Chemotherapy-induced gastrointestinal toxicity: Pathogenesis and current management.

Chemotherapy is the most common treatment for malignant tumors. However, chemotherapy-induced gastrointestinal toxicity (CIGT) has been a major concern for cancer patients, which reduces their quality of life and leads to treatment intolerance and even cessation. Nevertheless, prevention and treatment for CIGT are challenging, due to the prevalence and complexity of the condition. Chemotherapeutic drugs directly damage gastrointestinal mucosa to induce CIGT, including nausea, vomiting, anorexia, gastrointestinal mucositis, and diarrhea, etc. The pathogenesis of CIGT involves multiple factors, such as gut microbiota disorders, inflammatory responses and abnormal neurotransmitter levels, that synergistically contribute to its occurrence and development. In particular, the dysbiosis of gut microbiota is usually linked to abnormal immune responses that increases inflammatory cytokines' expression, which is a common characteristic of many types of CIGT. Chemotherapy-induced intestinal neurotoxicity is also a vital concern in CIGT. Currently, modern medicine is the dominant treatment of CIGT, however, traditional Chinese medicine (TCM) has attracted interest as a complementary and alternative therapy that can greatly alleviate CIGT. Accordingly, this review aimed to comprehensively summarize the pathogenesis and current management of CIGT using PubMed and Google Scholar databases, and proposed that future research for CIGT should focus on the gut microbiota, intestinal neurotoxicity, and promising TCM therapies, which may help to develop more effective interventions and optimize managements of CIGT.

Gastrointestinal inflammation plays a critical role in chemotherapy-induced nausea and vomiting.

Chemotherapy-induced nausea and vomiting (CINV) is a common side effect of patients with cancer receiving chemotherapeutic drugs. However, the pathological mechanism of CINV is biologically multifaceted and has not yet been fully elucidated. Despite this, increasing evidence indicates that gastrointestinal (GI) inflammation dramatically contributes to the incidence of CINV. It is well established that 5-hydroxytryptamine and substance P are critical meditators in both of CINV and GI inflammation by binding to their corresponding receptors. Meanwhile, antiemetic drugs used for the prophylaxis of CINV have demonstrated surprising effects on relieving GI inflammation, and anti-inflammatory drugs are also effective in preventing CINV. The commonalities between the pathogenesis and clinical treatment of GI inflammation and CINV indicate that GI inflammation is an essential mechanism in CINV. In this review, we provide novel insights into the crucial role of GI inflammation in CINV, with the aim to discover the novel antiemetic drugs against CINV from the perspective of alleviating GI inflammation.

Research Progress of Liujunzi Decoction in the Treatment of Tumor-Associated Anorexia.

Tumor-associated anorexia, mainly including cancerous anorexia and chemotherapy-induced anorexia, severely reduces the life quality of cancer patients but lacks of effective control until now. Liujunzi decoction (LJZD), a classical tonifying formula in traditional Chinese medicine, has promising effect in preventing and treating many kinds of anorexia. A growing number of evidence showed that LJZD is able to improve tumor-associated anorexia. Up to March 2022, a total of 58 articles studying LJZD or Rikkunshito (the name of LJZD in Japanese herbal medicine) in the treatment of tumor-associated anorexia are searched out in PubMed. This paper summarizes the effect of LJZD in ameliorating tumor-associated anorexia, in order to provide a theoretical basis for the clinical application of LJZD in treating tumor-associated anorexia, laying foundation for further research.

Gasdermin E: A Prospective Target for Therapy of Diseases.

Gasdermin E (GSDME) is a member of the gasdermin protein family, which mediates programmed cell death including apoptosis and pyroptosis. Recently, it was suggested that GSDME is activated by chemotherapeutic drugs to stimulate pyroptosis of cancer cells and trigger anti-tumor immunity, which is identified as a tumor suppressor. However, GSDME-mediated pyroptosis contributes to normal tissue damage, leading to pathological inflammations. Inhibiting GSDME-mediated pyroptosis might be a potential target in ameliorating inflammatory diseases. Therefore, targeting GSDME is a promising option for the treatment of diseases in the future. In this review, we introduce the roles of GSDME-driven programmed cell death in different diseases and the potential targeted therapies of GSDME, so as to provide a foundation for future research.

The Antiemetic Mechanisms of Gingerols against Chemotherapy-Induced Nausea and Vomiting.

Chemotherapy-induced nausea and vomiting (CINV) is a common and painful side effect that occurs in cancer patients receiving chemotherapeutic drugs. Although an abundance of agents are applied to prevent CINV, there is still lack of effective control in delayed nausea and vomiting. Ginger (Zingiber officinale Rosc.), a traditional antiemetic herb, draws attention due to its therapeutic effect in treating acute and delayed CINV. Its main bioactive pungent constituents, gingerols, contribute to the antiemetic effect against CINV primarily. A growing number of reports have made progress in investigating the mechanisms of gingerols and their single ingredients against CINV. In this review, we searched for relevant studies in PubMed database to summarize the mechanism of gingerols in the prevention of CINV and provided a preliminary prediction on the potential targets and signaling pathways using network pharmacology, laying a foundation for further researches.

Liujunzi Decoction ameliorated cisplatin-induced anorexia by inhibiting the JAK-STAT signaling pathway and coordinating anorexigenic and orexigenic neuropeptides in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: As a traditional Chinese formula, Liujunzi Decoction (LJZD) originated from the Yi Xue Zheng Zhuan, and has a promising effect in treating chemotherapy-induced anorexia (CIA). AIM OF THE STUDY: The present study aims to investigate whether LJZD acts on interleukin-6 (IL-6)/leptin mediated janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway that regulates hypothalamus anorexigenic and orexigenic peptides to ameliorate CIA, and also elucidates the potential mechanism by metabolomic analysis. MATERIALS AND METHODS: Network pharmacology analyses were conducted to screen out potential targets and pathways. The CIA rat model was established via an intraperitoneal injection of cisplatin. The histological changes of gastric antrum, liver and ileum were observed by HE staining. The serum levels of leptin, ghrelin, IL-6 and growth differentiation factor 15 (GDF15) were measured by ELISA. The JAK1/2 and STAT levels in gastric antrum and hypothalamus were detected by Western blot. The transcriptions of gastric antrum and hypothalamus IL-6R mRNA, and hypothalamus cocaine- and amphetamine-regulated transcript (CART), pro-opiomelanocortin (POMC), thyrotropin-releasing hormone (TRH), upregulated orexigenic peptides neuropeptide Y (NPY), and agouti-related protein (AGRP) mRNA were assessed by RT-qPCR. The blood samples of control, model and high dose LJZD groups were analyzed by metabolomic. RESULTS: Network pharmacology highlighted the IL-6/leptin mediated JAK-STAT signaling pathway, which regulated downstream anorexigenic and orexigenic peptides in hypothalamus. LJZD ameliorated CIA via stimulating food intake and water consumption in rats. Cisplatin-induced gastric antrum, liver, ileum injuries were ameliorated, serum leptin level reduction was elevated, and ghrelin, IL-6, GDF15 level increases were decreased after LJZD treatments. In gastric antrum and hypothalamus, LJZD inhibited cisplatin-induced activation of JAK-STAT signaling pathway, downregulated the transcriptions of downstream anorexigenic peptides CART, POMC, TRH, and upregulated orexigenic peptides NPY, AGRP in hypothalamus. Importantly, the effect of LJZD in treating CIA might partly relate to the improvements of 23 abnormal metabolites. CONCLUSION: This study implies that inhibiting JAK-STAT signaling pathway, regulating the expressions of anorexigenic and orexigenic peptides, and mediating various metabolic pathways might be potential mechanisms of LJZD's effect against CIA.

Research Progress on the Antiemetic Effect of Traditional Chinese Medicine Against Chemotherapy-Induced Nausea and Vomiting: A Review.

Chemotherapy-induced nausea and vomiting (CINV), a common side effect in antineoplastic treatment, dramatically decreases the quality of life as well as the compliance of cancer patients. Although numerous antiemetic agents have been used for CINV treatment, its adverse reactions as well as its inadequate control toward delayed emesis still limit its clinical usage. Traditional Chinese medicine (TCM), with more than 3,000 years of practical history in Asia, has been successfully applied to mitigate chemotherapy-induced side effects. Growing attention is drawn to the antiemetic effect of TCM against CINV due to its promising therapeutic property and higher safety recently. In this review, we summarize the classic antiemetic TCM-based treatment and its mechanisms, so as to provide a theoretical basis for further investigations of TCM against CINV in the future.