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Immune checkpoint inhibitors (ICIs) have changed the landscape of advanced cancer treatment. However, immune checkpoint inhibitors can trigger effector T cells against self-antigens as well as tumor antigens, resulting in immune-related toxicities in normal organs, referred to as immune-related adverse events (irAEs). A 56-year-old man with undifferentiated gastric carcinoma received sintilimab plus paclitaxel and tegafur therapy. After five cycles of treatment, the patient was referred to the hospital for sudden onset urinary frequency, micturition pain, and urinary incontinence. Cystoscopy revealed the entire bladder mucosa was red and edematous but there was no evidence of tumor. Oral administration of Chai-Ling-Tang (Sairei-To) alleviated lower urinary tract symptoms (LUTS). Histological analysis revealed numerous infiltrates of CD3-positive and CD8-positive cells into the urothelium but no atypia, indicating a diagnosis of immune-related cystitis. Interestingly, the urothelial epithelium infiltrated by lymphocytes and subepithelial inflammatory cells strongly expressed cell boundary PD-L1. The dose of Chai-Ling-Tang was maintained and stopped 2 months later without recurrence of LUTS. Since recovering from cystitis, the patient remains alive with no disease progression. This report shows that Chai-Ling-Tang is safe and effective for treating immune-related cystitis. The detailed mechanism of action requires further investigation. [ABSTRACT FROM AUTHOR]

Da-Chai-Hu-Tang (DCHT), a Chinese traditional herbal compound, has been utilized for the treatment of Hepatic diseases in China for over 1800 years. The DCHT formula contains eight herbals: Bupleurum chinense DC. (chaihu), Scutellaria baicalensis Georgi (huangqin), Paeonia lactiflora Pall. (baishao), Pinellia ternata (Thunb.) Makino (banxia), Rheum officinale Baill. (dahuang), Citrus × aurantium L. (zhishi), Zingiber officinale Roscoe (shengjiang), Ziziphus jujuba Mill. (dazao). Clinical studies have demonstrated the effectiveness of DCHT in hepatocellular carcinoma (HCC) and its ability to enhance the immunity of patients with hepatocellular carcinoma. A total of 20 Chinese articles have been published on the use of DCHT in treating HCC. The study aimed to validate the effect of DCHT in HCC cells and to identify related targets (TP53, AKT1, BCL2, STAT3) in treating HCC by DCHT in vitro experiments. Cell proliferation and migration were investigated in vitro. Flow cytometry analysis was used to evaluate the cell cycle and apoptosis. Apoptotic bodies in HepG2 cells were observed using a confocal microscope. Biochemical detection was employed to analyze LDH release, MDA levels, and SOD levels. Bioinformatics analysis was used to predict core targets between DCHT and HCC, as well as potential signaling pathways. The protein levels of metastasis-associated, apoptosis, and PI3K, AKT, p-AKT, and STAT3 were further determined through Western blotting. Following treatment with DCHT, the inhibition of viability, migration, and G2/M arrest was observed in HepG2 cells. Flow cytometry analysis and Morphological apoptosis studies provided evidence that DCHT could induce apoptosis in HepG2 cells. Biochemical detection revealed that DCHT could increase LDH release and the level of MDA, and inhibit the viability of the SOD. Bioinformatics analysis identified key targets such as TP53, AKT1, BCL2, STAT3. The PI3K/AKT/STAT3 signaling pathway emerged as a critical pathway in the KEGG enrichment analysis. Western blotting results indicated that DCHT could enhance the expression of E-cadherin, p53, and Bax, while reducing the content of N-cadherin, Bcl-2, PI3K, p-AKT, AKT1, and STAT3. The results proved that DCHT could inhibit the progression and metastasis of HCC by regulating the expression of E-cadherin, N-cadherin, p53, Bax, Bcl-2, PI3K, p-AKT, AKT, and STAT3 through the PI3K/AKT/STAT3 signaling pathway. [Display omitted] [ABSTRACT FROM AUTHOR]

• Xiao–Chai–Hu–Tang attenuates irinotecan-induced diarrhea by mediating gut microbiota. • Xiao–Chai–Hu–Tang attenuates irinotecan-induced diarrhea by inhibiting gut β-GUS. • Xiao–Chai–Hu–Tang significantly reduced the concentration of SN-38 in the gut. • Xiao–Chai–Hu–Tang active ingredient baicalein selectively inhibited EcGUS activity. Irinotecan (CPT-11, Camptosar@) is a first-line drug for metastatic colorectal cancer. CPT-11-induced diarrhea, which is closely related to the concentrations of β-glucuronidase (β-GUS) and SN-38 in the gut, largely limits its clinical application. Herein, Xiao–Chai–Hu–Tang (XCHT), a traditional Chinese formula, was applied to mitigate CPT-11-induced toxicity. This study initially explored the mechanism by which XCHT alleviated diarrhea, especially for β-GUS from the gut microbiota. First, we examined the levels of the proinflammatory cytokines and the anti-inflammatory cytokines in the intestine. Furthermore, we researched the community abundances of the gut microbiota in the CPT-11 and XCHT-treated mice based on 16S rRNA high-throughput sequencing technology. Meanwhile, the level of SN-38 and the concentrations of β-GUS in intestine were examined. We also resolved the 3D structure of β-GUS from gut microbiota by X-ray crystallography technology. Moreover, we used virtual screening, SPR analysis, and enzyme activity assays to confirm whether the main active ingredients from XCHT could selectively inhibit β-GUS. In XCHT-treated mice, the levels of the proinflammatory cytokines decreased, the anti-inflammatory cytokines increased, and the community abundances of beneficial Firmicutes and Bacteroidota improved in the gut microbiota. We also found that the concentrations of β-GUS and the level of SN-38, the major ingredient that induces diarrhea in the gut, significantly decreased after coadministration of XCHT with CPT-11 in the intestine. Additionally, we revealed the structural differences of β-GUS from different gut microbiota. Finally, we found that EcGUS had good affinity with baicalein and meanwhile could be selectively inhibited by baicalein from XCHT. Overall, XCHT could relieve the delayed diarrhea induced by CPT-11 through improving the abundance of beneficial gut microbiota and reduced inflammation. Furthermore, based on the three-dimensional structure, baicalein, especially, could be used as a candidate EcGUS inhibitor to alleviate CPT-11-induced diarrhea. [Display omitted] [ABSTRACT FROM AUTHOR]

Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion of pancreatic ductal adenocarcinoma (PDAC), which is a highly malignant tumor and lack of effective treatment. Although Xiao Chai Hu Tang (XCHT) has a good therapeutic effect on pancreatic cancer patients with advanced stage, the effect and mechanism of XCHT remains unclear in pancreatic tumorigenesis. To assess the therapeutic effects of XCHT on the malignant transformation from PanIN to PDAC and to reveal its mechanisms of pancreatic tumorigenesis. Syrian golden hamster were induced by N-Nitrosobis (2-oxopropyl) amine (BOP) to establish the pancreatic tumorigenesis model. The morphological changes of pancreatic tissue were observed by H&E and Masson staining; the Gene ontology (GO) analysis the transcriptional profiling changes; the mitochondrial ATP generation, mitochondrial redox status, mitochondrial DNA (mtDNA) N6-methyladenine (6mA) level and relative mtDNA genes expressions were examined. In addition, immunofluorescence detect the cell localization of 6mA in human pancreatic cancer PANC1 cell. Using the TCGA database, the prognostic effect of mtDNA 6mA demethylation ALKBH1 expression on pancreatic cancer patients was analyzed. We confirmed the mtDNA 6mA levels were gradually increased with the mitochondrial dysfunction in PanINs progression. XCHT showed the effect to inhibit the occurrence and development of pancreatic cancer in Syrian hamster pancreatic tumorigenesis model. In addition, the lack of ALKBH1 mediated mtDNA 6mA increase, mtDNA coded genes down-expression and abnormal redox status were rescued by XCHT. ALKBH1/mtDNA 6mA mediated mitochondrial dysfunction to induce the occurrence and progression of pancreatic cancer. XCHT can improve ALKBH1 expression and mtDNA 6mA level, regulate the oxidative stress and expression of mtDNA coded genes. This study investigated a new molecular mechanism of pancreatic tumorigenesis, and revealed the therapeutic efficacy of XCHT in pancreatic tumorigenesis for the first time. [Display omitted] [ABSTRACT FROM AUTHOR]

The herbal medicine designated Chai-Ling-Tang in China, Siryung-tang in South Korea, and Sairei-To (or Tsumura Saireito extract granules, TJ-114) in Japan is a complex polyherbal formulations with 12 plant components. It is used historically to treat Shaoyang syndrome, recorded in an ancient Chinese medical text "Treatise on Cold Damage Disorder" (Shanghan Lun). Chai-Ling-Tang formula combines two traditional Chinese herbal medicine prescriptions: Xiao-Chai-Hu-Tang and Wu-Ling-San (known as Sho-Saiko-To and Goreisan in Japan, and So Shi Ho Tang and Oreonsang in Korea, respectively). These traditional Chinese/Korean medicines and Kampo medicine have been used for more than 2000 years in East Asia, notably as regulators of body fluid homeostasis. This study aims to evaluate clinical uses, pharmacological effects and unwanted effects of Sairei-To through a narrative literature survey. The main active phytoconstituents and their mechanism of actions are also collated based on the literature. Several databases including SciFinder and PubMed were searched in sourcing information using keywords corresponding to the medicinal treatment names and the corresponding plants and phytochemicals. Relevant textbooks, reviews, and digital documents (mostly in English) were consulted to collate all available scientific literature and to provide a complete science-based survey of the topic. Sairei-To derives from ten plants and two fungi. The three major components are Bupleuri radix (Saiko), Pinelliae rhizoma (Hange), and Alismatis rhizoma (Takusha). The rest includes the species Scutellariae radix, Zizyphi fructus, Ginseng radix, Glycyrrhizae radix, Zingiberis rhizoma, Cinnamomi cortex, Atractylodis lanceae rhizoma, Poria sclerotium, and Polyporus sclerotium. The therapeutic uses of Sairei-To are very diversified, ranging from the treatment of autoimmune diseases, intestinal inflammatory disorders, edema, intestinal and kidney diseases, cancers, inflammatory skin pathologies, and other conditions such as reproductive failure. Sairei-To is considered as a safe and efficient medication, with potential rare unwanted side effects, notably lung injuries (pneumonitis essentially). Marked anti-inflammatory and immune-modulatory effects of Sairei-To have been reported, generally associated to the action of saponins (saikosaponins, glycyrrhizin), terpenoids (alisols) and flavonoids (baicalin, oroxylin A). Sairei-To is commonly used to treat inflammatory diseases and appears efficient to decrease the side effects of corticosteroids. Its immune-regulatory action is well recognized and exploited to treat certain skin lesions and chemotherapy-related toxic effects. The activity of the Sairei-To product relies on the synergistic action of its individual ingredients. Further studies are warranted to quantify the synergy of action inherent to this interesting botanical medication. [Display omitted] • Sairei-To is a 12-component herbal formulation used to treat many human diseases. • The product displays anti-inflammatory and immune-modulatory activities. • Saikosaponins and diverse terpenoids and flavonoids support the pharmacological activities. • The different components of the herbal product likely provide synergistic effects. [ABSTRACT FROM AUTHOR]

This work presents an integrated application of potential field data to discover potash-bearing evaporite sources in Aji-Chai salt deposit, located in east Azerbaijan province, northwest of Iran. Low density and diamagnetic effect of salt minerals, i.e. potash, give rise to promising potential field anomalies that assist to localize sought blind targets. The halokinetic-type potash-bearing salts in the prospect zone have flowed upward and intruded into surrounded sedimentary sequences dominated frequently by marl, gypsum and alluvium terraces. Processed gravity and magnetic data delineated a main potash source with negative gravity and magnetic amplitude responses. To better visualize these evaporite deposits, 3D model of density contrast and magnetic susceptibility was constructed through constrained inversion of potential field data. A mixed-norm regularization technique was taken into account to generate sharp and compact geophysical models. Since tectonic pressure causes vertical movement of the potash in the studied region, a simple vertical cylindrical shape is an appropriate geometry to simulate these geological targets. Therefore, structural index (i.e. decay rate of potential field amplitude with distance) of such assumed source was embedded in the inversion program as a geometrical constraint to image these geologically plausible sources. In addition, the top depth of the main and the adjacent sources were estimated 39 m and 22 m, respectively, via the combination of the analytic signal and the Euler deconvolution techniques. Drilling result also indicated that the main source of potash starts at a depth of 38 m. The 3D models of the density contrast and the magnetic susceptibility (assuming a superficial sedimentary cover as a hard constraint in the inversion algorithm) demonstrated that potash source has an extension in depth less than 150 m. [ABSTRACT FROM AUTHOR]