Gallstone (GS) disease is common and arises from a combination of genetic and environmental factors. Although genetic abnormalities specifically leading to cholesterol GSs are rare, there are clinically significant gene variants associated with cholesterol GSs. In contrast, most bilirubin GSs can be attributed to genetic defects. The pathogenesis of cholesterol and bilirubin GSs differs greatly. Cholesterol GSs are notably influenced by genetic variants within the ABC protein superfamily, including ABCG8, ABCG5, ABCB4, and ABCB11, as well as genes from the apolipoprotein family such as ApoB100 and ApoE (especially the E3/E3 and E3/E4 variants), and members of the MUC family. Conversely, bilirubin GSs are associated with genetic variants in highly expressed hepatic genes, notably UGT1A1, ABCC2 (MRP2), ABCC3 (MRP3), CFTR, and MUC, alongside genetic defects linked to hemolytic anemias and conditions impacting erythropoiesis. While genetic cases constitute a small portion of GS disease, recognizing genetic predisposition is essential for proper diagnosis, treatment, and genetic counseling.

The correlation between gut, secreted metabolites, and hepatic diseases has strengthened over the last decade. Interactions of intestinal permeability, gut microbes, and derived metabolites influence the development and progression of nonalcoholic fatty liver disease (NAFLD), a prevalent disease that affects more than 30% of the global population. NAFLD is now called metabolic dysfunction-associated steatotic liver disease (MASLD) to better reflect the disease process. Here, we describe mechanisms of NAFLD development, the role of gut bacteria, gut metabolites, interventions for diagnosis, and the prognosis of NAFLD. We discuss new paradigms that challenge the conventional, addressing disease etiology and translational approaches in a new dimension. Previous studies shed light on intricate relationships of the gut microbiome with the liver, or the gut-liver axis. Bidirectional communication between the gut and the liver involves exchange of metabolites, immune signaling, and inflammatory responses that has potential for novel NAFLD/nonalcoholic steatohepatitis (NASH) treatments. In this review, we propose exploring functional metagenomics to develop NAFLD diagnostic methods and risk assessment. The prospects of genetic engineering, fecal transplants, and specialized diet as targets of novel therapeutic regimes to combat NAFLD/NASH are discussed. Changes in lifestyle and diet in the population, combined with genetic predisposition, have led to an increasing number of cases of NAFLD. The microbiome responds to diet, exercise, and the environment, and can modulate NAFLD in cases with surgical impediments. It is thus vital to explore its emerging roles in human healthcare and not only liver disease.

Cancer is a significant global health issue and a primary cause of death. Extensive research has led to the development of various anticancer medications, driven by an improved knowledge and comprehension of the molecular pathways involved in cancer growth. However, there is a need for new approaches to enhance the effectiveness of existing cancer therapies. Dietary phytochemicals have gained increasing attention due to their potential role in tumor prevention. These bioactive compounds derived from plants exhibit a wide range of beneficial effects on human health, including their ability to inhibit carcinogenesis and promote anticancer activities. Examples of dietary phytochemicals with promising properties include vitamin D, vitamin E, lycopene, fisetin, genistein, epigallocatechin gallate, crocetin, curcumin, cyanidins, and gingerol. These compounds often exert their effects by regulating interconnected molecular pathways associated with cancer development and progression. Some of these pathways include the apoptosis pathway, cyclooxygenase-2 pathway, ATP-dependent chromatin remodeling pathway, DNA methylation-epigenetic pathway, Hedgehog signaling pathway, signal transducer and activator of transcription protein-3 pathway, tumor angiogenesis inhibition pathway, and Wnt pathway. This comprehensive review aims to summarize the current knowledge on the role of dietary phytochemicals in tumor prevention, highlighting their mechanisms of action and potential therapeutic applications.

Cannabis is a commonly used recreational and therapeutic substance in our society. There are a variety of established physical, social, and mental health impacts associated with cannabis use. However, there is no overview of the impact cannabis use has on the genitourinary system. Thus, this scoping review aims to present data on the impact of cannabis on the genitourinary system.

A scoping review search was undertaken on Embase, Medline, and Web of Science. There were no date restrictions applied. Studies that included data from humans, exposure to cannabis, and outcomes related to the genitourinary system were included. Opinion pieces, commentaries, perspectives, and studies not available in English were excluded.

A total of 50 articles met this review’s inclusion criteria. The various studies were thematically organized into four themes: adverse outcomes related to cancer (n = 4), non-cancerous urogenital illness (n = 31), kidney transplant (n = 4), and therapeutic use of cannabis (n = 11). There were several non-cancerous urogenital illnesses associated with cannabis use, including acute kidney injury, urinary retention, rhabdomyolysis, and renal infarcts. The data found in this review suggest that cannabis use may not be a contraindication to receiving a kidney transplant. Finally, several studies highlighted some of the therapeutic applications cannabis may have on the genitourinary system.

This review brings forward conflicting findings on the association between cannabis use and genitourinary malignancies. Moving forward, data from well-designed long-term research studies are needed to understand the impact cannabis use has on the genitourinary system.

Liver iron overload can induce hepatic expression of bone morphogenic protein (BMP) 6 and activate the BMP/SMAD pathway. However, serum iron overload can also activate SMAD but does not induce BMP6 expression. Therefore, the mechanisms through which serum iron overload activates the BMP/SMAD pathway remain unclear. This study aimed to clarify the role of SMURF1 in serum iron overload and the BMP/SMAD pathway.

A cell model of serum iron overload was established by treating hepatocytes with 2 mg/mL of holo-transferrin (Holo-Tf). A serum iron overload mouse model and a liver iron overload mouse model were established by intraperitoneally injecting 10 mg of Holo-Tf into C57BL/6 mice and administering a high-iron diet for 1 week followed by a low-iron diet for 2 days. Western blotting and real-time PCR were performed to evaluate the activation of the BMP/SMAD pathway and the expression of hepcidin.

Holo-Tf augmented the sensitivity and responsiveness of hepatocytes to BMP6. The E3 ubiquitin-protein ligase SMURF1 mediated Holo-Tf-induced SMAD1/5 activation and hepcidin expression; specifically, SMURF1 expression dramatically decreased when the serum iron concentration was increased. Additionally, the expression of SMURF1 substrates, which are important molecules involved in the transduction of BMP/SMAD signaling, was significantly upregulated. Furthermore, in vivo analyses confirmed that SMURF1 specifically regulated the BMP/SMAD pathway during serum iron overload.

SMURF1 can specifically regulate the BMP/SMAD pathway by augmenting the responsiveness of hepatocytes to BMPs during serum iron overload.

The results of new randomized clinical trials show that immunotherapy is the preferred treatment for a small proportion of metastatic colorectal cancers (mCRCs). For microsatellite instability-high mCRC, pembrolizumab, nivolumab, and ipilimumab are currently authorized as first- and second-line immune checkpoint agents. However, the problem concerns tumors with microsatellite stability where the “cold” microenvironment does not allow immunotherapy to function properly. All efforts are now aimed at ensuring that this microenvironment is inflamed and “hot”. In this review, we examine recent studies on immunotherapy for mCRC and assess novel drivers of immunotherapy response.

Our recent work has focused on the application of infinite group theory and related algebraic geometric tools in the context of transcription factors and microRNAs. We were able to differentiate between “healthy” nucleotide sequences and disrupted sequences that may be associated with various diseases. In this paper, we extend our efforts to the study of messenger RNA (mRNA) metabolism, showcasing the power of our approach.

To achieve this, we used: (a) infinite (finitely generated) groups , with generators representing the distinct nucleotides and a relation between them [e.g., the consensus sequence in the mRNA translation (i), the poly(A) tail in item (ii), and the microRNA seed in item (iii)]; (b) aperiodicity theory, which connects healthy groups to free groups of rank r and their profinite completion , and (c) the representation theory of groups over the space-time-spin group SL2(C), highlighting the role of surfaces with isolated singularities in the character variety.

We investigate (1) mRNA translation in prokaryotes and eukaryotes, (2) polyadenylation in eukaryotes, which is crucial for nuclear export, translation, stability, and splicing of mRNA, (3) microRNAs involved in RNA silencing and post-transcriptional regulation of gene expression, and (4) identification of disrupted sequences that could lead to potential illnesses.

Our approach could potentially contribute to the understanding of the molecular mechanisms underlying various diseases and help develop new diagnostic or therapeutic strategies.

Non-alcoholic fatty liver disease (NAFLD) is an extremely prevalent disease, and the presence and severity of liver fibrosis are considered one of the most important factors determining its prognosis. Hepatic stellate cells (HSCs) are essential in hepatic fibrogenesis associated with NAFLD. A number of factors underlying NAFLD pathogenesis may promote HSCs activation, leading to the development of profibrotic and proinflammatory signs. In addition, for the fibrogenic transdifferentiation of quiescent HSCs, alterations in multiple genes are necessary, where epigenetic regulation plays a defining role. Epigenetic regulation induces changes in gene activity without altering the coding sequence, and these changes are stably inherited after the factor causing the alteration has disappeared. Epigenetic modifications comprise several regulatory mechanisms, including DNA methylation, covalent histone modification, chromatin remodeling, and non-coding RNAs. Since the mechanisms underlying epigenetic regulation of HSCs fibrogenic activation are reversible and dynamic, molecular targeted therapies aimed at correcting these mechanisms provide promising prospects for novel therapeutic approaches for treating liver fibrosis associated with NAFLD.

The impact of the characteristics of extrahepatic organ failure (EHOF) including the onset time, number, type, and sequence on the prognosis of acute-on-chronic liver failure (ACLF) patients remains unknown. This study aimed to identify the association between the characteristics of EHOF and the prognosis of ACLF patients.

ACLF subjects enrolled at six hospitals in China were included in the analysis. The risk of mortality based on the characteristics of EHOF was evaluated. Survival of study groups was compared by Kaplan–Meier analysis and log-rank tests.

A total of 736 patients with ACLF were included. EHOF was observed in 402 patients (54.6%), of which 295 (73.4%) developed single EHOF (SEHOF) and 107 (26.6%) developed multiple EHOF (MEHOF). The most commonly observed EHOF was coagulation failure (47.0%), followed by renal (13.0%), brain (4.9%), respiratory (4.3%), and circulatory (2.3%) failure. Survival analysis found that MEHOF or SEHOF patients with brain failure had a worse prognosis. However, no significant outcome was found in the analysis of the effect of onset time and sequence of failed organs on prognosis. Patients were further divided into three risk subgroups by the EHOF characteristics. Kaplan–Meier analysis showed that risk stratification resulted in the differentiation of patients with different risks of mortality both in the training and validation cohorts.

The mortality of ACLF patients was determined by the number and type, but not the onset time and sequence of EHOF. Risk stratification applicable to clinical practice was established.

Biliary atresia (BA) is a congenital cholestatic disease that can seriously damage children’s liver function. It is one of the main reasons for liver transplantation in children. Early diagnosis of BA is crucial to the prognosis of patients, but there is still a lack of reliable non-invasive diagnostic methods. Additionally, as some children are in urgent need of liver transplantation, evaluating the stage of liver fibrosis and postoperative native liver survival in children with BA using a straightforward, efficient, and less traumatic method is a major focus of doctors. In recent years, an increasing number of BA-related biomarkers have been identified and have shown great potential in the following three aspects of clinical practice: diagnosis, evaluation of the stage of liver fibrosis, and prediction of native liver survival. This review focuses on the pathophysiological function and clinical application of three novel BA-related biomarkers, namely MMP-7, FGF-19, and M2BPGi. Furthermore, progress in well-known biomarkers of BA such as gamma-glutamyltransferase, circulating cytokines, and other potential biomarkers is discussed, aiming to provide a reference for clinical practice.

Sarcopenia is a well-known complication of chronic liver disease (CLD), and it is almost always observed in patients with cirrhosis, at least in those with decompensated disease. Since nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is becoming the leading cause of end-stage liver disease, a new scenario characterized by the frequent coexistence of NAFLD, obesity, and sarcopenia is emerging. Although it is not yet resolved whether the bidirectional relationship between sarcopenia and NAFLD subtends causal determinants, it is clear that the interaction of these two conditions is associated with an increased risk of poor outcomes. Notably, during the course of CLD, deregulation of the liver-muscle-adipose tissue axis has been described. Unfortunately, owing to the lack of properly designed studies, specific therapeutic guidelines for patients with sarcopenia in the context of NAFLD-related CLD have not yet been defined. Strategies aimed to induce the loss of fat mass together with the maintenance of lean body mass seem most appropriate. This can be achieved by properly designed diets integrated with specific nutritional supplementations and accompanied by adequate physical exercise. Future studies aiming to add to the knowledge of the correct assessment and approach to sarcopenia in the context of NAFLD-related CLD are eagerly awaited.

Hepatic lipid homeostasis is not only essential for maintaining normal cellular and systemic metabolic function but is also closely related to the steatosis of the liver. The controversy over the nomenclature of non-alcoholic fatty liver disease (NAFLD) in the past three years has once again sparked in-depth discussions on the pathogenesis of this disease and its impact on systemic metabolism. Pituitary-targeted gland axes (PTGA), an important hormone-regulating system, are indispensable in lipid homeostasis. This review focuses on the roles of thyroid hormones, adrenal hormones, sex hormones, and their receptors in hepatic lipid homeostasis, and summarizes recent research on pituitary target gland axes-related drugs regulating hepatic lipid metabolism. It also calls on researchers and clinicians to recognize the concept of endocrine-associated fatty liver disease (EAFLD) and to re-examine human lipid metabolism from the macroscopic perspective of homeostatic balance.

China accounts for 14.9% of total cirrhosis deaths worldwide. A detailed and comprehensive understanding of the contemporary status of cirrhosis mortality in China is crucial for establishing strategies for intervention and decreasing the disease burden of cirrhosis worldwide. The study aimed to report the cirrhosis mortality rates in our whole country or province over time.

Mortality data from 2008 to 2020 were retrieved from the Disease Surveillance Point System (DSPs) of the Chinese Center for Disease Control and Prevention. The crude mortality rate and age-standardized mortality rate of patients with cirrhosis were stratified by sex, residential location, and region. The average annual percentage change (AAPC) in cirrhosis mortality rates from 2008 to 2020 was also calculated.

The crude mortality rate of cirrhosis was 4.57/100,000 people in 2020. Compared with females and individuals living in urban areas, males and people living in rural areas had greater age-standardized mortality. The crude mortality rate and age-standardized mortality rate in provinces in Southwest China (Guangxi, Yunnan, Guizhou, and Qinghai) were greater than those in other provinces. Moreover, with increasing age, the age-specific mortality rate increased significantly. From 2008 to 2020, the mortality rate of cirrhosis in China decreased except for in males aged 50–59 years, females aged 45–49 years and females aged 80–84 years.

The mortality rate of patients with cirrhosis in China decreased from 2008 to 2020. In the future, interventions of cirrhosis mortality control need to pay more attention to all males, females aged 45–49 and 80–84 years, and people living in rural areas and in provinces in Southwest China.

Infectious diseases caused by pathogenic strains of bacteria are a global cause of morbidity and mortality. Hospital-acquired infections caused by Klebsiella pneumonia and Pseudomonas aeruginosa were found vulnerable during the COVID-19 pandemic. They are also responsible for the onset of certain life-threatening infectious diseases such as cystic fibrosis, endocarditis, bacteremia, and sepsis. Looking into the importance of these two superbugs there is a strong need for extensive comparative differential gene expression analysis among the wild-type and mutant for betterment of intensive care unit patients especially as such pathogenic bacterial strains have a dangerous role in the intensive care unit.

This study revealed the RNA microarray gene expression profiles of GSE24688, GSE4026, and GSE117438. The study compared all genes from three different datasets and all drug resistance genes from two divergent organisms, Klebsiella pneumonia and Pseudomonas aeruginosa.

10 numbers of shared significant genes and five drug resistance genes were obtained in this study. These putative genes may show intriguing patterns of connection with resistance mechanisms and can be used in the field of diagnostics and treatment. Our divergent analysis also revealed a very clear distinct relation between Klebsiella pneumoniae and Pseudomonas aeruginosa at the genetic level, though they both function under antimicrobial resistance.

This study enhances the understanding of the genetic basis, providing valuable knowledge for the development of new strategies to combat antibiotic resistance and enhance the efficacy of existing antibiotics.

Over time, the pursuit of unraveling the source and process of a regular cell’s conversion into cancer has resulted in diverse theories. These can be as diverse as considering cancer to be a supernatural ailment or comprehending the complex dynamics found within specific cancer subtypes, where several biological challenges must be addressed. Several validated screening methods are scarce for many types of cancer, and the existing ones have their limitations. This often results in low patient adherence and unnecessary medical procedures, increasing the financial burden on healthcare systems. Consequently, there is a pressing demand for inventive, precise, and less intrusive instruments for detecting cancer at an early stage. In recent times, multicancer early detection (MCED) tests have emerged as a promising approach. These tests utilize molecular analysis of tumor-related markers found in bodily fluids and incorporate artificial intelligence to simultaneously identify various cancer types and distinguish between them. Despite ongoing evaluation in numerous significant clinical trials, MCED tests may become clinically available soon without a standardized framework for assessing their performance and safety. Currently, it is only a few of them are available to doctors with different mechanisms to detect cancer but have not been approved by the Food and Drug Administration for the market. In this article, we aim to highlight the currently developed various strategies for MCED and the major factors that are preventing their clinical implementation.

The traditional definition of epigenetics encompasses all molecular pathways that affect how a genotype expresses itself on the way to a particular phenotype, with epigenetics serving as the interface between genotype and phenotype. Unlike genetic changes, which may have protracted, irreversible effects on health and the emergence of illnesses, epigenetic modifications are reversible and do not change the DNA sequence. However, they can affect how our bodies interpret DNA sequences. Gene expression regulated by epigenetics has emerged as a major contributing element to the etiology of many diseases over time and a crucial determinant of human health. One of the strongest arguments in support of gene expression controlled by epigenetics comes from the startling discovery that DNA methylation causes X-chromosome inactivation, which has been connected to several diseases. The intrinsic uterine environment, where the embryo and fetus grow and develop over time to become neonates is vulnerable to early epigenetic settings throughout development, affecting the offspring’s long-term health as well as their predisposition for different diseases. The epigenetic settings of germ cell development are influenced by environmental factors, which can result in transgenerational epigenetic effects. Therefore, in this article, we essentially provide a summary of the present level of understanding concerning the function of epigenetics regarding critical facets of human health, including in embryonic development and adulthood, with a particular emphasis on explaining the underlying diverse epigenetic mechanisms that regulate the onset of many human diseases, as well as cutting-edge technological tools used to study the human epigenome. Finally, we talk about the state of epigenetic therapies, which might be put to use in the treatment of a range of human diseases.

The high mortality rate in hepatocellular carcinoma (HCC) is partially due to the fact that a significant number of patients are diagnosed at an intermediate or advanced stage, with surgical treatment options unavailable. Conversion therapy, which involves both locoregional and systemic treatments, has the potential to downstage tumors in selected patients with initially unresectable HCC, thereby making surgical treatment a possibility and potentially increasing long-term survival. To optimize the conversion rate, it is necessary to maximize successful conversions and clearly define the target population for conversion treatment through a collaborative effort. In this review article, we summarize the clinical experience and evidence for conversion therapy in patients with ‘potentially resectable’ HCC from four perspectives: 1) defining the target population for conversion therapy, 2) selecting the appropriate conversion strategy, placing emphasis on the utilization of combination therapy that exhibits a significant objective response rate, 3) determining the timing and urgency of surgical resection, 4) promoting the adoption of a multidisciplinary team model. The authors are optimistic that with the continuous progress in treatment and a deeper understanding of HCC, the success rate of HCC conversion therapy will increase, and the overall survival of HCC patients will be prolonged.

The roles of γδ T cells in liver cancer, especially in the potential function of immunotherapy due to their direct cytotoxic effects on tumor cells and secretion of important cytokines and chemokines, have aroused research interest. This review briefly describes the basic characteristics of γδ T cells, focusing on their diverse effects on liver cancer. In particular, different subtypes of γδ T cells have diverse or even opposite effects on liver cancer. We provide a detailed description of the immune regulatory network of γδ T cells in liver cancer from two aspects: immune components and nonimmune components. The interactions between various components in this immune regulatory network are dynamic and pluralistic, ultimately determining the biological effects of γδ T cells in liver cancer. We also integrate the current knowledge of γδ T-cell immunotherapy for liver cancer treatment, emphasizing the potential of these cells in liver cancer immunotherapy.

The T-cell acute lymphoblastic leukemia 1 (TAL-1) transcription factor is crucial for T-cell differentiation, but the ectopic expression in 30% of cases can disrupt normal differentiation, and promote cancer progression. This can be due to microRNA (miRNA) dysregulation or other oncogenes. The present study covers articles related to T-cell acute lymphoblastic leukemia (T-ALL), TAL-1 and miRNA, which were published in the English language from 1994 to 2023. After analyzing the research, it is evident that the TAL-1 overexpression is associated with alterations in several miRNAs, which encompass both those that suppress tumors, and those that stimulate cell growth. The interplay between TAL-1 and miRNAs exhibits diverse dynamics. For example, specific miRNAs, such as miR-223, interact with the TAL-1 gene promoter, resulting in its upregulation. In contrast, the miR-17-92 cluster indirectly influences the stability of the TAL-1 transcription complex. Typically, the interaction between TAL-1 and its associated miRNAs follows a unidirectional pattern, in which miRNAs that target TAL-1 are downregulated, leading to elevated TAL-1 levels. Nevertheless, TAL-1 exhibits a bidirectional relationship with miR-223, in which each positively affects the expression of the other. In addition, there is a cooperative interaction between miR-146-5b and TAL-1. Unlike miR-223, TAL-1 reduces the expression of miR-146-5b, thereby inhibiting tumor growth. Individuals with T-ALL, who experience disruptions in the TAL-1 and miRNA network, often face a poor prognosis, and their tumors tend to be larger. In conclusion, delving deeper into the network of miRNAs associated with TAL-1 in T-ALL offers a novel perspective on cancer prognosis and the development of improved diagnostic and treatment strategies.