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Abstract 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. Graphical Abstract

Abstract 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.

Age-related osteoporosis is a metabolic skeletal disorder caused by estrogen deficiency in postmenopausal women. Prolonged use of anti-osteoporotic drugs such as bisphosphonates and FDA-approved anti-resorptive selective estrogen receptor modulators (SERMs) has been associated with various clinical drawbacks. We recently discovered a low-molecular-weight biocompatible and osteoanabolic phytoprotein, called HKUOT-S2 protein (32 kDa), from Dioscorea opposita Thunb that can accelerate bone defect healing. Here, we demonstrated that the HKUOT-S2 protein treatment can enhance osteoblasts-induced ossification and suppress osteoporosis development by upregulating skeletal estrogen receptors (ERs) ERα, ERβ, and GPR30 expressions in vivo. Also, HKUOT-S2 protein estrogenic activities promoted hMSCs-osteoblasts differentiation and functions by increasing osteogenic markers, ALP, and RUNX2 expressions, ALP activity, and osteoblast biomineralization in vitro. Fulvestrant treatment impaired the HKUOT-S2 protein-induced ERs expressions, osteoblasts differentiation, and functions. Finally, we demonstrated that the HKUOT-S2 protein could bind to ERs to exert osteogenic and osteoanabolic properties. Our results showed that the biocompatible HKUOT-S2 protein can exert estrogenic and osteoanabolic properties by positively modulating skeletal estrogen receptor signaling to promote ossification and suppress osteoporosis. Currently, there is no or limited data if any, on osteoanabolic SERMs. The HKUOT-S2 protein can be applied as a new osteoanabolic SERM for osteoporosis treatment.

The intricate interplay between the gut microbiome and colorectal cancer (CRC) presents novel avenues for early diagnosis and prognosis, crucial for improving patient outcomes. This comprehensive review synthesizes current findings on the gut microbiome’s contribution to CRC pathogenesis, highlighting its potential as a biomarker for non-invasive CRC screening strategies. We explore the mechanisms through which the microbiome influences CRC, including its roles in inflammation, metabolism, and immune response modulation. Furthermore, we assess the viability of microbial signatures as predictive tools for CRC prognosis, offering insights into personalized treatment approaches. Our analysis underscores the necessity for advanced metagenomic studies to elucidate the complex microbiome-CRC nexus, aiming to refine diagnostic accuracy and prognostic assessment in clinical settings. This review propels forward the understanding of the microbiome’s diagnostic and prognostic capabilities, paving the way for microbiome-based interventions in CRC management.

Abstract 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.

Abstract Background Par-3 Family Cell Polarity Regulator (PARD3) is a cellular protein essential for asymmetric cell division and polarized growth. This study aimed to study the role of PARD3 in hepatic tumorigenesis. Methods The essential role of PARD3 in mediating hepatic tumorigenesis was assessed in diet-induced spontaneous liver tumour and syngeneic tumour models. The mechanism of PARD3 was delineated by bulk and single-cell RNA sequencing. The clinical significance of PARD3 was identified by tissue array analysis. Results PARD3 was overexpressed in tumour tissues and PARD3 overexpression was positively correlated with high tumour stage as well as the poor prognosis in patients. In models of spontaneous liver cancer induced by choline-deficient, amino acid-defined (CDAA) and methionine-choline-deficient (MCD) diets, upregulation of PARD3 was induced specifically at the tumorigenesis stage rather than other early stages of liver disease progression. Site-directed knockout of PARD3 using an adeno-associated virus 8 (AAV8)-delivered CRISPR/Cas9 single-guide RNA (sgRNA) plasmid blocked hepatic tumorigenesis, while PARD3 overexpression accelerated liver tumour progression. In particular, single-cell sequencing analysis suggested that PARD3 was enriched in primitive tumour cells and its overexpression enhanced tumour-initiating cell (TICs). Overexpression of PARD3 maintained the self-renewal ability of the CD133+ TIC population within hepatocellular carcinoma (HCC) cells and promoted the in vitro and in vivo tumorigenicity of CD133+ TICs. Transcriptome analysis revealed that Sonic Hedgehog (SHH) signalling was activated in PARD3-overexpressing CD133+ TICs. Mechanistically, PARD3 interacted with aPKC to further activate SHH signalling and downstream stemness-related genes. Suppression of SHH signalling and aPKC expression attenuated the in vitro and in vivo tumorigenicity of PARD3-overexpressing CD133+ TICs. Tissue array analysis revealed that PARD3 expression was positively associated with the phosphorylation of aPKC, SOX2 and Gli1 and that the combination of these markers could be used to stratify HCC patients into two clusters with different clinicopathological characteristics and overall survival prognoses. The natural compound berberine was selected as a potent suppressor of PARD3 expression and could be used as a preventive agent for liver cancer that completely blocks diet-induced hepatic tumorigenesis in a PARD3-dependent manner. Conclusion This study revealed PARD3 as a potential preventive target of liver tumorigenesis via TIC regulation.

Cachexia is a late consequence of various diseases that is characterized by systemic muscle loss, with or without fat loss, leading to significant mortality. Multiple signaling pathways and molecules that increase catabolism, decrease anabolism, and interfere with muscle regeneration are activated. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play vital roles in cachexia muscle atrophy. This review mainly provides the mechanisms of specific ncRNAs to regulate muscle loss during cachexia and discusses the role of ncRNAs in cachectic biomarkers and novel therapeutic strategies that could offer new insights for clinical practice.

Objective:Diabetic retinopathy (DR) is a severe diabetic complication that leads to severe visual impairment or blindness. He-Ying-Qing-Re formula (HF), a traditional Chinese medicinal concoction, has been identified as an efficient therapy for DR with retinal vascular dysfunction for decades and has been experimentally reported to ameliorate retinal conditions in diabetic mice. This study endeavors to explore the therapeutic potential of HF with key ingredients in DR and its underlying novel mechanisms.Methods:Co-expression gene modules and hub genes were calculated by weighted gene co-expression network analysis (WGCNA) based on transcriptome sequencing data from high-glucose-treated adult retinal pigment epithelial cell line-19 (ARPE-19). The chromatographic fingerprint of HF was established by ultra-performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC-Q-TOF-MS). The molecular affinity of the herbal compound was measured by molecular docking. Reactive oxygen species (ROS) was measured by a DCFDA/H2DCFDA assay. Apoptosis was detected using the TUNEL Assay Kit, while ELISA, Western blot, and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used for detecting the cytokine, protein, and mRNA expressions, respectively.Results:Key compounds in HF were identified as luteolin, paeoniflorin, and nobiletin. For WGCNA, ME-salmon (“protein deacetylation”) was negatively correlated with ME-purple (“oxidative impairment”) in high-glucose-treated ARPE-19. Luteolin has a high affinity for SIRT1 and P53, as indicated by molecular docking. Luteolin has a hypoglycemic effect on type I diabetic mice. Moreover, HF and luteolin suppress oxidative stress production (ROS and MDA), inflammatory factor expression (IL-6, TNF-α, IL1-β, and MCP-1), and apoptosis, as shown in the in vivo and in vitro experiments. Concurrently, treatment with HF and luteolin led to an upregulation of SIRT1 and a corresponding downregulation of P53.Conclusion:Using HF and its active compound luteolin as therapeutic agents offers a promising approach to diabetic retinopathy treatment. It primarily suppressed protein acetylation and oxidative stress via the SIRT1/P53 pathway in retinal pigment epithelial cells.

Introduction: Hyperactivated histone deacetylases (HDACs) act as epigenetic repressors on gene transcription and are frequently observed in human hepatocellular carcinoma (HCC). Although multiple pharmacological HDAC inhibitors (HDACis) have been developed, none is available in human HCC. Objectives: To investigate the pharmacological effects of a fangchinoline derivative HL23, as a novel HDACi and its molecular mechanisms through TXNIP-mediated potassium deprivation in HCC. Methods: Both in vitro assays and orthotopic HCC mouse models were used to investigate the effects of HL23 in this study. The inhibitory activity of HL23 on HDACs was evaluated by in silico studies and cellular assays. Chromatin immunoprecipitation (ChIP) was conducted to confirm the regulation of HL23 on acetylation mark at TXNIP promoter. Genome-wide transcriptome analysis together with bioinformatic analysis were conducted to identify the regulatory mechanisms of HL23. The clinical significance of TXNIP and HDACs was evaluated by analysing publicly available database. Results: HL23 exerted compatible HDACs inhibition potency as Vorinostat (SAHA) while had superior anti-HCC effects than SAHA and sorafenib. Both in vitro and in vivo studies showed HL23 significantly suppressed HCC progression and metastasis. HL23 significantly upregulated TXNIP expression via regulating acetylation mark (H3K9ac) at TXNIP promoter. TXNIP was responsible for anti-HCC activity of HL23 through mediating potassium channel activity. HDAC1 was predicted to be the target of HL23 and HDAC1lowTXNIPhigh could jointly predict promising survival outcome of patients with HCC. Combination treatment with HL23 and sorafenib could significantly enhance sorafenib efficacy. Conclusion: Our study identified HL23 as a novel HDACi through enhancing acetylation at TXNIP promoter to trigger TXNIP-dependent potassium deprivation and enhance sorafenib efficacy in HCC treatment.

Introduction: The incidence of diabetic retinopathy (DR) has been found to be associated with the risk of developing Alzheimer‘s disease (AD). In addition to the common properties of neurodegeneration, their progressions are involved with abnormal vascular functions. However, the interactions between them have not been fully understood. This study aimed to investigate the key factor for the underlying interactions and shared signaling pathways in the vasculature of DR and AD.Methods: We retrieved single-cell RNA sequencing (scRNA-seq) data regarding human fibrovascular membrane (FVM) of proliferative diabetic retinopathy (PDR) and human hippocampus vessels of AD from the NCBI-GEO database. GSEA analysis was performed to analyze AD-related genes in endothelial cells and pericytes of PDR. CellChat was used for predicting cell-cell communication and the signaling pathway.Results: The data suggested that amyloid-beta precursor protein (APP) signaling was found crucial in the vasculature of PDR and AD. Endothelial cells and pericytes could pose influences on other cells mainly via APP signaling in PDR. The endothelial cells were mainly coordinated with macrophages in the hippocampus vasculature of AD via APP signaling. The bulk RNA-seq in mice with PDR validated that the expression of APP gene had a significant correlation with that of the AD genome-wide association studies (GWAS) gene.Discussion: Our study demonstrates that the vasculopathy of PDR and AD is likely to share a common signaling pathway, of which the APP-related pathway is a potential target.

Tumor microenvironment contributes to poor prognosis of pancreatic adenocarcinoma (PAAD) patients. Proper regulation could improve survival. Melatonin is an endogenous hormone that delivers multiple bioactivities. Here we showed that pancreatic melatonin level is associated with patients' survival. In PAAD mice models, melatonin supplementation suppressed tumor growth, while blockade of melatonin pathway exacerbated tumor progression. This anti-tumor effect was independent of cytotoxicity but associated with tumor-associated neutrophils (TANs), and TANs depletion reversed effects of melatonin. Melatonin induced TANs infiltration and activation, therefore induced cell apoptosis of PAAD cells. Cytokine arrays revealed that melatonin had minimal impact on neutrophils but induced secretion of Cxcl2 from tumor cells. Knockdown of Cxcl2 in tumor cells abolished neutrophil migration and activation. Melatonin-induced neutrophils presented an N1-like anti-tumor phenotype, with increased neutrophil extracellular traps (NETs) causing tumor cell apoptosis through cell-to-cell contact. Proteomics analysis revealed that this reactive oxygen species (ROS)-mediated inhibition was fueled by fatty acid oxidation (FAO) in neutrophils, while FAO inhibitor abolished the anti-tumor effect. Analysis of PAAD patient specimens revealed that CXCL2 expression was associated with neutrophil infiltration. CXCL2, or TANs, combined with NET marker, can better predict patients’ prognosis. Collectively, we discovered an anti-tumor mechanism of melatonin through recruiting N1-neutrophils and beneficial NET formation.

For hundreds of years, the drug discovery and development industry has aimed at identifying single components with a clear mechanism of action as desirable candidates for potential drugs. However, this conventional strategy of drug discovery and development has faced challenges including a low success rate and high development costs. Herein, we critically review state-of-the-art drug discovery and development based on multi-component Chinese medicine formulas. We review the policies and application status of new drugs based on multi-component Chinese medicines in the US, China, and the European Union. Moreover, we illustrate several excellent cases of ongoing applications. Biomedical technologies that may facilitate drug discovery and development based on multi-component Chinese medicine formulas are discussed, including network pharmacology, integrative omics, CRISPR gene editing, and chemometrics. Finally, we discuss potential problems and solutions in pre-clinical and clinical research in drug discovery and development based on multi-component Chinese medicine formulas. We hope that this review will promote discussion of the roles of multi-component Chinese medicine formulas in the discovery and development of new drugs for the treatment of human diseases.

Rheumatoid arthritis (RA) is a type of chronic autoimmune and inflammatory disease. In the pathological process of RA, the alteration of fibroblast-like synoviocyte (FLS) and its related factors is the main influence in the clinic and fundamental research. In RA, FLS exhibits a uniquely aggressive phenotype, leading to synovial hyperplasia, destruction of the cartilage and bone, and a pro-inflammatory environment in the synovial tissue for perpetuation and progression. Evidently, it is a highly promising way to target the pathological function of FLS for new anti-RA drugs. Based on this, we summed up the pathological mechanism of RA-FLS and reviewed the recent progress of small molecule drugs, including the synthetic small molecule compounds and natural products targeting RA-FLS. In the end, there were some views for further action. Compared with MAPK and NF-κB signaling pathways, the JAK/STAT signaling pathway has great potential for research as targets. A small number of synthetic small molecule compounds have entered the clinic to treat RA and are often used in combination with other drugs. Meanwhile, most natural products are currently in the experimental stage, not the clinical trial stage, such as triptolide. There is an urgent need to unremittingly develop new agents for RA.

Gastric cancer (GC) is the fifth most common cancer worldwide. Cuproptosis is associated with cell growth and death as well as tumorigenesis. Aiming to lucubrate the potential influence of CRGs in gastric cancer, we acquired datasets of gastric cancer patients from TCGA and GEO. The identification of molecular subtypes with CRGs expression was achieved through unsupervised learning-cluster analysis. To evaluate the application value of subtypes, the K-M survival analysis was conducted to evaluate the clinical prognostic characteristics. Subsequently, we performed Gene Set Variation Analysis (GSVA) and utilized ssGSEA to quantify the extent of immune infiltration. Further, the K-M survival analysis was used to identify the prognosis-related CRGs. Next, signature genes of diagnostic predictive value were screened using the least absolute shrinkage and selection operator (LASSO) algorithm from the expression matrix for TCGA, as well as the signature gene-related subtype was clustered by the “ConsensusClusterPlus” package. Finally, the immunological and drug sensitivity assessments of the signature gene-related subtypes were conducted. A total of 173 CRGs were identified, most of the CRGs undergo copy number variation in gastric cancer. Under different patient subtypes, immune cell levels differed significantly, and the subtype exhibiting high expression of the CRGs had a better prognosis. Furthermore, we selected 34 CRGs that were highly correlated with the prognosis of gastric cancer. By constructing a multivariate Cox proportional-hazards model and a hazard scoring system, we were able to categorize patients into high- and low-risk groups based on their hazard score. K-M analysis demonstrated a significant survival disadvantage in the high-risk group. Based on Lasso regression analysis, we screened 16 signature genes, a multivariate logistic regression model [cutoff: 0.149 (0.000, 0.974), AUC:0.987] and a prognosis network diagram was constructed and their prediction efficiency for gastric cancer prognostic diagnosis was well validated. According to the signature genes, the patients were separated to two signature subtypes. We found that patients with higher CRGs expression and better prognosis had lower levels of immune infiltration. Finally, according to the results of drug susceptibility analysis, docetaxel, 5-Fluorouracil, gemcitabin, and paclitaxel were found to be more sensitive to gastric cancer.

Hepatobiliary diseases have a high prevalence worldwide, with a wide range of diseases involved in the liver and biliary system. Modifications in gut microbiota have been proven to have an association with unbalanced intestinal homeostasis and the dysfunction of host metabolism and the immune system, which can be the risk factors for many hepatobiliary diseases, such as nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), nonalcoholic fatty steatohepatitis (NASH), hepatitis, cirrhosis, hepatocellular carcinoma (HCC) and cholestasis, as well as infection due to liver transplantation. Probiotics are commonly used gut microbiota-targeted strategies to treat dysbiosis and intestinal dysfunction, as well as the gut–liver axis, which can enhance the effectiveness of probiotics in the management of liver diseases. Recent studies have explored more potential single or mixed strains of probiotics, and bioinformatics methods can be used to investigate the potential mechanisms of probiotics on liver diseases. In this review, we summarize the preclinical and clinical studies on the role of probiotics in hepatobiliary diseases from 2018 to 2023, revealing the possible mechanism of probiotics in the treatment of hepatobiliary diseases and discussing the limitations of probiotics in treating hepatobiliary diseases. This review provides updated evidence for the development of probiotic products, exploration of new probiotic strains, and support for clinical studies. Further studies should focus on the safety, viability, and stability of probiotics, as well as medication dosage and duration in clinical practice.

Abstract Background Drug resistance to sorafenib greatly limited the benefits of treatment in patients with hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) participate in the development of drug resistance. The key miRNA regulators related to the clinical outcome of sorafenib treatment and their molecular mechanisms remain to be identified. Methods The clinical significance of miRNA-related epigenetic changes in sorafenib-resistant HCC was evaluated by analyzing publicly available databases and in-house human HCC tissues. The biological functions of miR-23a-3p were investigated both in vitro and in vivo. Proteomics and bioinformatics analyses were conducted to identify the mechanisms that regulating miR-23a-3p. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were used to validate the binding relationship of miR-23a-3p and its targets. Results We found that miR-23a-3p was the most prominent miRNA in HCC, which was overexpressed in sorafenib non-responders and indicated poor survival and HCC relapse. Sorafenib-resistant cells exhibited increased miR-23a-3p transcription in an ETS Proto-Oncogene 1 (ETS1)-dependent manner. CRISPR-Cas9 knockout of miR-23a-3p improved sorafenib response in HCC cells as well as orthotopic HCC tumours. Proteomics analysis suggested that sorafenib-induced ferroptosis was the key pathway suppressed by miR-23a-3p with reduced cellular iron accumulation and lipid peroxidation. MiR-23a-3p directly targeted the 3′-untranslated regions (UTR) of ACSL4, the key positive regulator of ferroptosis. The miR-23a-3p inhibitor rescued ACSL4 expression and induced ferrotoptic cell death in sorafenib-treated HCC cells. The co-delivery of ACSL4 siRNA and miR-23a-3p inhibitor abolished sorafenib response. Conclusion Our study demonstrates that ETS1/miR-23a-3p/ACSL4 axis contributes to sorafenib resistance in HCC through regulating ferroptosis. Our findings suggest that miR-23a-3p could be a potential target to improve sorafenib responsiveness in HCC patients.

Diabetic nephropathy (DN) has been recognized as a severe complication of diabetes mellitus and a dominant pathogeny of end-stage kidney disease, which causes serious health problems and great financial burden to human society worldwide. Conventional strategies, such as renin-angiotensin-aldosterone system blockade, blood glucose level control, and bodyweight reduction, may not achieve satisfactory outcomes in many clinical practices for DN management. Notably, due to the multi-target function, Chinese medicine possesses promising clinical benefits as primary or alternative therapies for DN treatment. Increasing studies have emphasized identifying bioactive compounds and molecular mechanisms of reno-protective effects of Chinese medicines. Signaling pathways involved in glucose/lipid metabolism regulation, antioxidation, anti-inflammation, anti-fibrosis, and podocyte protection have been identified as crucial mechanisms of action. Herein, we summarize the clinical efficacies of Chinese medicines and their bioactive components in treating and managing DN after reviewing the results demonstrated in clinical trials, systematic reviews, and meta-analyses, with a thorough discussion on the relative underlying mechanisms and molecular targets reported in animal and cellular experiments. We aim to provide comprehensive insights into the protective effects of Chinese medicines against DN.

Gastric, liver, and colorectal cancers belong to gastrointestinal (GI) cancers, one of the most threatening diseases in the world. The tonics class in Chinese medicines plays a critical role in antigastrointestinal cancer as adjuvants. However, it is a challenge to study the effects and underlying mechanisms of tonics due to their multiple components and multiple targets; OMICs were introduced to facilitate the investigation of the complex mixture of tonics. In this review, the online databases PubMed, ProQuest, Web of Knowledge, China National Knowledge Infrastructure (CNKI), Chongqing VIP, and Wanfang were retrieved from 1 January 2011 to 31 May 2022, in an aim to summarize and discuss the research progress of the effects and, especially, the underlying mechanisms of tonics for antigastrointestinal cancers via OMICs. The results showed that through the combination of OMICs and other technologies, tonics have been used for gastrointestinal cancer by targeting cancer hallmarks, enhancing body resistance to carcinogenesis, enhancing therapeutic effects, and/or decreasing side effects. In conclusion, tonics may play a promising role in gastric, liver, and colorectal cancers as adjuvants and can be well investigated via the combination of OMICs and other technologies, which deserves further study.

PI3K/Akt, an essential signaling pathway widely present in cells, has been shown to be relevant to neurological disorders. As an important class of natural products, terpenoids exist in large numbers and have diverse backbones, so they have a great chance to be identified as neuroprotective agents. In this review, we described and summarized recent research for a range of terpenoid natural products associated with the PI3K/Akt pathway by classifying their basic chemical structures of the terpenes, identified by electronic searches on PubMed, Web of Science for research, and Google Scholar websites. Only articles published in English were included. Our discussion here concerned 16 natural terpenoids and their mechanisms of action, the associated diseases, and the methods of experimentation used. We also reviewed the discovery of their chemical structures and their derivatives, and some compounds have been concluded for their structure–activity relationships (SAR). As a result, terpenoids are excellent candidates for research as natural neuroprotective agents, and our content will provide a stepping stone for further research into these natural products. It may be possible for more terpenoids to serve as neuroprotective agents in the future.

Background: Premna Puberula Pamp. Pectin (PP) was a Wudang functional food in China. It has the effect of dispelling fire, clearing heat and detoxification in folk medicine. However, little studies have been reported for their preparation, quality control, effects and toxicity. Methods: The P. Puberula leaves were collected from different pharms and seasons. The compounds in PP were identified using UPLC-Q-TOF-MS/MS. UV-VIS spectrophotometry with phenol-sulfuric acid and sodium nitrite aluminum nitrate were conducted for analyzing the water-soluble sugars and total flavonoids, respectively. L9(34) orthogonal experimental method was used to optimize the preparation process of PP. For the pharmacological effects of PP, the swelling right hind paw of ICR mice was modeled using subcutaneous injection of carrageenan gum solution, and the local tissue inflammatory reactions of the model mice were investigated using vernier calipers and HE staining. The serum inflammatory factor expression was detected using ELISA. The acute toxicity experiments were carried out for safety assessment of PP in ICR mice. Results: Fifty-three compounds were initially identified in PP among which flavonoids were dominant (19 out of 53). The average values of water-soluble sugar content and total flavonoid content of PP were 13.366 and 4.970 mg/g, respectively. The best preparation process of PP was powder-liquid ratio 1: 20, temperature 90 °C, and stirring time 3 min. Data showed that PP reduced paw edema and decrease the serum level of IL-6, TNF-α and IL-1β in the model mice. There was no toxic effect of PP on mice at a total dose of 6000 mg/kg/24h. Conclusion: In summary, by optimizing the preparation process, PP with stable quality can be obtained. PP has anti-inflammatory effects without toxicity.

Abstract Aconitum carmichaeli Debx.-derived herbal medicine has been used for anti-inflammation and anti-arrhythmia purpose for more than two thousand years. It is processed into Chuanwu (Radix Aconiti praeparata) and Fuzi (Radix Aconiti lateralis praeparata) in Traditional Chinese Medicine, which are two useful drugs but with toxic properties. There have been patients poisoned by accidental ingestion of Aconitum plants or misuse of the herbal drug, and this is of great concern to study in-depth. In this review, we provided the traditional and contemporary practice of using Aconitum herbs as medicine, from functions, processing methods to toxicity in ethnomedicine aspects to discuss the underlying connections of traditional and modern understanding on the toxicity of Aconitum plants. We summarized the functions and toxicology of the herbal drugs are analyzed from chemical and clinical aspects, with the help of traditional and modern knowledge of medicine. The medicinal doses and lethal doses determined by researches are summarized, and the usage and processing methods are updated and reviewed in the modern view. In addition, clinical management of poisoned cases using western medicine is discussed. This review provides insights and awareness of safety when using Aconitum-derived herbal medicine, and the application of modern scientific knowledge to optimize the detoxification processes. We suggest the possibility to renew the current standard processing method from the official Pharmacopoeia all over the world.

Primary liver cancer (PLC) is one of the most common malignant tumors in China. PLC is characterized by insidious onset, rapid progress, poor quality of life, and short survival time. Notably, current treatment strategies remain unsatisfactory. Traditional Chinese medicines (TCM) have been used to treat a variety of diseases, including liver diseases, for more than 2000 years. In this study, we performed a review of the use frequency and clinical efficacy of TCM in treating PLC. Relevant literature from January 1, 2009, to January 1, 2021 was retrieved from network databases of China National Knowledge Infrastructure (CNKI), Chongqing VIP, Wanfang, PubMed, and SinoMed. The most frequently used TCM and their efficacy in PLC treatment were summarized. Based on the inclusion and exclusion criteria, 33 articles were selected. Overall, the efficacy of the combination of TCM and Western medicines in the treatment of PLC was higher than that in the control groups (i.e. treatment with Western medicines alone) (65.11% vs. 44.31%, P

Gastrointestinal cancer (GIC), primarily including colorectal cancer, gastric cancer, liver cancer, pancreatic cancer, and esophageal cancer, is one of the most common causes of cancer-related deaths with increasing prevalence and poor prognosis. Medicinal plants have been shown to be a great resource for the treatment of GIC. Due to their complex manifestations of multi-component and multi-target, the underlying mechanisms how they function against GIC remain to be completely deciphered. Cell metabolism is of primary importance in the initialization and development of GIC, which is reported to be a potential target. As an essential supplement to the newest “omics” sciences, metabolomics focuses on the systematic study of the small exogenous and endogenous metabolites involved in extensive biochemical metabolic pathways of living system. In good agreement with the systemic perspective of medicinal plants, metabolomics offers a new insight into the efficacy assessment and action mechanism investigation of medicinal plants as adjuvant therapeutics for GIC therapy. In this review, the metabolomics investigations on metabolism-targeting therapies for GIC in the recent 10 years were systematically reviewed from five aspects of carbohydrate, lipid, amino acid, and nucleotide metabolisms, as well as other altered metabolisms (microbial metabolism, inflammation, and oxidation), with particular attention to the potential of active compounds, extracts, and formulae from medicinal plants. Meanwhile, the current perspectives and future challenges of metabolism-targeting therapies of medicinal plants for GIC were also discussed. In conclusion, the understanding of the action mechanisms of medicinal plants in GIC from the metabolomics perspective will contribute to the clinical application of potential candidates from the resourceful medicinal plants as novel and efficient adjuvant therapeutics for GIC therapy.

Introduction: The demanding nature of medical and health sciences studies can cause stress among students in these disciplines affecting their wellbeing and academic performance. The Perceived Stress Scale (PSS-10) is a widely used measure of perceived stress among medical students and healthcare professionals that has not yet been validated among medical and health sciences students in Hong Kong. The aim of this study is to establish the construct validity and reliability of the PSS-10 in this context. Methods: 267 final year medical and health sciences students were surveyed using the PSS-10. The data were analysed using exploratory factor analysis for construct validity and Cronbach’s alpha coefficient and corrected item-total correlations for reliability. Results: Exploratory factor analysis revealed a two-factor structure for PSS-10, with Cronbach’s alpha of 0.865 and 0.796, indicating good internal consistency. Corrected item-total correlations showed satisfactory correlation ranged from 0.539 to 0.748 for all items and their respective subscale. Both tests supported PSS-10 as a two-factor scale. Conclusion: The PSS-10 is a valid measure for assessing perceived stress in Hong Kong medical and health sciences students.

Abstract Altered energy metabolism of cancer cells shapes the immune cell response in the tumor microenvironment that facilitates tumor progression. Herein, we reported the novel of tumor cell-expressed Piwi Like RNA-Mediated Gene Silencing 1 (PIWIL1) in mediating the crosstalk of fatty acid metabolism and immune response of human hepatocellular carcinoma (HCC). PIWIL1 expression in HCC was increased compared to normal hepatic tissues and was positively correlated with the proliferation rate of HCC cell lines. PIWIL1 overexpression accelerated in vitro proliferation and in vivo growth of HCC tumors, while PIWIL1 knockdown showed opposite effects. PIWIL1 increased oxygen consumption and energy production via fatty acid metabolism without altering aerobic glycolysis. Inhibition of fatty acid metabolism abolished PIWIL1-induced HCC proliferation and growth. RNA-seq analysis revealed that immune system regulation might be involved, which was echoed by the experimental observation that PIWIL1-overexpressing HCC cells attracted myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment. MDSCs depletion reduced the proliferation and growth of PIWIL1-overexpressing HCC tumors. Complement C3, whose secretion was induced by PIWIL1 in HCC cells, mediates the interaction of HCC cells with MDSCs by activated p38 MAPK signaling in MDSCs, which in turn initiated expression of immunosuppressive cytokine IL10. Neutralizing IL10 secretion reduced the immunosuppressive activity of MDSCs in the microenvironment of PIWIL1-overexpressing HCC. Taken together, our study unraveled the critical role of PIWIL1 in initiating the interaction of cancer cell metabolism and immune cell response in HCC. Tumor cells-expressed PIWIL1 may be a potential target for the development of novel HCC treatment.

BackgroundGlypican 2 (GPC2), a member of glypican (GPC) family genes, produces proteoglycan with a glycosylphosphatidylinositol anchor. It has shown its ascending significance in multiple cancers such as neuroblastoma, malignant brain tumor, and small-cell lung cancer. However, no systematic pan-cancer analysis has been conducted to explore its function in diagnosis, prognosis, and immunological prediction.MethodsBy comprehensive use of datasets from The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), Genotype-Tissue Expression Project (GTEx), cBioPortal, Human Protein Atlas (HPA), UALCAN, StarBase, and Comparative Toxicogenomics Database (CTD), we adopted bioinformatics methods to excavate the potential carcinogenesis of GPC2, including dissecting the correlation between GPC2 and prognosis, gene mutation, immune cell infiltration, and DNA methylation of different tumors, and constructed the competing endogenous RNA (ceRNA) networks of GPC2 as well as explored the interaction of GPC2 with chemicals and genes.ResultsThe results indicated that GPC2 was highly expressed in most cancers, except in pancreatic adenocarcinoma, which presented at a quite low level. Furthermore, GPC2 showed the early diagnostic value in 16 kinds of tumors and was positively or negatively associated with the prognosis of different tumors. It also verified that GPC2 was a gene associated with most immune-infiltrating cells in pan-cancer, especially in thymoma. Moreover, the correlation with GPC2 expression varied depending on the type of immune-related genes. Additionally, GPC2 gene expression has a correlation with DNA methylation in 20 types of cancers.ConclusionThrough pan-cancer analysis, we discovered and verified that GPC2 might be useful in cancer detection for the first time. The expression level of GPC2 in a variety of tumors is significantly different from that of normal tissues. In addition, the performance of GPC2 in tumorigenesis and tumor immunity also confirms our conjecture. At the same time, it has high specificity and sensitivity in the detection of cancers. Therefore, GPC2 can be used as an auxiliary indicator for early tumor diagnosis and a prognostic marker for many types of tumors.

Abstract Background Chinese Medicine education is part of professional medical training in Hong Kong. An important element of this is herbal medicine, which requires both theoretical and practical knowledge. A field trip programme was adopted to provide students with direct experience of medicinal plants studied in lectures. However, problems with the current programme were identified in learning outcome assessment and long-term knowledge management. To improve the teaching quality, a Moodle e-learning module was designed for augmentation. This study aimed to quantitatively evaluate the effectiveness of the Moodle module in supplementing the current field trip programme. Methods Prospective quasi-experiment. Participants were 49 year-2 students in the Bachelor of Chinese Medicine programme. A Moodle module including five online activities regarding two groups of herbal plants was integrated before and after the field trip. Fill-in-the-blank questions were used to assess the learning outcome. Also, a questionnaire was developed to collect student feedback as the secondary outcome. Results For herbal plants in Group A, the assessment score was higher in Moodle group (29.65 ± 5.0) than for the control group (21.65 ± 6.5) (P

Abstract Background 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is an active compound derived from Polygonum multiflorum Thunb., a Chinese Taoist herbal medicine, which exerts lipid lowering, anti-cancer, anti-aging, anti-inflammatory and hepatoprotective effects. However, its role in protecting hepatocytes under pre-diabetic condition remains unclear. Methods In this study, we developed prediabetic SD rats by feeding high-fat and high-sugar diet. The body weight, blood lipid, blood glucose, and fasting insulin (FINS) and insulin resistance index (HOMA-IR) were detected and calculated to assess the potential risk of prediabetes. HE and Oil Red O staining was used, and blood level of biochemical index was detected to observe the liver injury. The autophagic cell death-associated signaling proteins, and the potential signaling factors p-Akt/Akt and p-Erk/Erk were detected using western blot to explore the potential effects of TSG on pre-diabetic liver and the underlying mechanisms. Results The results showed that the body weight in TSG-treated group was significantly decreased vs. the model group. The blood glucose, the level of FINS and HOMA-IR, TC and TG were decreased in TSG-treated group as well. Furthermore, TSG treatment significantly ameliorated lipid droplet accumulation, enhanced liver anti-oxidative response which may be associated with an increased activity of SOD and GSH-Px, and a decrease of LDLC and MDA. The autophagic cell death-associated proteins, p-AMPK, ATG12, LC3 II, and Beclin 1 were up-regulated in the TSG-treated group, while the upstream signaling pathway, PI3K/Akt and Erk, were activated. Conclusions TSG induced liver autophagic cell death to protect liver from prediabetic injury by activating PI3K/Akt and Erk. Graphical abstract

Abstract 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.

Hepatocellular carcinoma (HCC) remains a global medical problem. Programmed cell death protein 1 (PD-1) is a powerful weapon against many cancers, but it is not sensitive to some patients with HCC. We obtained datasets from the Gene Expression Omnibus (GEO) database on HCC patients and PD-1 immunotherapy to select seven intersecting DEGs. Through Lasso regression, two intersecting genes were acquired as predictors of HCC and PD-1 treatment prognosis, including HAMP and FOS. Logistic regression was performed to build a prediction model. HAMP had a better ability to diagnose HCC and predict PD1 treatment sensitivity. Further, we adapted the support vector machine (SVM) technique using HAMP to predict triple-classified outcomes after PD1 treatment in HCC patients, which had an excellent classification ability. We also performed external validation using TCGA data, which showed that HAMP was elevated in the early stage of HCC. HAMP was positively correlated with the infiltration of 18 major immune cells and the expression of 2 important immune checkpoints, PDCD1 and CTLA4. We discovered a biomarker that can be used for the early diagnosis, prognosis and PD1 immunotherapy efficacy prediction of HCC for the first time and developed a diagnostic model, prognostic model and prediction model of PD1 treatment sensitivity and treatment outcome for HCC patients accordingly.

BackgroundCOVID-19, caused by SARS-CoV-2 virus, is a global pandemic with high mortality and morbidity. Limited diagnostic methods hampered the infection control. Since the direct detection of virus mainly by RT-PCR may cause false-negative outcome, host response-dependent testing may serve as a complementary approach for improving COVID-19 diagnosis.ObjectiveOur study discovered a highly-preserved transcriptional profile of Type I interferon (IFN-I)-dependent genes for COVID-19 complementary diagnosis.MethodsComputational language R-dependent machine learning was adopted for mining highly-conserved transcriptional profile (RNA-sequencing) across heterogeneous samples infected by SARS-CoV-2 and other respiratory infections. The transcriptomics/high-throughput sequencing data were retrieved from NCBI-GEO datasets (GSE32155, GSE147507, GSE150316, GSE162835, GSE163151, GSE171668, GSE182569). Mathematical approaches for homological analysis were as follows: adjusted rand index-related similarity analysis, geometric and multi-dimensional data interpretation, UpsetR, t-distributed Stochastic Neighbor Embedding (t-SNE), and Weighted Gene Co-expression Network Analysis (WGCNA). Besides, Interferome Database was used for predicting the transcriptional factors possessing IFN-I promoter-binding sites to the key IFN-I genes for COVID-19 diagnosis.ResultsIn this study, we identified a highly-preserved gene module between SARS-CoV-2 infected nasal swab and postmortem lung tissue regulating IFN-I signaling for COVID-19 complementary diagnosis, in which the following 14 IFN-I-stimulated genes are highly-conserved, including BST2, IFIT1, IFIT2, IFIT3, IFITM1, ISG15, MX1, MX2, OAS1, OAS2, OAS3, OASL, RSAD2, and STAT1. The stratified severity of COVID-19 may also be identified by the transcriptional level of these 14 IFN-I genes.ConclusionUsing transcriptional and computational analysis on RNA-seq data retrieved from NCBI-GEO, we identified a highly-preserved 14-gene transcriptional profile regulating IFN-I signaling in nasal swab and postmortem lung tissue infected by SARS-CoV-2. Such a conserved biosignature involved in IFN-I-related host response may be leveraged for COVID-19 diagnosis.

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.

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.

Type-2 diabetes mellitus (T2DM) and therapy options have been studied increasingly due to their rising incidence and prevalence. The trend of applying traditional Chinese medicine (TCM) to treat T2DM is increasing as a crucial medical care for metabolic dysfunctions. Gegen Qinlian decoction (GQL), a well-known classical TCM formula used in China, has been clinically applied to treat various types of chronic metabolic diseases. However, antidiabetic effects of GQL administration during T2DM have never been studied systematically. We assessed physiological and molecular targets associated with therapeutic effects of GQL by evaluating network topological characteristics. The GQL-related biological pathways are closely associated with antidiabetic effects, including the TNF and PI3K–AKT signaling pathways. Associated primary biological processes such as RNA polymerase II promoter transcription participate in the inflammatory response, oxidative stress reduction, and glucose metabolic process, thereby exerting multiple biological effects on the antidiabetic mechanism. Furthermore, our results showed that GQL can affect blood glycemic levels and ameliorate inflammatory symptoms, and liver and pancreas tissue injury in high-fat diet plus streptozotocin-induced diabetic mice. In vivo and in vitro experiments confirmed that antidiabetic effects of GQL were associated with a modulation of the TNF and PI3K–AKT–MTOR pathways.

Background: The mental health of international students studying abroad has been neglected during the COVID-19 pandemic.Objective: This mixed-method study examined perceived public attitudes, personal beliefs, practice and stress toward facemask wearing as a preventive measure against COVID-19 among international University students from Hong Kong studying in the United Kingdom (UK) in the early stage (January–March 2020) of the pandemic.Methods: Our study included 2 parts: (i) an exponential, non-discriminative snowball sampling strategy was used to recruit 91 Chinese students studying in the UK to complete an online questionnaire survey, and (ii) online Zoom focus group interviews were conducted with 16 students who completed the online survey to gain an in-depth understanding of their experiences and coping methods during the pandemic.Results: Of the 91 students, 92.3% reported the UK public did not view facemask wearing as a preventive measure. 98.9% believed facemask wearing was an effective preventive measure, but 56% wore facemasks more than half of the time when out in public. 50.5% had internal conflicts of stress both when wearing and not wearing facemasks, which was more common in females than males [(62.5 vs. 31.5%), P = 0.004, Relative Risk (RR): 1.99 (1.17, 3.38)]. 61.5% reported public prejudiced attitudes against facemask wearing, also more common in females than males (71.4 vs. 45.7%), P = 0.02, RR: 1.56 (1.05, 2.32). The qualitative findings corroborated with the quantitative findings and reported that peer and family support were important for them to face such difficulties, and positive thinking and adaptability were effective methods on stress management.Conclusions: Since the outbreak of COVID-19, Chinese international students have been faced with a difficult, confusing, and sensitive situation. Owing to the ongoing pandemic, rising xenophobia and racist behaviors and the resumption of students' studies studies in the U.K., support from global communities are needed in their pursuit of quality education overseas. Our findings have significant implications on the proactive roles that governments should have, and the need for clear and accurate public health messaging to change public attitudes and mitigate prejudice. Academic institutions and mental health professionals need to proactively provide additional support to Chinese international students.

Abstract Background Pancreatic adenocarcinoma (PAAD) a highly lethal malignancy. The current use of clinical parameters may not accurately predict the clinical outcome, which further renders the unsatisfactory therapeutic outcome. Methods In this study, we retrospectively analyzed the clinical‐pathological characteristics and prognosis of 253 PAAD patients. Univariate, multivariate, and Kaplan‐Meier survival analyses were conducted to assess risk factors and clinical outcomes. For functional study, we performed bidirectional genetic manipulation of lactate dehydrogenase A (LDHA) in PAAD cell lines to measure PAAD progression by both in vitro and in vivo assays. Results LDHA is particularly overexpressed in PAAD tissues and elevated serum LDHA‐transcribed isoenzymes‐5 (LDH‐5) was associated with poorer patients’ clinical outcomes. Genetic overexpression of LDHA promoted the proliferation and invasion in vitro, and tumor growth and metastasis in vivo in murine PAAD orthotopic models, while knockdown of LDHA exhibited opposite effects. LDHA‐induced L‐lactate production was responsible for the LDHA‐facilitated PAAD progression. Mechanistically, LDHA overexpression reduced the phosphorylation of metabolic regulator AMPK and promoted the downstream mTOR phosphorylation in PAAD cells. Inhibition of mTOR repressed the LDHA‐induced proliferation and invasion. A natural product berberine was selected as functional inhibitor of LDHA, which reduced activity and expression of the protein in PAAD cells. Berberine inhibited PAAD cells proliferation and invasion in vitro, and suppressed tumor progression in vivo. The restoration of LDHA attenuated the suppressive effect of berberine on PAAD. Conclusions Our findings suggest that LDHA may be a novel biomarker and potential therapeutic target of human PAAD.

Abstract 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.

Abstract 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.

In recent years, replacing internal combustion engine vehicles with electric vehicles has been a significant option for supporting reducing carbon emissions because of fossil fuel shortage and environmental contamination. However, the rapid growth of electric vehicles (EVs) can bring new and uncertain load conditions to the electric network. Precise load forecasting for EV charging stations becomes vital to reduce the negative influence on the grid. To this end, a novel day-ahead load forecasting method is proposed to forecast loads of EV charging stations with Bayesian deep learning techniques. The proposed methodological framework applies long short-term memory (LSTM) network combined with Bayesian probability theory to capture uncertainty in forecasting. Based on the actual operational data of the EV charging station collected on the Caltech campus, the experiment results show the superior performance of the proposed method compared with other methods, indicating significant potential for practical applications.

Anthraquinones are bioactive natural products, some of which are active components in medicinal medicines, especially Chinese medicines. These compounds exert actions including purgation, anti-inflammation, immunoregulation, antihyperlipidemia, and anticancer effects. This study aimed to review the pharmacokinetics (PKs) of anthraquinones, which are importantly associated with their pharmacological and toxicological effects. Anthraquinones are absorbed mainly in intestines. The absorption rates of free anthraquinones are faster than those of their conjugated glycosides because of the higher liposolubility. A fluctuation in blood concentration and two absorption peaks of anthraquinones may result from the hepato-intestinal circulation, reabsorption, and transformation. Anthraquinones are widely distributed throughout the body, mainly in blood-flow rich organs and tissues, such as blood, intestines, stomach, liver, lung, kidney, and fat. The metabolic pathways of anthraquinones are hydrolysis, glycuronidation, sulfation, methylation/demethylation, hydroxylation/dehydroxylation, oxidation/reduction (hydrogenation), acetylation and esterification by intestinal flora and liver metabolic enzymes, among which hydrolysis, glycuronidation and sulfation are dominant. Of note, anthraquinones can be transformed into each other. The main excretion routes for anthraquinones are the kidney, recta, and gallbladder. Conclusion: Some anthraquinones and their glycosides, such as aloe-emodin, chrysophanol, emodin, physcion, rhein and sennosides, have attracted the most PK research interest due to their more biological activities and/or detectability. Anthraquinones are mainly absorbed in the intestines and are mostly distributed in blood flow-rich tissues and organs. Transformation into another anthraquinone may increase the blood concentration of the latter, leading to an increased pharmacological and/or toxicological effect. Drug-drug interactions influencing PK may provide insights into drug compatibility theory to enhance or reduce pharmacological/toxicological effects in Chinese medicine formulae and deserve deep investigation.

Background: The outbreak of the pandemic coronavirus disease 2019 (COVID-19) has now become a global pandemic spreading throughout the world. Unfortunately, due to the high infectiousness of the novel β-coronavirus, it is very likely to become an ordinary epidemic. The development of dietary supplements and functional foods might provide a strategy for the prevention and management of COVID-19.Scope and Approach: A great diversity of potential edible and medicinal plants and/or natural compounds showed potential benefits in managing SARS, which may also combat COVID-19. Moreover, many plants and compounds have currently been proposed to be protective against COVID-19. This information is based on data-driven approaches and computational chemical biology techniques. In this study, we review promising candidates of edible and medicinal plants for the prevention and management of COVID-19. We primarily focus on analyzing their underlying mechanisms. We aim to identify dietary supplements and functional foods that assist in managing this epidemic.Key findings and Conclusion: We infer that acetoside, glyasperin, isorhamnetin, and several flavonoid compounds may prevent and/or be effective in managing COVID-19 by targeting the viral infection, reducing the host cytokine storm, regulating the immune response, and providing organ protection. These bioactive dietary components (used either alone or in combination) might assist in the development of dietary supplements or functional foods for managing COVID-19.

Purpose: Chemotherapy-induced gastrointestinal (CIGI) toxicity affects the quality of life of patients with colorectal cancer (CRC) and the clinical application of treatment drugs. This review aims to evaluate the efficacy of traditional herbal medicines (HMs) in alleviating symptoms of CIGI toxicity (including nausea and vomiting, anorexia, diarrhea, constipation, oral mucositis, abdominal pain, and abdominal distension), and to explore further individual herb or herbal combinations in alleviating the CIGI toxicity.Methods: Nine electronic databases were screened from 2010 to 2020. Twenty-two randomized controlled trials with a total of 1,995 patients evaluating the complementary efficacy of HMs with chemotherapy compared with chemotherapy-alone were included. Further, sensitivity analyses of orally administered multi-ingredient HM interventions were explored based on the composition of HM interventions.Results: The meta-analysis showed that HM treatment combined with chemotherapy significantly alleviated the overall CIGI toxicity (RR = 0.78 [0.72, 0.84], p < 0.001, I2 = 44%), nausea and vomiting (RR = 0.74 [0.66, 0.82], p < 0.001, I2 = 35%), diarrhea (P = 0.02, RR = 0.64, 95% CI = 0.44–0.93, I2 = 50%), oral mucositis (RR = 0.65 [0.48, 0.88], P = 0.005, I2 = 24%), and abdominal distension (RR = 0.36 [0.18, 0.73], P = 0.004, I2 = 0%). However, no statistically significant effects of HMs were shown in studies with a double-blind design for CIGI toxicity. Based on the ingredients of the HMs, further sensitivity analyses identified five herbs [Glycyrrhiza uralensis Fisch., Atractylodes macrocephala Koidz., Astragalus membranaceus (Fisch.) Bge., Codonopsis pilosula (Franch.) Nannf., and the pericarp of Citrus reticulata Blanco.] that were associated with significant reductions in CIGI toxicity.Conclusion: A statistically significant effect of HMs combined with chemotherapy on alleviating the overall CIGI toxicity, nausea and vomiting, diarrhea, oral mucositis, or abdominal distension is only shown in studies without a double-blind design. Further well-designed, double-blinded, large-scaled randomized controlled trials (RCTs) are warranted to comprehensively evaluate the treatment efficacy. Further clinical research that includes the five herbs with chemotherapy for patients, the safety of the combinations of these herbs, and the potential synergistic effects of these combinations of herbs should be conducted.

BackgroundChemotherapy usually induces a variety of side-effects in cancer treatment as it cannot tell normal cells apart from cancer cells and kills both. Chinese herbal medicine (CHM) has been regarded as a potential effective intervention for relieving the side-effects of chemotherapy in breast cancer patients.ObjectiveThis study aims to conduct a comprehensive systematic review and meta-analysis to evaluate the efficacy of CHM as adjuvant therapy for reducing the chemotherapy-induced side-effects in the treatment of breast cancer.MethodsMain electronic databases were searched up to May 2020 for Randomized Controlled Trials (RCTs) evaluating the effect of CHM on breast cancer patients with chemotherapy. The PRISMA statement was adopted in this study and meta-analyses were performed.ResultsThe included studies showed unsatisfied quality. Results based on available literature indicated that the adjunctive use of CHM with chemotherapy may reduce the chemotherapeutic agents-associated adverse events, including nausea and vomiting, diarrhea, alopecia, myelosuppression, and impaired immune function.ConclusionA confident conclusion could not be have due to the lack of large scale and high quality trials.

Non-alcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease without effective therapy. Selenium, as an essential trace element for humans, is notable for its antioxidant properties. The previous study shows that selenium levels in NAFLD patients are lower than normal ones. Selenium supplementation can effectively alleviate metabolic disorders by relieving anti-oxidative stress and anti-inflammatory regulation. However, the correlation between selenium and NAFLD has not been fully clarified. Herein, we review the current studies on selenium in regulating the different stages of NAFLD and summarize relevant clinical trials to highlight the potential roles of selenium in NAFLD treatment.

Background: The coronavirus disease 2019 (COVID-19) pandemic has disrupted university teaching globally. The mental health impacts on international university students have been overlooked.Aims: This study examined the differences in COVID-19-related stressors and mental health impacts between international university students studying in the UK or USA who returned to their home country or region (returnees) and those who stayed in their institution country (stayers), and identified COVID-19-related stressors and coping strategies that were predictors of mental health.Method: An online questionnaire survey was conducted from April 28 through May 12, 2020 using an exponential, non-discriminative snowball sampling strategy (registered at the National Institutes of Health: NCT04365361).Results: A total of 124 full-time international university students (36.3% male) were included: 75.8% had returned to their home country or region for reasons related to COVID-19; 77.4% were pursuing a bachelor's program, and 53.2% were in programs with practicum component. 84.7% of all students had moderate-to-high perceived stress, 12.1% had moderate-to-severe symptoms of anxiety and depression, and 17.7% had moderate-to-severe symptoms of insomnia. Compared with returnees, stayers had significantly higher stress from COVID-19-related stressors such as personal health and lack of social support (Cohen's d: 0.57–1.11), higher perceived stress [10-item Perceived Stress Scale (PSS-10)] {22.6 ± 6.2 vs. 19.1 ± 6.1, β [95% confidence interval (CI)]: 4.039 (0.816, 7.261), Cohen's d: 0.52}, and more severe insomnia symptoms [Insomnia Severity Index (ISI)] [11.8 ± 6.1 vs. 7.6 ± 5.2, β (95% CI): 3.087 (0.262, 5.912), Cohen's d: 0.45], with moderate-to-large effect sizes. Compared with males, females reported significantly higher stress from uncertainties about academic program (Cohen's d: 0.45) with a small effect size. In the total sample, stress related to academics (e.g., personal attainment, uncertainties about academic program, and changes in teaching/learning format), health (including personal health and health of family and friends), availability of reliable COVID-19-related information, and lack of social support predicted more negative mental health impacts. Resilience, positive thinking, and exercise were predictors of less severe mental health impacts.Conclusions: Stayers experienced more adverse mental health impacts than returnees. We call on educators and mental health professionals to provide appropriate support for international students, particularly the stayers, during the pandemic.