.00001) and QOL (MD = 5.76, 95%CI = [4.04, 7.48], p < 0.00001), suggesting that HMs or HMs combined with conventional treatment have an ameliorating effect on cachexia in each respect. Subgroup analysis showed that the five HMs with the best effect on improving KPS and their optimal doses were Coicis Semen (Yiyiren) in 10 g group, Citri Reticulatae Pericarpium (Chenpi) in 15 g group, Dioscoreae Rhizoma (Shanyao) in 10 g group, Ophiopogonis Radix (Maidong) in 10 g group and Ginseng Radix Et Rhizoma (Renshen) in 20 g group. In addition, there were HM combinations of levels 2-6. Egger's test showed publication bias for five outcomes. HMs have a significant effect on improving cancer cachexia on FAACT, TCM syndrome, KPS, QOL, appetite, nutritional status (evaluated by PG-SGA scale), weight, levels of albumin and haemoglobin. And the Adverse events rate is less than that of Western Medicine. The herbs with the best curative effect and their optimal dose were Dioscoreae R. (10 g), Citri R.P. (15 g), Coicis S. (10 g), Ophiopogonis R. (10 g) and Ginseng R.E.R. (20 g). Due to the quality of included studies is not high, further high-quality studies are needed to firmly establish the clinical efficacy of HM.

Immunomodulatory potential of natural products from herbal medicines as immune checkpoints inhibitors: Helping to fight against cancer via multiple targets.

Immunotherapy sheds new light to cancer treatment and is satisfied by cancer patients. However, immunotoxicity, single-source antibodies, and single-targeting stratege are potential challenges to the success of cancer immunotherapy. A huge number of promising lead compounds for cancer treatment are of natural origin from herbal medicines. The application of natural products from herbal medicines that have immunomodulatory properties could alter the landscape of immunotherapy drastically. The present study summarizes current medication for cancer immunotherapy and discusses the potential chemicals from herbal medicines as immune checkpoint inhibitors that have a broad range of immunomodulatory effects. Therefore, this review provides valuable insights into the efficacy and mechanism of actions of cancer immunotherapies, including natural products and combined treatment with immune checkpoint inhibitors, which could confer an improved clinical outcome for cancer treatment.

Lysyl Oxidase-Like 4 Fosters an Immunosuppressive Microenvironment During Hepatocarcinogenesis.

BACKGROUND AND AIMS: Lysyl oxidase-like 4 (LOXL4) is an amine oxidase that is primarily involved in extracellular matrix remodeling and is highly expressed in HCC tissues, but its functional role in mediating liver carcinogenesis is poorly understood. Therefore, we aimed to investigate the role of LOXL4 in hepatocarcinogenesis. APPROACH AND RESULTS: Here, we demonstrate that hepatic LOXL4 expression was increased during the liver carcinogenesis in mice concomitantly fed a choline-deficient, l-amino acid-defined diet. LOXL4 was secreted by the neoplastic cells and primarily localized within hepatic macrophages through exosome internalization. Supplementation of LOXL4 had minimal effect on neoplastic cells. In vitro exposure of macrophages to LOXL4 invoked an immunosuppressive phenotype and activated programmed death ligand 1 (PD-L1) expression, which further suppressed the function of CD8+ T cells. Injection of LOXL4 promoted macrophages infiltration into the liver and accelerated tumor growth, which was further abolished by adoptive T-cell transfer or PD-L1 neutralization. Label-free proteomics analysis revealed that the immunosuppressive function of LOXL4 on macrophages primarily relied on interferon (IFN)-mediated signal transducer and activator of transcription-dependent PD-L1 activation. Hydrogen peroxide scavenger or copper chelation on macrophages abolished the IFN-mediated PD-L1 presentation by LOXL4. In human HCC tissue, expression of LOXL4 in CD68+ cells was positively correlated with PD-L1 level. High expression of LOXL4 in CD68+ cells and low expression of CD8A in tumor tissue cooperatively predict poor survival of patients with HCC. CONCLUSIONS: LOXL4 facilitates immune evasion by tumor cells and leads to hepatocarcinogenesis. Our study unveils the role of LOXL4 in fostering an immunosuppressive microenvironment during hepatocarcinogenesis.

Adjunctive berberine reduces antipsychotic-associated weight gain and metabolic syndrome in patients with schizophrenia: a randomized controlled trial.

AIM: The aim of this study was to evaluate the efficacy and safety of berberine as an adjuvant in treating antipsychotic-associated weight gain and metabolic syndrome. METHODS: One hundred thirteen participants with schizophrenia spectrum disorders who had developed metabolic syndrome were recruited. They were randomly assigned to berberine (600 mg/d, n = 58) or placebo (n = 55) groups for 12 weeks. The primary outcome was the change from baseline to week 12 in net weight. Secondary outcomes included body mass index, waist circumference, serum glucose and lipid profiles, and the severity of psychotic symptoms. RESULTS: Compared with the placebo group, the berberine group showed a significantly greater reduction in weight gain at 9 weeks (mean difference [MD], -0.75; 95% CI, -1.42 to -0.07 [P = 0.031, d = 0.41]) and 12 weeks (MD, -1.08; 95% CI, -1.76 to -0.40 [P = 0.002, d = 0.59]). Patients who received berberine also showed statistically significant improvements in end point in body mass index (MD, -0.41; 95% CI, -0.65 to -0.17 [P = 0.001, d = 0.64]), total cholesterol (MD, -0.58; 95% CI, -0.74 to -0.41 [P < 0.001, d = 1.31]), low-density lipoprotein (MD, -0.52; 95% CI, -0.68 to -0.35 [P < 0.001, d = 1.19]), and glycated hemoglobin (MD, -0.09; 95% CI, -0.18 to 0 [P = 0.05, d = 0.37]). Berberine was well tolerated without serious adverse events and aggravation of psychotic symptoms compared with placebo. CONCLUSION: The findings suggest that berberine is effective in attenuating antipsychotic-associated weight gain and metabolic syndrome.

Broad-spectrum antiviral activity of Spatholobus suberectus Dunn against SARS-CoV-2, SARS-CoV-1, H5N1, and other enveloped viruses.

The current COVID-19 pandemic caused by SARS-Cov-2 is responsible for more than 6 million deaths globally. The development of broad-spectrum and cost-effective antivirals is urgently needed. Medicinal plants are renowned as a complementary approach in which antiviral natural products have been established as safe and effective drugs. Here, we report that the percolation extract of Spatholobus suberectus Dunn (SSP) is a broad-spectrum viral entry inhibitor against SARS-CoV-1/2 and other enveloped viruses. The viral inhibitory activities of the SSP were evaluated by using pseudotyped SARS-CoV-1 and 2, HIV-1ADA and HXB2 , and H5N1. SSP effectively inhibited viral entry and with EC50 values ranging from 3.6 to 5.1 µg/ml. Pre-treatment of pseudovirus or target cells with SSP showed consistent inhibitory activities with the respective EC50 value of 2.3 or 2.1 µg/ml. SSP blocked both SARS-CoV-2 spike glycoprotein and the host ACE2 receptor. In vivo studies indicated that there was no abnormal toxicity and behavior in long-term SSP treatment. Based on these findings, we concluded that SSP has the potential to be developed as a drug candidate for preventing and treating COVID-19 and other emerging enveloped viruses.

Research Progress on the Therapeutic Effect of Polysaccharides on Non-Alcoholic Fatty Liver Disease through the Regulation of the Gut-Liver Axis.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease affecting global public health at present, which can induce cirrhosis and liver cancer in serious cases. However, NAFLD is a multifactorial disease, and there is still a lack of research on its mechanism and therapeutic strategy. With the development of the gut-liver axis theory, the association between the gut-liver axis and the pathogenesis of NAFLD has been gradually disclosed. Polysaccharides, as a kind of natural product, have the advantages of low toxicity, multi-target and multi-pathway action. It has been reported that polysaccharides can affect the gut-liver axis at multiple interrelated levels, such as maintaining the ecological balance of gut microbiota (GM), regulating the metabolites of GM and improving the intestinal barrier function, which thereby plays a protective role in NAFLD. These studies have great scientific significance in understanding NAFLD based on the gut-liver axis and developing safe and effective medical treatments. Herein, we reviewed the recent progress of polysaccharides in improving nonalcoholic fatty liver disease (NAFLD) through the gut-liver axis.

Potential Focal Adhesion Kinase Inhibitors in Management of Cancer: Therapeutic Opportunities from Herbal Medicine.

Focal adhesion kinase (FAK) is a multifunctional protein involved in cellular communication, integrating and transducing extracellular signals from cell-surface membrane receptors. It plays a central role intracellularly and extracellularly within the tumor microenvironment. Perturbations in FAK signaling promote tumor occurrence and development, and studies have revealed its biological behavior in tumor cell proliferation, migration, and adhesion. Herein we provide an overview of the complex biology of the FAK family members and their context-dependent nature. Next, with a focus on cancer, we highlight the activities of FAK signaling in different types of cancer and how knowledge of them is being used for screening natural compounds used in herbal medicine to fight tumor development.

Gallic Acid and Diabetes Mellitus: Its Association with Oxidative Stress.

Diabetes mellitus (DM) is a severe chronic metabolic disease with increased mortality and morbidity. The pathological progression of DM is intimately connected with the formation and activation of oxidative stress (OS). Especially, the involvement of OS with hyperglycemia, insulin resistance, and inflammation has shown a vital role in the pathophysiological development of DM and related complications. Interestingly, accumulating studies have focused on the exploration of natural antioxidants for their improvement on DM. Of specific interest is gallic acid (GA), which is rich in many edible and herbal plants and has progressively demonstrated robust antioxidative and anti-inflammatory effects on metabolic disorders. To provide a better understanding of its potential therapeutic impacts and enhancement of human health care, the available research evidence supporting the effective antidiabetic properties of GA and relevant derivatives are needed to be summarized and discussed, with emphasis on its regulation on OS and inflammation against DM. This review aims to highlight the latest viewpoints and current research information on the role of OS in diabetes and to provide scientific support for GA as a potential antihypoglycemic agent for DM and its complications.

Epigenetic regulation in human cancer: the potential role of epi-drug in cancer therapy.

Epigenetics is dynamic and heritable modifications to the genome that occur independently of DNA sequence. It requires interactions cohesively with various enzymes and other molecular components. Aberrant epigenetic alterations can lead to inappropriate onset of genetic expressions and promote tumorigenesis. As the epigenetic modifiers are susceptible to extrinsic factors and reversible, they are becoming promising targets in multiple cancer therapies. Recently, various epi-drugs have been developed and implicated in clinical use. The use of epi-drugs alone, or in combination with chemotherapy or immunotherapy, has shown compelling outcomes, including augmentation of anti-tumoral effects, overcoming drug resistance, and activation of host immune response.

Combination of Gentiana rhodantha and Gerbera anandria in the BL02 formula as therapeutics to non-small cell lung carcinoma acting via Rap1/cdc42 signaling: A transcriptomics/ bio-informatics biological validation approach.

BACKGROUND: Non-small cell lung cancer (NSCLC) ranks the most commonly diagnosed and highest mortality-leading cancer worldwide despite a variety of treatment strategies are available. The highly heterogeneous and aggressive property of NSCLC as well as its poor prognosis indicates the need for novel therapeutic targets identification. The objective of this study is to identify potential targets from the adjuvant herbal formula BL02 using a combined approach of high throughput transcriptomics and network pharmacology. METHODS: The quality and stability of BL02 were assessed by UHPLC analysis. The inhibitory effect of BL02 on NSCLC was measured by in vivo orthotopic intrathoracic mouse model and in vitro cellular models. EGFR-mutant HCC827 and wild type A549 cell lines were employed. Transcriptomics analysis was introduced to profile the gene expression of NSCLC cells treated with BL02; Network pharmacology and molecular docking analyses predicted the interaction of compounds and NSCLC targets. Immuno-blotting and pull-down assays verified the putative targets. RESULTS: The UHPLC analysis revealed that BL02 was relatively stable between batches of production and for 24 months of storage. Orally administration of BL02 was safe and effective to inhibit pulmonary NSCLC growth in mice implanted with A549 and HCC827-generated tumors. BL02 exhibited relatively low cytotoxicity to NSCLC cells in vitro, but potently suppressed NSCLC cell motility. The transcriptomic analysis illustrated that EGFR and cellular adhesion-related signaling is involved in BL02 action. Further bioinformatics analysis validated BL02 activity is mediated by cdc42-regulated signaling. BL02 depolymerized the actin cytoskeleton through suppressing cdc42 and deactivating its upstream molecule Rap1. These effects may be primarily mediated by the direct binding of 5-methylcoumarin-4-cellobioside and mangiferin from BL02 to Rap1 protein. CONCLUSION: Our study proposes an integration model of experimental, transcriptomic and bioinformatics analyses in the identification of novel therapeutic target of NSCLC from an adjuvant herbal formula BL02. Our findings revealed that inhibition of Rap1/cdc42 signaling by active compounds 5-methylcoumarin-4-cellobioside and mangiferin from BL02 might be potentially effective therapy for NSCLC.

Tumor microenvironment-driven non-cell-autonomous resistance to antineoplastic treatment.

Drug resistance is of great concern in cancer treatment because most effective drugs are limited by the development of resistance following some periods of therapeutic administration. The tumor microenvironment (TME), which includes various types of cells and extracellular components, mediates tumor progression and affects treatment efficacy. TME-mediated drug resistance is associated with tumor cells and their pericellular matrix. Noninherent-adaptive drug resistance refers to a non-cell-autonomous mechanism in which the resistance lies in the treatment process rather than genetic or epigenetic changes, and this mechanism is closely related to the TME. A new concept is therefore proposed in which tumor cell resistance to targeted therapy may be due to non-cell-autonomous mechanisms. However, knowledge of non-cell-autonomous mechanisms of resistance to different treatments is not comprehensive. In this review, we outlined TME factors and molecular events involved in the regulation of non-cell-autonomous resistance of cancer, summarized how the TME contributes to non-cell-autonomous drug resistance in different types of antineoplastic treatment, and discussed the novel strategies to investigate and overcome the non-cell-autonomous mechanism of cancer non-cell-autonomous resistance.

OMICs approaches-assisted identification of macrophages-derived MIP-1γ as the therapeutic target of botanical products TNTL in diabetic retinopathy.

BACKGROUND: Inflammatory reaction in the dysfunction of retinal endotheliocytes has been considered to play a vital role in diabetic retinopathy (DR). Anti-inflammatory therapy so far gains poor outcome as DR treatment. This study aims to identify a novel therapeutic target of DR from the OMICs studies of a traditional anti-DR botanical products TNTL. METHODS: Hyperglycemic mice were treated with TNTL. The anti-hyperglycemic effect of TNTL was validated to confirm the biological consistency of the herbal products from batches. Improvement of DR by TNTL was examined by various assays on the retina. Next-generation transcriptome sequencing and cytokine array was used to identify the therapeutic targets. In vitro study was performed to validate the target. RESULTS: We observed that TNTL at its high doses possessed anti-hyperglycemic effect in murine type I diabetic model, while at its doses without reducing blood glucose, it suppressed DR incidence. TNTL restored the blood-retina barrier integrity, suppressed retinal neovascularization, and attenuated the retinal ganglion cell degeneration. Transcriptomic analysis on the retina tissue of hyperglycemic mice with or without TNTL revealed that the inflammatory retina microenvironment was significantly repressed. TNTL treatment suppressed pro-inflammatory macrophages in the retina, which resulted in the inactivation of endothelial cell migration, restoration of endothelial cell monolayer integrity, and prevention of leakage. Cytokine array analysis suggested that TNTL could significantly inhibit the secretion of MIP1γ from pro-inflammatory macrophages. Prevention of endothelial dysfunction by TNTL may be mediated by the inhibition of MIP1γ/CCR1 axis. More specifically, TNTL suppressed MIP1γ release from pro-inflammatory macrophages, which in turn inhibited the activation of CCR1-associated signaling pathways in endothelial cells. CONCLUSION: Our findings demonstrated that TNTL might be an alternative treatment to DR, and the primary source of potential drug candidates against DR targeting MIP1γ/CCR1 axis in the retinal microenvironment.