Hepatocellular carcinoma (HCC) remains challenging to treat in advanced stages, primarily due to the development of resistance to sorafenib. There is an urgent need for novel therapeutic strategies to overcome this resistance. This study aimed to investigate the potential of oleanolic acid (OA), a natural hepatoprotective compound, in mitigating sorafenib resistance and elucidate its underlying molecular mechanisms.

Sorafenib-resistant Huh7 and HepG2 cell lines were established to mimic the resistant phenotype. The effects of OA on these cells were evaluated by assessing cell invasion, migration, and sensitivity to sorafenib. Gene expression analysis was conducted to identify molecular changes induced by OA treatment, with a focus on fabp3 expression.

Oleanolic acid significantly inhibited the invasive and migratory capabilities of sorafenib-resistant Huh7 and HepG2 cells (p < 0.01). Furthermore, OA treatment downregulated fabp3 expression and restored the cells’ sensitivity to sorafenib.

Oleanolic acid shows promise as an adjunct therapy for overcoming sorafenib resistance in HCC. By reducing cell aggressiveness and restoring drug sensitivity, OA may enhance the therapeutic efficacy of current treatments for advanced HCC.

Autoimmune hepatitis (AIH) is a chronic, progressive inflammatory liver disease characterized by autoimmune-mediated hepatic injury. Currently, glucocorticoid drugs, primarily prednisone, with or without azathioprine, are commonly recommended as first-line therapeutic agents in treatment guidelines by many scientific associations. However, the primary objective of treatment is to achieve a complete biochemical response, which is defined as the normalization of both transaminases and immunoglobulin G levels within six to twelve months. Ideally, this should also be accompanied by histological remission. Nevertheless, corticosteroid therapy is associated with significant adverse effects, potentially resulting in treatment discontinuation. In this context, it has become evident that standard treatment is inadequate for a proportion of patients, leading to the emergence of other treatment options and lines. Novel immunomodulatory agents, a class of drugs that regulate the body’s immune functions, have been confirmed to possess properties that modulate immune balance and induce immune tolerance. In recent years, these agents have played an increasingly significant role in the clinical management of AIH. This article provided an in-depth review of recent advancements in the development of novel immunomodulators, including immune cell nucleic acid inhibitors, calmodulin phosphate inhibitors, mammalian target of rapamycin inhibitors, tumor necrosis factor-α inhibitors, interleukin-2, anti-CD20 monoclonal antibodies, and B cell-activating factor inhibitors, for the treatment of AIH.

Camels are commonly administered butylscopolamine (BSA), an antimuscarinic quaternary ammonium derivative, to reduce spasms in the smooth muscles of their urinary and gastrointestinal tracts. However, its presence in body fluids after racing is prohibited by animal racing authorities. The current study aimed to conduct a pilot pharmacokinetic study of BSA in healthy camels. The goal was to obtain initial pharmacokinetic parameters and use these parameters to predict plasma concentrations from the dose and clearance. This will help advise on a withdrawal time for BSA administration before camel racing. The pharmacokinetics of BSA were evaluated in three healthy camels after a single intravenous dose of 0.2 mg/kg body weight. Sensitive liquid chromatography with tandem mass spectrometry was used for the quantification of BSA and the internal standard, ipratropium, in plasma. BSA concentration versus time data were best described by a two-compartment open model. The pharmacokinetic parameters (median and range) were as follows: terminal elimination half-life was 2.29 (1.48–2.46) h, plasma clearance was 1,018.5 (772.4–1,024.0) mL/h/kg, volume of distribution at steady state was 931.9 (700.0–1,068.7) mL/kg, Cmax was 443.9 (351.1–443.9) ng/mL, and Tmax was 0.5 (0.25–0.75) h. BSA’s irrelevant plasma concentration was estimated to be 20 ng/mL. Consequently, it can be concluded that plasma would not contain BSA at the screening level of 20 ng/mL at the usual dose of 0.2 mg/kg body weight 24 h before camel racing.

The spatial heterogeneity of tumors has long been a subject of significant interest in oncology. Recent research has revealed that tumors and their microenvironments undergo dynamic changes over time, particularly in the form of periodic circadian rhythms. Disruptions to these rhythms have been recognized as a pivotal factor in the advancement of tumorigenesis. Such disruptions not only induce dysregulation of gene expression within tumor cells, influencing tumor growth, metabolism, the cell cycle, and vascular homeostasis but also facilitate metastasis. Furthermore, they mediate the remodeling of the tumor immune microenvironment, fostering the development of an immunosuppressive milieu. Additionally, the in vivo metabolism and therapeutic responsiveness of tumor treatments—including chemotherapy, targeted therapy, and immunotherapy—have been shown to be modulated by circadian rhythms. This suggests that time-specific drug administration may enhance treatment efficacy, offering novel insights for precision cancer therapy. In this review, we systematically update contemporary research on the impact of circadian rhythms on tumor biology, encompassing both tumor progression and the efficacy of drug therapies. Building upon these insights, we explore the potential for a synergistic approach that integrates the targeting of rhythmic genes with current tumor treatment modalities. We also discuss the feasibility of tailoring tumor therapy to the rhythmic alterations that define in vivo metabolism and the efficacy of specific therapeutic agents, highlighting the significance of rhythm-based strategies in the personalized treatment of tumors and the prevention of associated diseases.

Wilson’s disease (WD) is a rare autosomal recessive genetic disorder that can be treated with medications. The lack of a single, specific diagnostic indicator leads to diagnostic difficulties, which may result in disease progression to cirrhosis and even liver cancer. Thus, this study aimed to analyze the clinical data, imaging, histopathological manifestations, genetic testing results, and treatment effects of patients with WD hepatic type, and to explore the factors related to WD cirrhosis.

A single-center retrospective study was performed. 48 WD patients with a Leipzig score ≥ 4 were divided into a cirrhosis group and a non-cirrhosis group based on the presence of cirrhosis. Logistic regression analysis and odds ratios were used to describe the strength of association between risk factors and cirrhosis. The predictive value of the model for cirrhosis occurrence was evaluated by calculating the area under the receiver operating characteristic curve and the cutoff value.

All 48 patients diagnosed with WD had liver damage, with males accounting for 54.17%. The median age at diagnosis was 28 years (range: 10.25–40.5 years), and 39.58% of patients had cirrhosis. The most prevalent mutation was c.2333G>T (p.Arg778Leu), found in 41.30% (19/46) of cases. Imaging revealed fatty liver in 31.25% (15/48) of patients and “honeycomb-like” cirrhosis nodules in 73.68% (14/19). Compared with the non-cirrhosis group, the cirrhosis group had a higher positive rate for the Kayser-Fleischer (K-F) ring, older age at diagnosis, and higher levels of immunoglobulin G, but lower levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, white blood cells, and platelets (p < 0.05). Age at diagnosis (odds ratio = 1.072, 95% confidence interval = 1.007–1.142, p = 0.03) and the K-F ring (odds ratio = 18.657, 95% confidence interval = 1.451–239.924, p = 0.025) were independent risk factors for WD-related cirrhosis. The best values of area under the receiver operating characteristic curve for age at diagnosis combined with the K-F ring in predicting WD cirrhosis were 0.909. The average follow-up time for 33 patients was 48.6 months (range: 12–72 months). The biochemical recovery rate was over 60% after 12–72 months of treatment with zinc gluconate and/or penicillamine.

Age at diagnosis, combined with the K-F ring, is a simple and effective risk factor for WD-related cirrhosis. Zinc gluconate and penicillamine are safe and effective treatments.

Cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/2B) deletions are frequently identified in patients with biliary tract cancer; however, standard treatment options for this genetic alteration are lacking. Here, we present the case of a 64-year-old woman diagnosed with intrahepatic cholangiocarcinoma and hilar lymph node metastasis who underwent radical surgery. Postoperative pathology confirmed moderately differentiated adenocarcinoma. The tumor recurred during the second cycle of adjuvant chemotherapy following surgery, and the metastatic sites included the cranial region, right lung, and right adrenal gland. Genetic analysis revealed a CDKN2A/2B deletion, indicating palbociclib sensitivity. Subsequently, the patient received palbociclib plus lenvatinib as systemic therapy, along with stereotactic radiotherapy for the intracranial lesion. Notably, the right pulmonary metastasis significantly regressed after 12 months of treatment, with the complete disappearance of the intracranial tumor. However, the disease progressed at 32.2 months, with significant enlargement of the right adrenal gland metastasis and new metastasis in the right lung. The progression-free survival and overall survival were 32.2 months and 34.4 months, respectively. In conclusion, our case demonstrates that palbociclib plus lenvatinib is a promising chemotherapy-free second-line treatment for intrahepatic cholangiocarcinoma with a CDKN2A/2B deletion.

Microscopic colitis is a chronic inflammatory disease of the colon that describes patients who present with watery diarrhea, normal or minimal endoscopic findings, and chronic inflammation identified on colonic biopsy. As the name suggests, microscopic colitis requires histologic evaluation for diagnosis. The two most well-established histologic patterns are collagenous colitis and lymphocytic colitis. In this review, we highlighted the key histologic features of microscopic colitis on biopsy specimens, along with its endoscopic findings, pathogenesis, and underlying molecular mechanisms. We also discussed important mimickers—including amyloidosis, collagenous colitis, ischemic colitis, and radiation colitis—emphasizing their distinguishing histopathologic characteristics. Recognizing these mimickers is crucial, as their treatment strategies are significantly different.

Protein disulfide isomerases (PDIs) are essential enzymes that facilitate the proper folding of proteins and maintain protein quality within the endoplasmic reticulum. Dysregulation of PDIs has been correlated with numerous disorders, including cancer and rheumatoid arthritis (RA). E64FC26 (EFC), a small molecule that inhibits a wide range of PDI family members, has shown promise as a therapeutic agent in oncology. However, its effects on RA have not yet been studied. This research investigates the efficacy of EFC as a potential treatment for RA.

To investigate EFC’s effects on RA fibroblast-like synoviocytes, several assays were employed, including Cell Counting Kit-8 for cell viability, EdU for cell proliferation, Transwell for migration and invasion, TUNEL for apoptosis, and in vitro tube formation assays for angiogenesis. Flow cytometry was used to assess apoptosis in detail. Cytokine production was analyzed using ELISA and real-time polymerase chain reaction. In vivo, a collagen-induced arthritis model was developed in DBA mice to evaluate EFC’s effects on inflammation, disease progression, and bone damage. RNA sequencing was utilized to identify the molecular pathways influenced by EFC treatment.

EFC exhibited significant anti-inflammatory effects on RA fibroblast-like synoviocytes, reducing cell proliferation, migration, invasion, angiogenic activity, and cytokine secretion, while simultaneously promoting apoptosis. In vivo experiments using the collagen-induced arthritis mouse model showed that EFC alleviated inflammation, slowed disease progression, and preserved joint and bone integrity. RNA sequencing data suggested that EFC acts through pathways associated with inflammation and apoptosis regulation.

The findings of this research underscore EFC’s therapeutic potential in managing RA. These results pave the way for the development of inhibitors targeting the PDI family as innovative treatments for RA.

Heme oxygenase 1 (HO-1) has an influential yet insufficiently investigated effect on Sirtuin 1 (SIRT1), a histone deacetylase activated by nicotinamide adenine dinucleotide, which may impact the transforming growth factor-β (TGF-ß)/Smad3 pathway in nonalcoholic fatty liver disease (NAFLD)-related liver fibrosis. This study aimed to elucidate the regulation of NAFLD-related liver fibrosis induced by HO-1 through the SIRT1/TGF-ß/Smad3 pathway.

HO-1 induction and inhibition were established in C57BL/6J mice fed a methionine- and choline-deficient (MCD) diet. Additionally, wild-type mice were fed either a normal diet or an MCD diet. Hematoxylin and eosin, Masson’s trichrome, and Sirius Red staining were used to assess hepatic steatosis, inflammation, and fibrosis. In vitro, plasmid overexpression and small interfering RNA silencing of HO-1 were performed in LX-2 cells. Cell viability was assessed using the Cell Counting Kit-8, and apoptosis was evaluated via terminal deoxynucleotidyl transferase dUTP nick-end labeling and immunofluorescence. Flow cytometry was employed to assess apoptosis and reactive oxygen species production. Western blot and real-time quantitative reverse transcription polymerase chain reaction were used to analyze the mRNA and protein expression of genes related to HO-1, SIRT1, the TGF-ß signaling pathway, and fibrosis.

MCD-fed mice developed significant liver damage, including steatosis, inflammatory infiltration, and pericellular fibrosis. Zinc protoporphyrin treatment exacerbated these conditions. Corroborating these findings, silencing HO-1 in LX-2 cells increased the expression of fibrosis-related genes. Furthermore, HO-1 overexpression not only increased SIRT1 expression but also reduced the activity of key regulatory factors in the TGF-ß signaling pathway, suggesting a potential interaction between HO-1 and the SIRT1/TGF-ß pathway.

HO-1 inhibits the activation of the TGF-ß/Smad3 pathway in NAFLD-related liver fibrosis through SIRT1. These findings provide insights into new therapeutic strategies for treating NAFLD-associated liver fibrosis.

Recent studies have highlighted a link between amyotrophic lateral sclerosis (ALS) and gut microbiota. This prospective study aimed to evaluate the effects of electroacupuncture combined with Chinese herbal medicine on gut microbiota and metabolomics in ALS patients.

Ten ALS patients were randomly assigned to either a treatment group (electroacupuncture with Chinese herbal medicine, n = 6) or a control group (waiting treatment, n = 4). Healthy controls (age- and sex-matched, n = 10) were also included. Data were collected after 12 sessions of electroacupuncture and follow-ups at three and six months. ALS functional rating scale scores were documented pre- and post-treatment. Stool samples were collected at two time points (T0 and T4 weeks) and analyzed, and metabolomic profiles from urine samples were analyzed post-treatment. Heatmap correlation analysis was used to explore relationships between microbiota, metabolomics, and clinical outcomes.

Treatment with electroacupuncture reduced Eisenbergiella abundance in the treatment group. A significant positive correlation was found between Lachnospiraceae and ALS functional rating scale scores (P < 0.005 and P < 0.001, respectively). Differential expression of purine metabolism was observed in ALS patients (P = 0.0017).

Imbalances in the gut microbiome and metabolic disorders have been found among patients with ALS. These imbalances appear to be partially mitigated by treatment with electroacupuncture combined with Chinese herbal medicine. Our research suggests that Eisenbergiella might be a diagnostic biomarker and a potential therapeutic target for ALS.