[Guidelines for post-marketing research on clinical effectiveness of Chinese patent medicines].

Due to the lack of specialized guidance, the post-marketing research on clinical effectiveness of Chinese patent medicines demonstrates varied quality and lacks high-quality evidence, failing to meet the demands of policy-making, clinical decision-making, and industrial decision-making. To address this issue, this project gathered experts in clinical medicine, clinical pharmacy, evidence-based medicine, drug epidemiology, medical ethics, and policy and regulation in China. They referred to the model of international post-marketing research on medicines and developed Guidelines for post-marketing research on clinical effectiveness of Chinese patent medicines under the framework of relevant laws and regulations and technical guidance documents in China. The guidelines were developed with consideration to the characteristics of Chinese patent medicines, China's national conditions, and all the stakeholders including marketing authorization holders, clinical researchers, drug administration, and users. The development of the guidelines followed the requirements for developing group standards set by the China Association of Chinese Medicine. The guidelines fully implement the concept of full life-cycle research, emphasizing the combination of traditional Chinese medicine(TCM) theory, human use experience, and clinical trials and pay attention to the compliance, scientificity, and ethics of research. The guidelines clarify the topic selection and decision-making path of the post-marketing research on effectiveness of Chinese patent medicines through six steps: determining research purpose, analyzing drug characteristics, evaluating research basis, proposing clinical orientation, clarifying research purpose, and implementing classified research. The general principles of research design and implementation were clarified from eight aspects: research type, research objects, sample size, efficacy indicators, bias, missing data, evidence level, and practicality. It focuses on the research on the TCM syndrome-based efficacy evaluation, clinical value-oriented mechanism of action, and the effectiveness of Chinese patent medicines with different routes of administration. The guidelines provide a universal methodological basis for the post-marketing research on clinical effectiveness of Chinese patent medicines.

Glycyrrhizin and the Related Preparations: An Inspiring Resource for the Treatment of Liver Diseases.

Liver diseases and their related complications endanger the health of millions of people worldwide. The prevention and treatment of liver diseases are still serious challenges both in China and globally. With the improvement of living standards, the prevalence of metabolic liver diseases, including non-alcoholic fatty liver disease and alcoholic liver disease, has increased at an alarming rate, resulting in more cases of end-stage liver disease. Therefore, the discovery of novel therapeutic drugs for the treatment of liver diseases is urgently needed. Glycyrrhizin (GL), a triterpene glycoside from the roots of licorice plants, possesses a wide range of pharmacological and biological activities. Currently, GL preparations (GLPs) have certain advantages in the treatment of liver diseases, with good clinical effects and fewer adverse reactions, and have shown broad application prospects through multitargeting therapeutic mechanisms, including antisteatotic, anti-oxidative stress, anti-inflammatory, immunoregulatory, antifibrotic, anticancer, and drug interaction activities. This review summarizes the currently known biological activities of GLPs and their medical applications in the treatment of liver diseases, and highlights the potential of these preparations as promising therapeutic options and their alluring prospects for the treatment of liver diseases.

(-)-Asarinin alleviates gastric precancerous lesions by promoting mitochondrial ROS accumulation and inhibiting the STAT3 signaling pathway.

BACKGROUND: (-)-Asarinin (Asarinin) is the primary component in the extract of the herb Asarum sieboldii Miq. It possesses various functions, including pain relief, anti-viral and anti-tuberculous bacilli effects, and inhibition of tumor growth. Gastric precancerous lesion (GPL) is a common but potentially carcinogenic chronic gastrointestinal disease, and its progression can lead to gastric dysfunction and cancer development. However, the protective effects of asarinin against GPL and the underlying mechanisms remain unexplored. METHODS: A premalignant cell model (methylnitronitrosoguanidine-induced malignant transformation of human gastric epithelial cell strain, MC cells) and a GPL animal model were established and then were treated with asarinin. The cytotoxic effect of asarinin was assessed using a CCK8 assay. Detection of intracellular reactive oxygen species (ROS) using DCFH-DA. Apoptosis in MC cells was evaluated using an annexin V-FITC/PI assay. We performed western blot analysis and immunohistochemistry (IHC) to analyze relevant markers, investigating the in vitro and in vivo therapeutic effects of asarinin on GPL and its intrinsic mechanisms. RESULTS: Our findings showed that asarinin inhibited MC cell proliferation, enhanced intracellular ROS levels, and induced cell apoptosis. Further investigations revealed that the pharmacological effects of asarinin on MC cells were blocked by the ROS scavenger N-acetylcysteine. IHC revealed a significant upregulation of phospho-signal transducer and activator of transcription 3 (p-STAT3) protein expression in human GPL tissues. In vitro, asarinin exerted its pro-apoptotic effects in MC cells by modulating the STAT3 signaling pathway. Agonists of STAT3 were able to abolish the effects of asarinin on MC cells. In vivo, asarinin induced ROS accumulation and inhibited the STAT3 pathway in gastric mucosa of mice, thereby halting and even reversing the development of GPL. CONCLUSION: Asarinin induces apoptosis and delays the progression of GPL by promoting mitochondrial ROS production, decreasing mitochondrial membrane potential (MMP), and inhibiting the STAT3 pathway.

Synergistic inhibition effects of andrographolide and baicalin on coronavirus mechanisms by downregulation of ACE2 protein level.

The SARS-CoV-2 virus, belonging to the Coronavirus genus, which poses a threat to human health worldwide. Current therapies focus on inhibiting viral replication or using anti-inflammatory/immunomodulatory compounds to enhance host immunity. This makes the active ingredients of traditional Chinese medicine compounds ideal therapies due to their proven safety and minimal toxicity. Previous research suggests that andrographolide and baicalin inhibit coronaviruses; however, their synergistic effects remain unclear. Here, we studied the antiviral mechanisms of their synergistic use in vitro and in vivo. We selected the SARS-CoV-2 pseudovirus for viral studies and found that synergistic andrographolide and baicalein significantly reduced angiotensin-converting enzyme 2 protein level and viral entry of SARS-CoV-2 into cells compared to singal compound individually and inhibited the major protease activity of SARS-CoV-2. This mechanism is essential to reduce the pathogenesis of SARS-CoV-2. In addition, their synergistic use in vivo also inhibited the elevation of pro-inflammatory cytokines, including IL-6 and TNF-α-the primary cytokines in the development of acute respiratory distress syndrome (the main cause of COVID-19 deaths). In conclusion, this study shows that synergistic andrographolide and baicalein treatment acts as potent inhibitors of coronavirus mechanisms in vitro and in vivo-and is more effective together than in isolation.

Jin-Gui-Shen-Qi Wan alleviates fibrosis in mouse diabetic nephropathy via MHC class II.

ETHNOPHARMACOLOGICAL RELEVANCE: Jin-Gui-Shen-Qi Wan (JGSQW) is a traditional Chinese medicine formula that has been traditionally used to alleviate urinary system ailments such as frequent urination and polyuria. Clinical studies have indicated that when combined with hypoglycaemic drugs, JGSQW exhibits a synergistic effect and can improve diabetic nephropathy (DN), yet its underlying mechanism and targets remain unclear. AIM OF THE STUDY: This study aims to investigate the therapeutic efficacy of JGSQW and its underlying mechanisms using a DN db/db mouse model. MATERIALS AND METHODS: Ultrahigh-performance liquid chromatography coupled with mass spectrometry was utilized to analyse the primary active compounds, blood levels, and pharmacokinetics of JGSQW. Additionally, the therapeutic effects of JGSQW and metformin on blood glucose levels, lipid levels, renal function, and renal pathology in diabetic nephropathy mice were investigated using a db/db mouse model. Proteomic analysis was carried out to identify the primary target of JGSQW in treating DN. The mechanism of action was verified by western blotting, immunohistochemistry, and immunofluorescence. Then, molecular docking and molecular dynamics, transfection, drug affinity responsive target stability (DARTS) assay and cell thermal migration assay (CETSA) further validated the targeted binding effect. RESULTS: JGSQW combined with metformin significantly improved the blood glucose levels, blood lipids, renal function, and renal pathology of DN mice. JGSQW mainly exerted its therapeutic effect on DN by targeting major histocompatibility complex class II (MHC class II) molecules. Immunohistochemistry results showed that JGSQW inhibited the expression of collagen I, fibronectin, and alpha smooth muscle actin (α-SMA) expression. Immunofluorescence and Western blot results showed that JGSQW inhibited the expression of H2-Ab1 and H2-Aa, which are MHC class II molecules, thereby suppressing CD4+ T-cell infiltration and improving diabetic kidney fibrosis. The binding ability of paeoniflorin to H2-Aa was predicted and verified by molecular, DARTS, and CETSA assays. Treatment with 80 µM paeoniflorin effectively alleviated high glucose-induced injury in the MPC-5 injury model. H2-Aa was overexpressed at this model concentration, and Western blotting further confirmed that paeoniflorin reduced glomerular podocyte fibrosis by regulating H2-Aa. CONCLUSIONS: JGSQW combined with metformin may have a synergistic effect to alleviates renal fibrosis in diabetic nephropathy by downregulating immune complex MHC class II molecules and attenuating the antigen presentation effect of MHC class II on CD4.

Natural products for gastric carcinoma prevention and treatment: Focus on their antioxidant stress actions in the Correa's cascade.

BACKGROUND: Correa's cascade is a pathological process beginning from gastritis to gastric precancerous lesions, and finally to gastric carcinoma (GC). While the pathogenesis of GC remains unclear, oxidative stress plays a prominent role throughout the entire Correa's cascade process. Studies have shown that some natural products (NPs) could halt and even reverse the development of the Correa's cascade by targeting oxidative stress. METHODS: To review the effects and mechanism by which NPs inhibit the Correa's cascade through targeting oxidative stress, data were collected from PubMed, Embase, Web of Science, ScienceDirect, and China National Knowledge Infrastructure databases from initial establishment to April 2023. NPs were classified and summarized by their mechanisms of action. RESULTS: NPs, such as terpenoid, polyphenols and alkaloids, exert multistep antioxidant stress effects on the Correa's cascade. These effects include preventing gastric mucosal inflammation (stage 1), reversing gastric precancerous lesions (stage 2), and inhibiting gastric carcinoma (stage 3). NPs can directly impact the conversion of gastritis to GC by targeting oxidative stress and modulating signaling pathways involving IL-8, Nrf2, TNF-α, NF-κB, and ROS/MAPK. Among which polyphenols have been studied more and are of high research value. CONCLUSIONS: NPs display a beneficial multi-step action on the Correa's cascade, and have potential value for clinical application in the prevention and treatment of gastric cancer by regulating the level of oxidative stress.

Cell membrane-based biomimetic technology for cancer phototherapy: Mechanisms, recent advances and perspectives.

Despite significant advances in medical technology and antitumour treatments, the diagnosis and treatment of tumours have undergone remarkable transformations. Noninvasive phototherapy methods, such as photodynamic therapy (PDT) and photothermal therapy (PTT), have gained significant interest in antitumour medicine. However, traditional photosensitisers or photothermal agents face challenges like immune system recognition, rapid clearance from the bloodstream, limited tumour accumulation, and phototoxicity concerns. Researchers combine photosensitisers or photothermal agents with natural cell membranes to overcome these obstacles to create a nano biomimetic therapeutic platform. When used to coat nanoparticles, red blood cells, platelets, cancer cells, macrophages, lymphocytes, and bacterial outer membranes could provide prolonged circulation, tumour targeting, immune stimulation, or antigenicity. This article covers the principles of cellular membrane biomimetic nanotechnology and phototherapy, along with recent advancements in applying nano biomimetic technology to PDT, PTT, PCT, and combined diagnosis and treatment. Furthermore, the challenges and issues of using nano biomimetic nanoparticles in phototherapy are discussed. STATEMENT OF SIGNIFICANCE: Currently, there has been significant progress in the field of cell membrane biomimetic technology. Researchers are exploring its potential application in tumor diagnosis and treatment through phototherapy. Scholars have conducted extensive research on combining cell membrane technology and phototherapy in anticancer diagnosis and treatment. This review aims to highlight the mechanisms of phototherapy and the latest advancements in single phototherapy (PTT, PDT) and combination phototherapy (PCT, PRT, and PIT), as well as diagnostic approaches. The review provides an overview of various cell membrane technologies, including RBC membranes, platelet membranes, macrophage cell membranes, tumour cell membranes, bacterial membranes, hybrid membranes, and their potential for anticancer applications under phototherapy. Lastly, the review discusses the challenges and future directions in this field.

Gold-Crowned Bismuth-Based Nanocomposites for Sonodynamic, Photothermal, and Chemotherapeutic Cancer Therapy.

Conventional inorganic semiconductor nanoparticles have emerged as photothermal agents in photothermal therapy and as sonosensitizers in sonodynamic therapy. However, their weak drug-loading capabilities and the deficient techniques for multifunctional inorganic nanoparticles limit their applications. A bismuth-based gold-crowned nanocomposite (BACN) was rationally designed and successfully synthesized and could then be used to prepare nanoplatforms with excellent biocompatibilities for synergistic therapy and real-time imaging. Because of the constituent gold nanoparticles and pyridine, the nanoplatforms functioned as drug delivery vehicles, ultrasonically activated sonosensitizers, and photothermal agents. The BACNs exhibited excellent photothermal conversion efficiency (79.1%) in the second near-infrared biowindow (1064 nm). Cellular and mouse experiments demonstrated that under laser and ultrasound irradiation bufalin-loaded BACNs significantly reduced cancer cell counts and completely eradicated tumors, along with great therapeutic biosafety and no discernible recurrence. Additionally, BACNs were also used as contrast agents in computed tomography-photoacoustic imaging. The versatile BACN nanoplatform with multitreatment effects and trimodal imaging properties shows immense potential as an antitumor nanotherapeutic system.

Jin-Gui-Shen-Qi Wan ameliorates diabetic retinopathy by inhibiting apoptosis of retinal ganglion cells through the Akt/HIF-1α pathway.

BACKGROUND: Jin-Gui-Shen-Qi Wan (JGSQ) has been used in China for thousands of years to treat various ailments, including frequent urination, blurred vision, and soreness in the waist and knees. It has traditional therapeutic advantages in improving eye diseases. AIM OF THE STUDY: Clinical studies have confirmed the therapeutic efficacy of JGSQ in improving diabetes and vision; however, its efficacy and pharmacological effects in treating diabetic retinopathy (DR) remain unclear. Therefore, the aim of this study was to investigate the specific pharmacological effects and potential mechanisms of JGSQ in improving DR through a db/db model. MATERIALS AND METHODS: db/db mice were given three different doses of orally administered JGSQ and metformin for 8 weeks, and then PAS staining of the retinal vascular network patch, transmission electron microscopy, H&E staining, and TUNEL staining were performed to determine the potential role of JGSQ in improving DR-induced neuronal cell apoptosis. Furthermore, network pharmacology analysis and molecular docking were carried out to identify the main potential targets of JGSQ, and the efficacy of JGSQ in improving DR was evaluated through western blotting and immunofluorescence staining, revealing its mechanism of action. RESULTS: According to the results from H&E, TUNEL, and PAS staining of the retinal vascular network patch and transmission electron microscopy, JGSQ does not have an advantage in improving the abnormal morphology of vascular endothelial cells, but it has a significant effect on protecting retinal ganglion cells from apoptosis. Through network pharmacology and molecular docking, AKT, GAPDH, TNF, TP53, and IL-6 were identified as the main core targets of JGSQ. Subsequently, through western blot and immunofluorescence staining, it was found that JGSQ can inhibit HIF-1α, promote p-AKT expression, and inhibit TP53 expression. At the same time, inhibiting the release of inflammatory factors protects retinal ganglion cells and improves apoptosis in DR. CONCLUSION: These results indicated that in the db/db DR mouse model, JGSQ can inhibit the expression of inflammatory cytokines and protect retinal ganglion cells from apoptosis, possibly by modulating the Akt/HIF-1α pathway.

Chelerythrine chloride inhibits the progression of colorectal cancer by targeting cancer-associated fibroblasts through intervention with WNT10B/ß-catenin and TGFß2/Smad2/3 axis.

Chelerythrine chloride (CHE) is a benzodiazepine alkaloid derived from natural herbs with significant anti-tumor and anti-inflammatory activities. However, the exact role and underlying mechanisms of CHE in colorectal cancer (CRC) remain unclear. Therefore, this study is aimed to investigate the influence of CHE on the progression of CRC. Cell Counting Kit-8 assay (CCK-8), transwell, apoptosis rate, cell cycle distribution, reactive oxygen species (ROS), and colony formation determined the anti-proliferative activity of CHE in CRC cell lines. Transcriptome sequencing and western blot were used to explore the mechanism. Finally, H&E staining, Ki67, TUNEL, and immunofluorescence were conducted to verify the anti-CRC activity and potential mechanisms of CHE in vivo. CHE had a prominent inhibitory effect on the proliferation of CRC cells. CHE induces G1 and S phase arrest and induces cell apoptosis by ROS accumulation. Cancer-associated fibroblasts (CAFs) play a key role in CRC metastasis. Then, this study found that CHE regulates WNT10B/ß-catenin and TGFß2/Smad2/3 axis, thereby decreasing the expression of α-SMA, which is a maker of CAFs. Taken together, CHE is a candidate drug and a potent compound for metastatic CRC, which can intervene CAFs in a dual pathway to effectively inhibit the invasion and migration of cancer cells, which can provide a new choice for future clinical treatment.

Formation of a traditional Chinese medicine self-assembly nanostrategy and its application in cancer: a promising treatment.

Traditional Chinese medicine (TCM) has been used for centuries to prevent and treat a variety of illnesses, and its popularity is increasing worldwide. However, the clinical applications of natural active components in TCM are hindered by the poor solubility and low bioavailability of these compounds. To address these issues, Chinese medicine self-assembly nanostrategy (CSAN) is being developed. Many active components of TCM possess self-assembly properties, allowing them to form nanoparticles (NPs) through various noncovalent forces. Self-assembled NPs (SANs) are also present in TCM decoctions, and they are closely linked to the therapeutic effects of these remedies. SAN is gaining popularity in the nano research field due to its simplicity, eco-friendliness, and enhanced biodegradability and biocompatibility compared to traditional nano preparation methods. The self-assembly of active ingredients from TCM that exhibit antitumour effects or are combined with other antitumour drugs has generated considerable interest in the field of cancer therapeutics. This paper provides a review of the principles and forms of CSAN, as well as an overview of recent reports on TCM that can be used for self-assembly. Additionally, the application of CSAN in various cancer diseases is summarized, and finally, a concluding summary and thoughts are proposed. We strongly believe that CSAN has the potential to offer fresh strategies and perspectives for the modernization of TCM.

[Technical points of human use experience of ethnic medicine].

Ethnic medicine has a rich history of application. Because of the large number of ethnic groups, wide geographical distribution, and unique medical systems in China, the research on the human use experience(HUE) of ethnic medicine should combine the characteristics of ethnic medicine, be based on practical experience, and respect folk practice and tradition. The clinical positioning of ethnic medicine should consider three factors, i.e., population region, dominant diseases, and clinical demand. We should consider the development of traditional preparations that meet the needs of ethnic regions and encourage the development of new drugs that can be popularized and used nationwide for the dominant diseases of ethnic medicines. Attention should be paid to the problems such as a large number of customary articles or substitutes of ethnic medicinal materials, the phenomena of foreign bodies with the same name and different names for the same substance, the different standards of medicinal materials, and the poor processing standards. The name, processing method, source, medicinal parts, and dosage of ethnic medicinal materials or decoction pieces should be determined, and resources should be carefully evaluated to ensure the safety of medicinal resources and ecology. The preparation of ethnic medicine is mostly in the form of pills, powder, ointment, etc., with simple processing technology. The problems of low-quality stan-dards of some preparations, different prescriptions with the same name, and inconsistent processing technology should be overcome, and the process route and main process parameters should be clarified to lay the foundation for the subsequent empirical research on HUE. In the collection and analysis of the HUE data of ethnic medicine, the core guiding ideology of "patient-centered" should be established, and the experience data of patients should be collected. The problems of weak links existing in the inheritance of ethnic medicine should be solved, and flexible and diverse methods should be adopted. Meanwhile, on the premise of complying with the requirements of the principles of medical ethics, we should respect the religion, culture, and customs of ethnic areas to obtain the key HUE information of ethnic medicine. On the basis of the patient preference information and differences in regional disease epidemiology, population characteristics, and medical practice, whether the HUE conclusions of ethnic medicine can be extrapolated to patients outside the region is evaluated from the aspects of clinical benefits, risk tolerance, risk acceptance, etc. The HUE research on ethnic medicine is carried out in a clear way to guide the research and development of new ethnic medicines.

[Thoughts of treatment of tumor diseases based on toxic pathogen theory].

The toxic pathogen theory, an important part of the theories of traditional Chinese medicine(TCM), began in the Qin and Han dynasties, formed in the Jin, Sui, Tang, and Song dynasties, developed rapidly in the Ming and Qing dynasties, and conti-nued to develop in contemporary times based on the achievements of its predecessors. The continuous exploration, practice, and inheri-tance of many medical practitioners over the generations have facilitated the enrichment of its connotation. The toxic pathogen is violent, fierce, dangerous, prolonged, rapid in transmission, easy to hurt the internal organs, hidden, and latent, with many changes, and it is closely related to the development of tumor diseases. TCM has a history of thousands of years in the prevention and treatment of tumor diseases. It is gradually realized that the etiology of tumor is mainly attributed to the deficiency of healthy Qi and excess of to-xic pathogen, and the struggle between healthy Qi and toxic pathogen runs through the whole course of tumor, with the deficiency of healthy Qi as the prerequisite and the invasion of toxic pathogen as the root of the occurrence. The toxic pathogen has a strong carcinogenic effect and is involved in the whole process of tumor development, which is closely related to the malignant behaviors of tumors, including proliferation, invasion, and metastasis. This study discussed the historical origin and modern interpretation of the toxic pathogen theory in the prevention and treatment of tumors, with aims of sorting out the theoretical system based on the toxic pathogen theory in the treatment of tumor diseases, and illustrating the importance of the toxic pathogen theory in the treatment of tumors in the context of modern research on pharmacological mechanisms and the development and marketing of relevant anti-tumor Chinese medicinal preparations.

[CiteSpace knowledge map of research hotspots and frontiers of Polygalae Radix].

In this study, the Web of Science and China National Knowledge Infrastructure(CNKI) were searched comprehensively for the literature about the research on Polygalae Radix. After manual screening, 1 207 Chinese articles and 263 English articles were included in this study. Excel was used to draw the line chart of the annual number of relevant publications. CiteSpace 6.1.R3 was used for the visual analysis of author cooperation, publishing institutions, keyword co-occurrence, keyword clustering, and bursts in the research on Polygalae Radix. The results showed that the number of articles published in Chinese and English increased linearly, which indicated the rising research popularity of Polygalae Radix. WANG J and LIU X were the authors publishing the most articles in Chinese and English, respectively. Shanxi University of Chinese Medicine and Chinese Academy of Medical Sciences were the research institutions with the largest number of Chinese and English publications in this field, respectively. The institutions publishing the relevant articles in English formed a system with the Chinese Academy of Medical Sciences as the core. According to the keywords, the research hotspots of Polygalae Radix included variety selection and breeding, quality standard, extraction and identification of active chemical components, prescription compatibility, processing, clinical medication rules, and pharmacological mechanism. The research frontiers were the molecular mechanisms of Polygalae Radix and its active components in exerting the protective effect on brain nerve, regulating receptor pathways, alleviating anxiety and Alzheimer's disease, as well as data mining and clinical medication summary. This study has reference significance for the topic selection and frontier identification of the future research on Polygalae Radix.

[Guideline for clinical comprehensive evaluation of Chinese patent medicine (2022 version)].

Currently,the research or publications related to the clinical comprehensive evaluation of Chinese patent medicine are increasing,which attracts the broad attention of all circles. According to the completed clinical evaluation report on Chinese patent medicine,there are still practical problems and technical difficulties such as unclear responsibility of the evaluation organization,unclear evaluation subject,miscellaneous evaluation objects,and incomplete and nonstandard evaluation process. In terms of evaluation standards and specifications,there are different types of specifications or guidelines with different emphases issued by different academic groups or relevant institutions. The professional guideline is required to guide the standardized and efficient clinical comprehensive evaluation of Chinese patent medicine and further improve the authority and quality of evaluation. In combination with the characteristics of Chinese patent medicine and the latest research achievement at home and abroad,the detailed specifications were formulated from six aspects including design,theme selection,content and index,outcome,application and appraisal,and quality control. The guideline was developed based on the guideline development requirements of China Assoication of Chinese medicine. After several rounds of expert consensus and public consultation,the current version of the guideline has been developed.

Targeting lipid metabolism with natural products: A novel strategy for gastrointestinal cancer therapy.

Gastrointestinal cancer (GIC), including gastric cancer and colorectal cancer, is a common malignant tumor originating from gastrointestinal epithelial cells. Although the pathogenesis of GIC remains unclear, aberrant lipid metabolism has emerged as a hallmark of cancer. Several enzymes, proteins, and transcription factors are involved in lipid metabolism reprogramming in GIC, and their abnormal expression can promote lipid synthesis and accumulation of lipid droplets through numerous mechanisms, thereby affecting the growth, proliferation, and metastasis of GIC cells. Studies show that some natural compounds, including flavonoids, alkaloids, and saponins, can inhibit the de novo synthesis of lipids in GIC, reduce the level of lipid accumulation, and subsequently, inhibit the occurrence and development of GIC by regulating Sterol regulatory element-binding protein 1 (SREBP-1), adenosine monophosphate-activated protein kinase (AMPK), 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), phosphatidylinositol-3-kinase/Akt and the mammalian target of rapamycin PI3K/Akt/mTOR, amongst other targets and pathways. Therefore, targeting tumor lipid metabolism is the focus of anti-gastrointestinal tumor therapy. Although most natural products require further high-quality studies to firmly establish their clinical efficacy, we review the potential of natural products in the treatment of GIC and summarize the application prospect of lipid metabolism as a new target for the treatment of GIC, hoping to provide a reference for drug development for gastrointestinal tumors.

Gallic acid alleviates gastric precancerous lesions through inhibition of epithelial mesenchymal transition via Wnt/ß-catenin signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Gallic acid (GA) is a natural polyphenolic compound derived from Rhus chinensis Mill. with a variety of biological activities such as astringent sweat, cough, dysentery, hemostasis, and detoxification, and is widely used in China as a treatment for cough, bleeding, and gastrointestinal disorders. In recent years, the anticancer activity of GA has been demonstrated in a variety of cancers, affecting multiple cellular pathways associated with cancer onset, development and progression. AIM OF THE STUDY: To investigate the role and potential mechanism of GA on gastric precancerous lesions (GPL), the key turning point of gastritis to gastric cancer, with the aim of delaying, blocking or reversing the dynamic overall process of "inflammation-cancer transformation" and thus blocking GPL to prevent the development of gastric cancer. MATERIALS AND METHODS: In this study, we established N-Nitroso-N-methylurea (MNU)-induced GPL mice model and induced precancerous lesions of gastric cancer cells (MC), i.e. epithelial mesenchymal transition (EMT), in human gastric mucosal epithelial cells (GES-1) with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). We used conventional pathology, immunohistochemistry, RNA sequencing, Western blot and other techniques to study the therapeutic effect of GA on GPL and its possiblemechanism in vitro and in vivo. RESULTS: The results showed that compared with normal GES-1 cells, MC cells had the characteristics of malignant cells such as abnormal proliferation, invasion and metastasis, accompanied by decreased expression of EMT-related protein E-cadherin and increased expression of N-cadherin and Vimentin. GA can inhibit the malignant behavior of MC cell proliferation and induce its G0/G1 phase arrest, which is achieved by downregulating the Wnt/ß-catenin signaling pathway and thereby inhibiting the EMT process. However, when we incubated with the Wnt pathway activator (Wnt agonist 1), the effect of GA was reversed. Furthermore, analysis of human gastric specimens showed that activation of the Wnt/ß-catenin pathway was significantly associated with GPL pathological changes. Meanwhile, GA reversed MNU-induced intestinal metaplasia and partial dysplasia in GPL mice. CONCLUSION: Taken together, these results indicate that GA prevents the occurrence and development of GPL by inhibiting the Wnt/ß-catenin signaling pathway and then inhibiting the EMT process, which may become potential candidates for the treatment of GPL.

Berbamine dihydrochloride suppresses the progression of colorectal cancer via RTKs/Akt axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Berberis amurensis Rupr. is used to treat cancer as a traditional herbal medicine. Berbamine (BBM) is a natural bisbenzylisoquinoline alkaloid extracted from Berberis amurensis which possesses multiple pharmacological activity including anticancer. AIM OF THE STUDY: To investigate the influence of BBM on the progression of colorectal cancer (CRC) and further explore the underlying mechanism of BBM based on the RTKs/Akt signaling pathway. MATERIALS AND METHODS: In vitro, cell viability and colony formation were conducted to detect BBM inhibitory of CRC cell lines. Transwell was detected the ability of migration and invasion by BBM. Apoptosis detection assay, cell cycle assay and the measurement of ROS were detected to confirm the inductive effect of cell apoptosis. RT-qPCR and Western blot to clarify the specific mechanism of anticancer. Finally, we conducted HE staining, Ki67, Tunnel and immunochemistry were confirmed the anti-colorectal cancer activity of BBM from vivo study. RESULTS: We found that BBM could inhibit CRC cell lines growth. Moreover, BBM presented an inhibitory effect the ability of migration and invasion in CRC cells. Furthermore, the occurrence of apoptosis was involved in the anti-colorectal cancer role of BBM. BBM also triggered ROS accumulation in CRC cells that might be a key factor for the inductive effect of BBM in cell apoptosis. Cell cycle assay revealed that BBM induced the arrest of G1-S phase and increased the p21 levels but decreased CyclinE1, CyclinE2, CDK6, CyclinD1. RT-qPCR manifested that the down-regulation effect of BBM on AKT1, EGFR, PDGFRα and FGFR4 genes. The results also showed that BBM could decreased the expression levels of phosphor-AKT, PDGFRα, PDGFRß, EGFR, FGFR3 and FGFR4 which belong to RTKs family. Consistently, BBM remarkably suppressed tumor xenograft growth in nude mice. CONCLUSION: Taken together, all the results as presented above suggest that BBM as a novel multitargeted receptor tyrosine kinase inhibitor plays a crucial role in the inhibitory effect of CRC and may be a promising therapeutic agent for the CRC in clinic.

Targeting cancer stem cells and signalling pathways through phytochemicals: A promising approach against colorectal cancer.

BACKGROUND: Cancer stem cells (CSCs) are strongly associated with high tumourigenicity, chemotherapy or radiotherapy resistance, and metastasis and recurrence, particularly in colorectal cancer (CRC). Therefore, targeting CSCs may be a promising approach. Recently, discovery and research on phytochemicals that effectively target colorectal CSCs have been gaining popularity because of their broad safety profile and multi-target and multi-pathway modes of action. PURPOSE: This review aimed to elucidate and summarise the effects and mechanisms of phytochemicals with potential anti-CSC agents that could contribute to the better management of CRC. METHODS: We reviewed PubMed, EMBASE, Web of Science, Ovid, ScienceDirect and China National Knowledge Infrastructure databases from the original publication date to March 2022 to review the mechanisms by which phytochemicals inhibit CRC progression by targeting CSCs and their key signalling pathways. Phytochemicals were classified and summarised based on the mechanisms of action. RESULTS: We observed that phytochemicals could affect the biological properties of colorectal CSCs. Phytochemicals significantly inhibit self-renewal, migration, invasion, colony formation, and chemoresistance and induce apoptosis and differentiation of CSCs by regulating the Wnt/ß-catenin pathway (e.g., diallyl trisulfide and genistein), the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin pathway (e.g., caffeic acid and piperlongumine), the neurogenic locus notch homolog protein pathway (e.g., honokiol, quercetin, and α-mangostin), the Janus kinase-signal transducer and activator of transcription pathway (e.g., curcumin, morin, and ursolic acid), and other key signalling pathways. It is worth noting that several phytochemicals, such as resveratrol, silibinin, evodiamine, and thymoquinone, highlight multi-target and multi-pathway effects in restraining the malignant biological behaviour of CSCs. CONCLUSIONS: This review demonstrates the potential of targeted therapies for colorectal CSCs using phytochemicals. Phytochemicals could serve as novel therapeutic agents for CRC and aid in drug development.

Phytochemicals and mitochondria: Therapeutic allies against gastric cancer.

BACKGROUND: Mitochondria are the energy factories of cells with the ability to modulate the cell cycle, cellular differentiation, signal transduction, growth, and apoptosis. Existing drugs targeting mitochondria in cancer treatment have disadvantages of drug resistance and side effects. Phytochemicals, which are widely found in plants, are bioactive compounds that could facilitate the development of new drugs for gastric cancer. Studies have shown that some phytochemicals can suppress the development of gastric cancer. METHODS: We searched for data from PubMed, China National Knowledge Infrastructure, Web of Science, and Embase databases from initial establishment to December 2021 to review the mechanism by which phytochemicals suppress gastric cancer cell growth by modulating mitochondrial function. Phytochemicals were classified and summarized by their mechanisms of action. RESULTS: Phytochemicals can interfere with mitochondria through several mechanisms to reach the goal of promoting apoptosis in gastric cancer cells. Some phytochemicals, e.g., daidzein and tetrandrine promoted cytochrome c spillover into the cytoplasm by modulating the members of the B-cell lymphoma-2 protein family and induced apoptotic body activity by activating the caspase protein family. Phytochemicals (e.g., celastrol and shikonin) could promote the accumulation of reactive oxygen species and reduce the mitochondrial membrane potential. Several phytochemicals (e.g., berberine and oleanolic acid) activated mitochondrial apoptotic submission via the phosphatidylinositol-3-kinase/Akt signaling pathway, thereby triggering apoptosis in gastric cancer cells. Several well-known phytochemicals that target mitochondria, including berberine, ginsenoside, and baicalein, showed the advantages of multiple targets, high efficacy, and fewer side effects. CONCLUSIONS: Phytochemicals could target the mitochondria in the treatment of gastric cancer, providing potential directions and evidence for clinical translation. Drug discovery focused on phytochemicals has great potential to break barriers in cancer treatment.