Both alcohol-associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease are leading contributors to chronic liver diseases. These conditions often coexist, exacerbating disease progression. Despite ALD being a leading cause of liver transplantation, many individuals with alcohol use disorder (AUD) do not receive treatment. In this review, we discussed the epidemiology of ALD in AUD, various treatment options for AUD, and their efficacy on liver health. Our critical analysis of current evidence underscores the need for integrated models involving multiple stakeholders to improve ALD management.

The liver plays a crucial role in maintaining whole-body homeostasis in both health and disease, engaging in important communication with other organs. The coordination of multiple signaling pathways is essential for facilitating such interorgan communication. Among these pathways, the transforming growth factor-β (TGF-β) and HIPPO signaling pathways serve critical functions as tumor suppressors, exerting pivotal control over liver development, size, and tissue regeneration. In the normal hepatic context, these pathways exhibit significant crosstalk through various molecular mechanisms. This interaction is context-dependent within the hepatic microenvironment, regulating diverse cellular processes from development to adulthood. Disruptions in the regulation of these pathways and their crosstalk contribute to the onset of liver diseases. This review delves into the intricate interplay between the canonical pathways of TGF-β and HIPPO, exploring their involvement in liver development and various pathologies such as fibrosis, cirrhosis, and tumorigenesis. Special attention is given to their impact on the epithelial-to-mesenchymal transition process, a crucial element associated with liver wound healing and cancer metastasis. By addressing these molecular interactions, the review aimed to provide insights into the underlying mechanisms that influence liver physiology and pathology, offering potential avenues for therapeutic interventions.

Idiopathic pulmonary fibrosis is a chronic, progressive, incurable lung disease, leading to irreversible lung tissue remodeling. The Notch signaling pathway, essential for lung development, has gained attention for its role in pulmonary fibrosis. While Notch1 and Notch3 have been extensively studied, the involvement of other Notch receptors, especially Notch4, remains less explored. This study aimed to evaluate the impact of Notch4 on lung fibroblast activation and its potential interaction with the transforming growth factor-beta 1 (TGFβ1) signaling.

Primary human lung fibroblasts were transduced with lentivirus containing the intracellular domain of NOTCH4 (N4ICD). Changes in gene expression in transduced cells were assessed using real-time polymerase chain reaction, immunofluorescence staining, and Western blotting. Transcriptomic analysis was also performed on N4ICD-transduced lung fibroblasts.

N4ICD overexpression significantly upregulated key fibrotic markers such as ACTA2 and COL1A1. It also induced the TGFβ1 pathway, as evidenced by SMAD2 phosphorylation and elevated TGFβ1 mRNA level. Transcriptomic analysis revealed that N4ICD-induced cells exhibited characteristics of highly invasive myofibroblasts.

This study establishes Notch4 as a novel contributor to pulmonary fibrosis, by demonstrating its ability to induce myofibroblast differentiation and interact with the TGFβ1 pathway.

The years 2019–2021 of the twenty-first century are synonymous with the COVID era, as the Coronavirus disease 2019 (COVID-19) wreaked havoc and continues to be aggressively persecuted. Globally, about 300 million COVID-19 cases and nearly 5.3 million fatalities have been recorded so far. Since then, the coronavirus RNA genome has rapidly mutated, giving rise to several mutant and recombinant variants. On March 9, 2022, a new recombinant known as Deltacron/Delmicron emerged due to inter-lineage recombination between Delta and Omicron. Many researchers consider it a “grey rhino” occurrence rather than a “black swan” event. However, some groups of scientists claim it is a “laboratory error”. Another COVID-19 variant, XE (a recombination of BA.1 and BA.2), has been discovered, which has a transmission rate ten times higher than the fastest-spreading Omicron subvariant BA.2. Delta and Omicron, two of the most novel strains, co-circulated for many weeks in several parts of the globe, allowing for coinfections and eventual recombination. Consequently, the recombinant strains XD and XF are associated with a very high transmission rate and reduced neutralizing antibody response. Under these circumstances, researchers are rushing to develop a vaccine with high efficacy against the circulating mutants and the variants likely to emerge in the near future. This review article provides recent updates on newly identified sub-variants of Omicron with an in-depth focus on their genomic alterations, infectivity patterns, and pathogenic manifestations.

Experimental models using 2/3 partial hepatectomy or chemical injury have helped identify the pathways associated with liver regeneration (LR). Several microRNAs (miRNAs) have been identified as modulators of LR, but the molecular mechanisms underlying their activity are still unclear. Given the development of new therapies targeting miRNAs, this is an important question to address. This review discusses recent studies exploring the molecular mechanisms of miRNA-dependent regulation of LR. In particular, the finding that circ-RBM23 promotes LR by sequestering cytoplasmic miRNA139-5p has furthered the understanding of the molecular mechanisms underlying circRNA activity. Interestingly, although miRNAs are generally considered negative regulators of their target mRNAs, miRNAs182-5p promotes LR by upregulating Cyp7a. Furthermore, mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) were shown to enhance LR after 2/3 partial hepatectomy by releasing miRNAs that inhibit gene expression to promote an anti-inflammatory response or miRNA-regulatory factors. Since the administration of MSCs-EVs has no hepatotoxic side effects, this may represent a therapeutic strategy to promote LR. miRNAs also mediate LR after chemical injury. This is the case for miR194 and miR21, whose downregulation activates pro-regeneration pathways to ameliorate acetaminophen-induced liver injury. In addition, the downregulation of miR21 has been shown to improve autophagy and haemostasis after acetaminophen overdose. Although further studies are needed to improve their efficacy as therapeutics, the evidence gathered in this review has led to a better understanding of the molecular mechanisms associated with the control of LR by miRNAs.

Gut dysbiosis and abnormal cytokine profiles are common in cirrhosis. This study aimed to evaluate the correlations between them.

In the blood plasma of cirrhosis patients and controls, 27 cytokines were examined using a multiplex assay. The plasma levels of nitrites (stable metabolites of the endothelial dysfunction biomarker nitric oxide) and lipopolysaccharide (LPS) were examined. The fecal microbiota was assessed by 16S rRNA gene sequencing.

Levels of IL-1b, IL-2, IL-6, IL-13, IP-10, IFN-g, TNF-a, LPS, and nitrites were higher in cirrhosis patients than in controls, while levels of IL-4, IL-7, and PDGF-BB were lower. The LPS level was directly correlated with the levels of IL-1b, IL1-Ra, IL-9, IL-17, PDGF-BB, IL-6, TNF-a, and nitrites. The nitrite level was significantly directly correlated with the levels of TNF-a, GM-CSF, IL-17, and IL-12, and inversely correlated with the IL-7 level. TNF-a levels were directly correlated with ascites severity and the abundance of Negativicutes, Enterobacteriaceae, Veillonellaceae, and Klebsiella, while inversely correlated with the abundance of Firmicutes, Clostridia, and Subdoligranulum. IFN-g levels were directly correlated with the abundance of Bacteroidaceae, Lactobacillaceae, Bacteroides, and Megasphaera, and inversely correlated with the abundance of Verrucomicrobiota, Akkermansiaceae, Coriobacteriaceae, Akkermansia, Collinsella, and Gemella. IL-1b levels were directly correlated with the abundance of Comamonadaceae and Enterobacteriaceae and inversely correlated with the abundance of Marinifilaceae and Dialister. IL-6 levels were directly correlated with the abundance of Enterobacteriaceae, hepatic encephalopathy, and ascites severity, and inversely correlated with the abundance of Peptostreptococcaceae, Streptococcaceae, and Streptococcus.

The abundance of harmful gut microbiota taxa and endotoxinemia directly correlates with the levels of proinflammatory cytokines.

The brain-gut axis represents a bidirectional communication network that integrates neural, hormonal, and immunological signaling between the central nervous system and the gastrointestinal tract. Adverse childhood experiences (ACEs) have increasingly been recognized for their profound impact on this axis, with implications for both mental and physical health outcomes. This mini-review explores the emerging field of epigenomics—specifically, how epigenetic modifications incurred by ACEs can influence the brain-gut axis and contribute to the pathophysiology of various disorders. We examine the evidence linking epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs to the modulation of gene expression involved in stress responses, neurodevelopment, and immune function—all of which intersect at the brain-gut axis. Additionally, we discuss the emerging potential of the gut microbiome as both a target and mediator of epigenetic changes, further influencing brain-gut communication in the context of ACEs. The methodological and therapeutic challenges posed by these insights are significant. The reversibility of epigenetic marks and the long-term consequences of early life stress require innovative and comprehensive approaches to intervention. This underscores the need for comprehensive strategies encompassing psychosocial, pharmacological, neuromodulation, and lifestyle interventions tailored to address ACEs’ individualized and persistent effects. Future directions call for a multi-disciplinary approach and longitudinal studies to uncover the full extent of ACEs’ impact on epigenetic regulation and the brain-gut axis, with the goal of developing targeted therapies to mitigate the long-lasting effects on health.

Inflammatory Bowel Diseases (IBD) still represent a significant medical challenge. The course of IBD is characterized by the development of fibrotic, inflammatory, or dysplastic lesions over time. Recent advancements in operative endoscopy have introduced new strategies to address these issues. Inflammatory and fibrotic strictures pose a challenge for clinicians and represent a surgical risk. Endoscopic treatments include dilation, stent placement, and electroincisional techniques. Moreover, endoscopic approaches can also be considered in the management of IBD-related surgical complications. Addressing colorectal dysplastic lesions is a crucial concern, and several resection endoscopic techniques are available, including endoscopic mucosal resection and endoscopic submucosal dissection. This review aimed to summarize the pros and cons of advanced therapeutic endoscopic approaches in the management of IBD.

The hepatitis E virus (HEV) is a zoonotic disease, and infection with HEV in humans primarily causes acute infections and can progress to chronic manifestation in immunocompromised individuals. Over the past decade, guidelines for diagnosing and treating HEV infection have been developed. This study aimed to systematically assess the quality of current guidelines for diagnosing and treating HEV infection, and we analyzed the differences in guideline quality and primary recommendations and explored possible reasons for these differences.

Guidelines published between 2013 and 2022 were searched, and studies were identified using selection criteria. The study assessed the quality of the included guidelines using the Appraisal of Guidelines for Research and Evaluation tool, extracted the primary recommendations in the guidelines, determined the highest level of evidence supporting the recommendations, and reclassified the evidence using the Oxford Centre for Evidence-Based Medicine grading system.

Seven guidelines were included in the final analysis. The quality of the guidelines varied widely. The discrepancies may have been caused by the lack of external experts, the failure to consider influencing factors in guideline application, and the lack of consideration of the public’s opinion. Analysis of the heterogeneity in primary recommendations revealed differences in algorithms for managing chronic HEV infection, the dosage of ribavirin, and a low level of evidence supporting the primary recommendations.

Guideline quality and primary recommendations vary considerably. Refinement by guideline developers and researchers would facilitate updating and applying guidelines for diagnosing and treating HEV infection.

The incidence and prevalence of inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn’s disease, are rapidly increasing. Currently, colonoscopy is the gold standard for diagnosing and monitoring the course of IBD. However, the recently implemented “treat-to-target” strategy, which involves meticulously pursuing multiple therapeutic objectives, has opened avenues for non-invasive diagnostic and monitoring tools. These tools aim to assess disease activity and predict the likelihood of recurrence. Research studies into serum and fecal biomarkers in IBD have been ongoing for several years. Among the most relevant biomarkers, fecal calprotectin and C-reactive protein have shown the best accuracy, with good-to-optimal correlation with endoscopic, histologic, or transmural activity. Numerous studies have explored the potential advantages of using multi-target tools that combine serum and fecal biomarkers with clinical activity indexes to enhance diagnostic and monitoring effectiveness. Encouraging findings have emerged for fecal lactoferrin, autoantibodies, micro-RNA, gene expression, and many other serological and fecal markers. However, limited evidence has hindered their widespread adoption in routine clinical practice. This review aimed to summarize the available data on the utilization of biomarkers in IBD.

Gluten has multiple harmful effects that compromise human health, not only in gluten-dependent diseases but also in non-gluten-affected chronic inflammatory conditions. After consumption, the indigestible gluten peptides are modified by luminal microbial transglutaminase or transported through the gut epithelium to interact with the highly populated mucosal immune cells. As a disruptor of gut permeability, gluten peptides compromise tight junction integrity, allowing foreign immunogenic molecules to reach internal compartments. Gliadin peptides are distributed systemically to remote organs, where they encounter endogenous tissue transglutaminase. Following post-translational deamidation or transamidation, the peptides become immunogenic and pro-inflammatory, inducing organ dysfunction and pathology. Cross-reactivity and sequence homology between gluten/gliadin peptides and human epitopes may contribute to molecular mimicry in autoimmunity induction. A gluten-free diet can prevent these phenomena through various mechanisms. As proof of concept, gluten withdrawal alleviates disease activity in chronic inflammatory, metabolic, and autoimmune conditions, and even in neurodegeneration. We recommend combining the gluten-free and Mediterranean diets to leverage the advantages of both. Before recommending gluten withdrawal for non-gluten-dependent conditions, patients should be asked about gut symptomatology and screened for celiac-associated antibodies. The current list of gluten-induced diseases includes celiac disease, dermatitis herpetiformis, gluten ataxia, gluten allergy, and non-celiac gluten sensitivity. In view of gluten being a universal pro-inflammatory molecule, other non-celiac autoinflammatory and neurodegenerative conditions should be investigated for potential gluten avoidance.

Functional Gastrointestinal Disorders (FGIDs), also recently referred to as disorders of gut-brain interaction, are common in the pediatric population and vary according to age groups, i.e., neonatal/toddler and child/adolescent FGIDs. Pediatric FGIDs tend to evolve and persist into adulthood, contributing to financial burdens and psychological problems. Despite several decades of progress and advancements in molecular biology and medical sciences, the exact pathophysiology remains unknown, although genetic, psychosocial, gut dysbiosis, visceral hypersensitivity, and neuroimmune causes have been implicated. The ROME IV criteria facilitate easier and earlier diagnosis of FGIDs, excluding organic causes while minimizing unnecessary investigations. Dietary, psychosocial, neuro-stimulatory, and pharmacological management methods exist, although fewer trials have focused on pediatric drug-based management. Early identification and appropriate treatment hold the potential for cure and improvement in quality of life.

Precision medicine involves tailoring an individual’s genes or proteins to prevent, diagnose, or treat diseases such as cancer. Given the recent advances in cancer immunotherapy, there is now a focus on developing vaccines as a new treatment modality. Therapeutic vaccines for cancer are a precision medicine approach that has made enormous progress in recent years due to advances in vaccine engineering. This technology uses antigens derived from the patient’s tumor to create vaccines that are unique and specific to that patient. Although challenges remain, significant progress has been made in recent years, largely due to the advent of mRNA vaccines. This mini-review primarily focuses on developments in vaccine engineering, outstanding therapeutic obstacles, and recent human clinical trials.

Fuzi, the processed product of daughter roots of Aconitum carmichaelii Debx., is a well-known Chinese medicine for the treatment of heart failure (HF) and related cardiac diseases. This study aimed to investigate the molecular mechanism of the cardioprotective effects of Fuzi water decoction (FWD) and Fuzi water-soluble alkaloids (FWA) on the model of HF.

The HF model of rats was prepared through intravenous injection of propafenone hydrochloride. The normal group, model group, FWD-treated groups (1.25 g/kg, 2.5 g/kg, 5 g/kg) and positive group (Shenfu Injection, 3.3 mL/kg) were set up. Heart rate, LV+dp/dtmax, and LV-dp/dtmax were recorded at 5 m, 10 m, 20 m, 30 m, and 60 m after drug administration, respectively. The contents of atrial natriuretic peptide, brain natriuretic peptide (BNP), angiotensin II, and aldosterone in serum were determined 20 m post-administration. An in vitro cardiomyocyte hypertrophy model with HDAC2 overexpression was constructed and verified by lentivirus transfection. The experiment included a blank group, FWD-treated groups (3 mg/mL, 1.5 mg/mL), and FWA-treated groups (4 mg/mL, 2 mg/mL). For transcriptome analysis, the model group, blank group, and FWD-treated group (2.5 g/kg) at 20 m and 60 m in vivo, and different dose groups in vitro, were selected to analyze the therapeutic mechanisms of FWD and FWA.

All FWD treatment groups showed an increased heart rate, among which the groups with 2.5 g/kg and 5 g/kg FWD showed better effects, significantly increasing LV+dp/dtmax and LV-dp/dtmax after 20 m of administration and significantly reducing BNP and aldosterone serum levels. In the constructed cardiomyocyte hypertrophy model, HDAC2 expression, atrial natriuretic peptide and BNP protein levels, and cell surface area increased. Transcriptome data from both in vivo and in vitro showed that FWD and FWA could exert cardioprotective effects through pathways such as the PI3K-Akt signaling pathway, NF-κB signaling pathway, and ATP-binding cassette (ABC) transporters, involving key genes such as ITGB1, TLR2, and CDKN1A. Fuzi inhibited the hypertrophic gene HDAC2. Additionally, based on weighted gene co-expression network analysis, ABC transporters may be an important molecular pathway for FWA in treating HF.

Both FWD and FWA can ameliorate HF by regulating apoptosis, proliferation, and anti-fibrosis, with ABC transporters potentially being the main pathway for the action of FWA.

Patients with corona virus disease 2019 (COVID-19) face not only physical strains but also significant psychological stress, highlighting the importance of addressing their mental health concerns. This study aimed to evaluate the impact of Lianhua Qingwen on the psychological well-being of asymptomatic and mildly symptomatic COVID-19 patients, providing empirical evidence to guide clinical practices.

Conducted in eight shelter hospitals in Shanghai, the study employed a cluster randomization method to allocate patients equally into either the Lianhua Qingwen group or the control group. The Lianhua Qingwen group received oral doses of four capsules or one packet of granules three times daily for 14 days. In contrast, the control group received standardized treatment according to the diagnostic and treatment plan, excluding Lianhua Qingwen. Mental health was assessed using the Self-rating Depression Scale and Self-rating Anxiety Scale, with symptom reporting on the 7th and 14th days, accompanied by nucleic acid test result screenshots. A follow-up investigation on new disease occurrence was conducted six months post-discharge.

Among the 2,652 valid questionnaire respondents, the Lianhua Qingwen group accounted for 1,665 cases, characterized by a higher proportion of females (32.7% vs. 26.9%), younger age (44.8 vs. 46.2 years), lower percentages of asymptomatic infections (27.6% vs. 38.5%), higher baseline Patient Health Questionnaire-9 scores (2.7 vs. 1.9), and higher Generalized Anxiety Disorder 7 scores (1.9 vs. 1.4). Further multivariate logistic regression analysis explored factors influencing the alleviation of depressive and anxiety symptoms during follow-up, revealing that Lianhua Qingwen use was an independent factor in reducing anxiety (odds ratio = 1.37, 95% confidence interval 1.14–1.65, p = 0.001) and depression (odds ratio = 1.42, 95% confidence interval 1.19–1.69, p < 0.0001). Lianhua Qingwen increased the likelihood of reducing anxiety by 37% and depression by 42%.

Lianhua Qingwen significantly alleviated anxiety and depression symptoms in COVID-19 patients, suggesting its potential therapeutic efficacy in mitigating these conditions.

The tumor microenvironment is a dynamic cellular landscape critical to cancer progression. Within it, tumor-infiltrating lymphocytes hold a dual role, contributing to both tumor suppression and progression. This review synthesized current knowledge on tumor-infiltrating lymphocytes, emphasizing their prognostic significance and therapeutic potential. By dissecting their interactions within the tumor microenvironment and with cancer cells, we sought to uncover the complexities of the immune response in cancer and explored the future direction of immunotherapeutic strategies.

Molecular analysis of breast cancer tissue has revealed that breast cancer is not a uniform disease. Each breast cancer patient has several molecular signatures that differ from those of others. Therefore, breast cancer therapy should be personalized, depending on its molecular signatures. Breast cancer with hormonal receptors can be treated with a selective estrogen receptor modulator or selective estrogen receptor degrader therapy, while breast cancer with overexpression of human epidermal growth factor receptor 2 (HER2)-neu gene responds excellently to anti-HER2-neu therapy. For patients with advanced breast cancer that already has distant metastasis and a poor prognosis, a new agent has been discovered. The phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) inhibitor has been proven effective in treating advanced breast cancer with a PIK3CA gene mutation. This therapy can be administered to HER2-negative breast cancer patients and in combination with selective estrogen receptor degrader therapy for post-menopausal patients with positive hormonal receptors. Although this treatment is effective, it cannot be given to every advanced breast cancer patient. Before administering the treatment, a PIK3CA mutation test is compulsory. PIK3CA mutation detection in breast cancer can predict the cancer’s response to the PIK3CA inhibitor, providing information on which patients will benefit from the treatment.

Esophageal cancer is one of the most common malignant tumors in the digestive tract in China. Due to late diagnosis and rapid progression, it leads to a poor survival prognosis. Early diagnosis and treatment are crucial for improving the prognosis of esophageal cancer. Implementing simple and efficient screening methods is more in line with China’s healthcare economics and national conditions. This article mainly introduces the current status of esophageal cancer screening and new technologies for esophageal cancer screening in China, including endoscopic technology, biomarker detection, exhaled breath detection, and artificial intelligence assisted screening, and looks ahead to its future development trends.

Erdheim-Chester Disease (ECD) is a type of systemic histiocytosis mostly observed in adults, characterized by the infiltration of foamy CD68+ and CD1a- histiocytes into multiple organ systems, often associated with MAPK pathway mutations. Conventional treatment of ECD has been challenging. Currently, targeted drugs (BRAF and MEK inhibitors) are recommended. This report aimed to describe the necessity of targeted therapy for ECD. A 39-year-old Japanese man presented with complaints of weight loss, polyuria/polydipsia, bilateral leg pain, and facial xanthoma/xanthelasma palpebrarum (XP) lesions. A biopsy of the bone lesions confirmed BRAF-positive ECD. The ECD lesions initially showed a good response to the cladribine/dexamethasone regimen; however, XP lesions were exacerbated during infliximab therapy, and did not respond to other conventional regimens. Eventually, XP lesions improved with trametinib (a MEK inhibitor) and dabrafenib (a BRAF inhibitor). Targeted therapy is indispensable in the management of ECD.