Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists are increasingly used in the management of type 2 diabetes mellitus and obesity due to their ability to stimulate insulin secretion, delay gastric emptying, and suppress appetite. The combination of GLP-1 and GIP agonists improves glycemic control and promotes weight loss. However, the introduction of these novel therapies has raised safety concerns, including the risk of cholestatic hepatitis. We report a case of a patient with obesity who was prescribed a GLP-1/GIP dual-receptor agonist as part of his treatment regimen. Importantly, both before the initiation of this therapy and during the course of treatment, the patient was not taking any other medications. Shortly after receiving four doses of the therapy, the patient developed symptoms of severe cholestatic hepatitis, including jaundice and elevated liver enzyme levels. During hospitalization, no alternative causes for the condition were identified, and a liver biopsy confirmed the diagnosis of drug-induced cholestatic hepatitis. This is the first recorded case of cholestatic hepatitis induced by a GLP-1/GIP dual agonist, and it aimed to raise global awareness of this potential side effect.

Like other drugs, adjuvants are ligands with distinct structures that interact with specific cell receptors, modulating the immune response. This definition excludes formulations and delivery systems. New adjuvants may be discovered using methods based on a ligand and its receptor’s structural and functional traits, a process known as rational drug design. This strategy requires detailed information about both the receptors and their ligands. Such information is obtained using techniques like X-ray crystallography and 2D-nuclear magnetic resonance (NMR) to establish the spatial interactions between a ligand’s functional groups and its receptor. This data is necessary to establish reliable structure-activity relationships, which, when applied to computer-aided drug design, facilitate the creation of better adjuvants as an empirical strategy. Since Quillaja saponin adjuvants likely act separately on innate and adaptive immune cells via specific functional groups and unidentified cell receptors, it is crucial to identify these receptors. This task may be achieved using bioorthogonal chemistry and proteomic methods to identify and isolate the receptors. Initially focusing on those unidentified receptors where chemical modifications of these glycosides, such as the aldehyde group and fucose residue, cause drastic changes in adjuvanticity. The isolated receptor(s) can then be characterized by X-ray crystallography and/or 2D-NMR; this information can be applied to computer-aided drug design to rationally design new derivatives. This methodology will prevent the proposition of dubious structure-activity relationships based on incomplete immunological data, unknown receptors, and unsuspected physical factors, providing essential information for designing new adjuvants and elucidating these compounds’ mechanisms of action.

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder associated with liver disease, ranging from fibrosis to hepatocellular carcinoma. The disease remains asymptomatic until its final stages when liver transplantation is the only available therapy. Biomarkers offer an advantage for disease evaluation. The presence of microRNAs (miRNAs) in plasma extracellular vesicles (EVs) presents a noninvasive approach to assess the molecular signatures of the disease. In this study, we aimed to identify miRNA biomarkers to distinguish molecular signatures of the liver disease associated with AATD in AATD individuals.

Using small RNA sequencing and qPCR, we examined plasma EV miRNAs in healthy controls (n = 20) and AATD patients (n = 17). We compared the EV miRNAs of AATD individuals with and without liver disease, developing an approach for detecting liver disease. A set of miRNAs identified in the AATD testing cohort was validated in a separate cohort of AATD patients (n = 45).

We identified differential expression of 178 EV miRNAs in the plasma of the AATD testing cohort compared to controls. We categorized AATD individuals into those with and without liver disease, identifying 39 differentially expressed miRNAs. Six miRNAs were selected to test their ability to discriminate liver disease in AATD. These were validated for their specificity and sensitivity in an independent cohort of 45 AATD individuals. Our logistic model established composite scores with three- and four-miRNA combinations, achieving areas under the curve of 0.737 and 0.751, respectively, for predicting AATD liver disease.

We introduce plasma EV-derived miRNAs as potential biomarkers for evaluating AATD liver disease. Plasma EV-associated miRNAs may represent a molecular signature of AATD liver disease and could serve as valuable tools for its detection and monitoring.

Necroptosis is critical for regulating intestinal epithelial cells (IECs). Butyric acid (BA), produced during intestinal microbial metabolism, protects the intestinal epithelial barrier. However, whether necroptosis occurs in IECs during liver cirrhosis and whether sodium butyrate (NaB) can regulate necroptosis have not yet been reported. In this study, we aimed to investigate whether IECs undergo necroptosis in cirrhosis and whether NaB can regulate necroptosis and the related regulatory mechanisms.

Serum levels of RIPK3, MLKL, and Zonulin, as well as fecal BA levels, were measured and correlated in 48 patients with liver cirrhosis and 20 healthy controls. A rat model of liver cirrhosis was established, and NaB was administered. The expressions of MLKL, p-MLKL, and tight junction proteins were measured. We conducted an in vitro investigation of the effect of NaB on necroptosis in the HT29 cell line.

Serum levels of RIPK3, MLKL, and Zonulin in the liver cirrhosis group were higher, while fecal BA levels were lower than those in the control group. Zonulin levels were positively correlated with RIPK3 and MLKL levels, while fecal BA levels were negatively correlated with serum MLKL levels, but not with RIPK3 levels. NaB reduced the mRNA and protein expression of MLKL but had no effect on RIPK1 and RIPK3 in vitro. Rescue experiments demonstrated that NaB inhibited necroptosis through E2F1-mediated regulation of MLKL.

NaB alleviates intestinal mucosal injury and reduces necroptosis in IECs in liver cirrhosis. It also inhibits the necroptosis of IECs and protects the intestinal barrier by reducing E2F1 expression and downregulating MLKL expression levels. These results can be employed to develop a novel strategy for treating complications arising from liver cirrhosis.

Despite its crucial role in interventional therapies for liver malignancy, cone-beam computed tomography (CBCT) has not yet been fully integrated into clinical practice due to several complicating factors, including nonstandardized operations and limited recognition of CBCT among interventional radiologists. In response, the Chinese College of Interventionalists has released a consensus statement aimed at standardizing and promoting the application of CBCT in the interventional therapies for liver malignancy. This statement summarizes CBCT scanning techniques, and operational standards, and highlights its potential applications in clinical practice.

Infection with HPV16, a high-risk human papillomavirus (HPV), can cause cervical cancer in humans. These infections carry a high risk of morbidity and mortality globally in females. This study aimed to conduct an in vivo comparison of Poly (D,L-lactic-co-glycolide) (PLGA)-encapsulated peptide mixture nanoparticles and PLGA microspheres as delivery systems for vaccines.

PLGA polymers were used to form microspheres for a therapeutic vaccine against cervical cancer. The target antigens were the L1 and L2 capsid proteins and the E6 and E7 oncoproteins from HPV16. These antigens were selected based on their immunogenicity, allergenicity, and toxicity. We predicted epitopes for cytotoxic T lymphocytes (CTLs) and helper T lymphocytes. In our investigation of CTL epitopes, we employed synthetic chimeric PLGA microsphere peptides, consisting of multiple H-2Db-restricted HPV16 peptides, coupled with other immune-potentiating adjuvants as predicted by our work.

H-2Db-restricted HPV16 peptides, when administered subcutaneously, enabled CTLs to eliminate in vitro TC-1 tumor cells expressing E6 and E7 of HPV16. Additionally, TC-1 cells protected C57BL/6 mice against in vivo challenges. To address this problem, peptide-based vaccines, which are among the most effective vaccine systems, have been extensively studied. Combining peptide-based vaccinations with microsphere peptide mixture particles and delivery technologies enhances their efficacy in stimulating cellular immune responses and eliminating tumor cells.

This approach may provide a potential therapeutic candidate vaccine based on microsphere-encapsulated peptides for the prevention of cervical cancer caused by HPV.

Data regarding risk factors and long-term outcomes of U.S. patients with biopsy-proven metabolic dysfunction-associated steatotic liver disease (MASLD) are limited. This study aimed to investigate the role of clinical and histologic risk factors on long-term outcomes in patients with MASLD.

A retrospective cohort study of 451 adults with biopsy-proven MASLD was conducted at a U.S. academic hospital from 2012 to 2020. An experienced pathologist evaluated the index liver biopsy. Patients with a prior liver transplant or alternative etiologies of chronic liver disease were excluded. The duration of the risk exposure was determined from the date of the index liver biopsy to an outcome event or the last follow-up examination. Outcome events of interest included incident liver-related events, liver decompensation, and all-cause mortality.

In the final cohort of 406 patients followed for a median of 3.7 years (interquartile range: 4.8 years), 35 patients died, 41 developed hepatic decompensation, and 70 experienced a liver-related event. Among histologic risk factors, stage 3 (adjusted Hazard ratio (aHR) 2.68, 95% confidence interval (CI) 1.18–6.11) and stage 4 (aHR 6.96, 95% CI 3.55–13.64) fibrosis were associated with incident liver-related events compared to stage 0–1 fibrosis. Stage 4 (aHR 8.46, 95% CI 3.26–21.99) fibrosis alone was associated with incident liver decompensation events compared to stage 0–1 fibrosis. Among clinical risk factors, hypertension (aHR 2.58, 95% CI 1.05–6.34) was associated with incident liver decompensation.

In a U.S. single-center cohort of patients with biopsy-proven MASLD, advanced fibrosis was the primary risk factor for incident liver decompensation and liver-related events.

Isofraxidin, an important coumarin compound found in the medicinal plant Sarcandra glabra, is reported to have anti-inflammatory activity. However, its natural concentration is insufficient to meet the existing demand for this valuable molecule. Therefore, biotechnological approaches are necessary to enhance the isofraxidin content.

Endophytes were isolated from the roots, stems, and leaves of Sarcandra glabra and fermented with Sarcandra glabra, respectively. The target strains capable of increasing isofraxidin content were screened using high-performance liquid chromatography. Their genes were amplified, and the polymerase chain reaction products were sequenced. BLAST analysis was used to compare the sequences with those in GenBank, and a phylogenetic tree was constructed for species identification.

Fifteen endophytic bacteria and six endophytic fungi were isolated from the roots, stems, and leaves of Sarcandra glabra. Among them, Enterobacter, Bacillus wiedmannii, Trametes versicolor from the roots, and Diaporthe celeris and Diaporthe hongkongensis from the leaves increased the isofraxidin content in Sarcandra glabra. The isofraxidin content in Sarcandra glabra fermented by endophytes Enterobacter, Bacillus wiedmannii, Trametes versicolor, Diaporthe celeris, and Diaporthe hongkongensis was 1.37, 1.27, 1.11, 1.40, and 1.16 times higher than in the blank samples, respectively.

The fermentation of Sarcandra glabra with specific endophytes can increase its isofraxidin content. These findings provide preliminary scientific evidence for the potential of using microorganisms to enhance the quality of traditional Chinese medicine.

Gastrointestinal endoscopy has undergone significant transformation since its first introduction in the early 20th century. Despite advances in modern endoscopy, its precision in detecting and removing colorectal cancer (CRC) varies; colorectal polyps or cancer are still missed in 2.1-5.9% of cases. Additionally, post-colonoscopy CRC occurs in 30% of patients who have undergone incomplete polyp resection. When biopsies are taken, only 11.4% are found to be malignant, rendering 88.6% of tissue removal unnecessary. To address these shortcomings, modern endoscopy is evolving. Current endoscopic modalities include wide-field and microscopic-field endoscopy. Wide-field view endoscopy remains the most frequently used type and includes the current standard of practice—white light endoscopy—as well as other modalities such as virtual and dye-based chromoendoscopy, ultrathin endoscopy, and capsule endoscopy. Microscopic field endoscopy encompasses several new emerging modalities that can provide microscopic resolution capable of diagnosing lesions in vivo (optical biopsy), thus reducing the number of unnecessary biopsies. However, the emerging technology comes with a learning curve and requires time for endoscopists to master and achieve interobserver agreement. Consequently, there is a growing opportunity to develop machine learning technology to assist with the learning process. We review current modalities available for the diagnosis of CRC, including the current standard of practice, new enhanced imaging modalities, and optical biopsy.

Peroxisome proliferator-activated receptors (PPARs) participate in the fatty acid oxidation, the homeostasis of lipid and glucose metabolism, the regulation of insulin sensitivity, and numerous metabolic processes, making them novel and important therapeutic targets for cancer treatment. However, PPARs manifest dual functions, wherein their activation and inhibition engender diverse outcomes in different types of tumors. The specificity of drugs for tumors is also a challenge when targeting PPARs. In recent years, proteolysis targeting chimeras (PROTACs) have gained significant attention in the field of cancer therapy, demonstrating potent therapeutic potential in both basic and clinical research. Furthermore, heterobifunctional molecules derived from PROTACs have ventured into domains that extend beyond protein degradation. Currently, there are no developed PPAR-targeting PROTACs. Therefore, our review delves into various aspects, including the dual roles of PPARs, known inhibitors, agonists, ligands, and co-crystal structures, and explores the feasibility and advantages of PPAR-targeting PROTACs and other heterobifunctional molecules in cancer therapy.