NcRNA Regulated Pyroptosis in Liver Diseases and Traditional Chinese Medicine Intervention: A Narrative Review.

Pyroptosis is a novel pro-inflammatory mode of programmed cell death that differs from ferroptosis, necrosis, and apoptosis in terms of its onset and regulatory mechanisms. Pyroptosis is dependent on cysteine aspartate protein hydrolase (caspase)-mediated activation of GSDMD, NLRP3, and the release of pro-inflammatory cytokines, interleukin-1 (IL-1ß), and interleukin-18 (IL-18), ultimately leading to cell death. Non-coding RNA (ncRNA) is a type of RNA that does not encode proteins in gene transcription but plays an important regulatory role in other post-transcriptional links. NcRNA mediates pyroptosis by regulating various related pyroptosis factors, which we termed the pyroptosis signaling pathway. Previous researches have manifested that pyroptosis is closely related to the development of liver diseases, and is essential for liver injury, alcoholic fatty liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, and liver cancer. In this review, we attempt to address the role of the ncRNA-mediated pyroptosis pathway in the above liver diseases and their pathogenesis in recent years, and briefly outline that TCM (Traditional Chinese Medicine) intervene in liver diseases by modulating ncRNA-mediated pyroptosis, which will provide a strategy to find new therapeutic targets for the prevention and treatment of liver diseases in the future.

A comprehensive review of bupleuri radix and its bioactive components： with a major focus on treating chronic liver diseases.

ETHNOPHARMACOLOGICAL RELEVANCE: Bupleuri Radix (BR) has been recognized as an essential herbal medicine for relieving liver depression for thousands of years. Contemporary research has provided compelling evidence of its pharmacological effects, including anti-inflammatory, immunomodulatory, metabolic regulation, and anticancer properties, positioning it as a promising treatment option for various liver diseases. Hepatitis, steatohepatitis, cirrhosis, and liver cancer are among the prevalent and impactful liver diseases worldwide. However, there remains a lack of comprehensive systematic reviews that explore the prescription, bio-active components, and underlying mechanisms of BR in treating liver diseases. AIM OF THE REVIEW: To summarize the BR classical Chinese medical prescription and ingredients in treating liver diseases and their mechanisms to inform reference for further development and research. MATERIALS AND METHODS: Literature in the last three decades of BR and its classical Chinese medical prescription and ingredients were collated and summarized by searching PubMed, Wiley, Springer, Google Scholar, Web of Science, CNKI, etc. RESULTS: BR and its classical prescriptions, such as Xiao Chai Hu decoction, Da Chai Hu decoction, Si Ni San, and Chai Hu Shu Gan San, have been utilized for centuries as effective therapies for liver diseases, including hepatitis, steatohepatitis, cirrhosis, and liver cancer. BR is a rich source of active ingredients, such as saikosaponins, polysaccharides, flavonoids, sterols, organic acids, and so on. These bioactive compounds exhibit a wide range of beneficial effects, including anti-inflammatory, antioxidant, immunomodulatory, and lipid metabolism regulation. However, it is important to acknowledge that BR and its constituents can also possess hepatotoxicity, which is associated with cytochrome P450 (CYP450) enzymes and oxidative stress. Therefore, caution should be exercised when using BR in therapeutic applications to ensure the safe and appropriate utilization of its potential benefits while minimizing any potential risks. CONCLUSIONS: To sum up, BR, its compounds, and its based traditional Chinese medicine are effective in liver diseases through multiple targets, multiple pathways, and multiple effects. Advances in pharmacological and toxicological investigations of BR and its bio-active components in the future will provide further contributions to the discovery of novel therapeutics for liver diseases.

Probiotics-A Promising Novel Therapeutic Approach in the Management of Chronic Liver Diseases.

An increased incidence of liver diseases has been observed in recent years and is associated with gut dysbiosis, which causes bacterial infection, intestinal permeability, and further leads to disease-related complications. Probiotics, active microbial strains, are gaining more clinical importance due to their beneficial effect in the management of many diseases, including liver diseases. Clinical scenarios show strong evidence that probiotics have efficacy in treating liver diseases due to their ability to improve epithelial barrier function, prevent bacterial translocation, and boost the immune system. Moreover, probiotics survive both bile and gastric acid to reach the gut and exert their health benefit. Evidence shows that probiotics are a promising approach to prevent several complications in clinical practice. Herein, we discuss the recent evidence, challenges, and appropriate use of probiotics in managing advanced liver diseases, which may have an impact on future therapeutic strategies. Furthermore, the superior effect of strain-specific probiotics and their efficacy and safety in managing liver diseases are discussed.

Glycyrrhizin and the Related Preparations: An Inspiring Resource for the Treatment of Liver Diseases.

Liver diseases and their related complications endanger the health of millions of people worldwide. The prevention and treatment of liver diseases are still serious challenges both in China and globally. With the improvement of living standards, the prevalence of metabolic liver diseases, including non-alcoholic fatty liver disease and alcoholic liver disease, has increased at an alarming rate, resulting in more cases of end-stage liver disease. Therefore, the discovery of novel therapeutic drugs for the treatment of liver diseases is urgently needed. Glycyrrhizin (GL), a triterpene glycoside from the roots of licorice plants, possesses a wide range of pharmacological and biological activities. Currently, GL preparations (GLPs) have certain advantages in the treatment of liver diseases, with good clinical effects and fewer adverse reactions, and have shown broad application prospects through multitargeting therapeutic mechanisms, including antisteatotic, anti-oxidative stress, anti-inflammatory, immunoregulatory, antifibrotic, anticancer, and drug interaction activities. This review summarizes the currently known biological activities of GLPs and their medical applications in the treatment of liver diseases, and highlights the potential of these preparations as promising therapeutic options and their alluring prospects for the treatment of liver diseases.

Therapeutic approaches for cholestatic liver diseases: the role of nitric oxide pathway.

Cholestasis describes bile secretion or flow impairment, which is clinically manifested with fatigue, pruritus, and jaundice. Neutrophils play a crucial role in many diseases such as cholestasis liver diseases through mediating several oxidative and inflammatory pathways. Data have been collected from clinical, in vitro, and in vivo studies published between 2000 and December 2021 in English and obtained from the PubMed, Google Scholar, Scopus, and Cochrane libraries. Although nitric oxide plays an important role in the pathogenesis of cholestatic liver diseases, excessive levels of NO in serum and affected tissues, mainly synthesized by the inducible nitric oxide synthase (iNOS) enzyme, can exacerbate inflammation. NO induces the inflammatory and oxidative processes, which finally leads to cell damage. We found that natural products such as baicalin, curcumin, resveratrol, and lycopene, as well as chemical likes ursodeoxycholic acid, dexamethasone, rosuvastatin, melatonin, and sildenafil, are able to markedly attenuate the NO production and iNOS expression, mainly through inducing the nuclear factor κB (NF-κB), Janus kinase and signal transducer and activator of transcription (JAK/STAT), and toll like receptor-4 (TLR4) signaling pathways. This study summarizes the latest scientific data about the bile acid signaling pathway, the neutrophil chemotaxis recruitment process during cholestasis, and the role of NO in cholestasis liver diseases. Literature review directed us to propose that suppression of NO and its related pathways could be a therapeutic option for preventing or treating cholestatic liver diseases.

Interface between Resolvins and Efferocytosis in Health and Disease.

Acute inflammation resolution acts as a vital process for active host response, tissue support, and homeostasis maintenance, during which resolvin D (RvD) and E (RvE) as mediators derived from omega-3 polyunsaturated fatty acids display specific and stereoselective anti-inflammations like restricting neutrophil infiltration and pro-resolving activities. On the other side of the coin, potent macrophage-mediated apoptotic cell clearance, namely efferocytosis, is essential for successful inflammation resolution. Further studies mentioned a linkage between efferocytosis and resolvins. For instance, resolvin D1 (RvD1), which is endogenously formed from docosahexaenoic acid within the inflammation resolution, thereby provoking efferocytosis. There is still limited information regarding the mechanism of action of RvD1-related efferocytosis enhancement at the molecular level. The current review article was conducted to explore recent data on how the efferocytosis process and resolvins relate to each other during the inflammation resolution in illness and health. Understanding different aspects of this connection sheds light on new curative approaches for medical conditions caused by defective efferocytosis and disrupted inflammation resolution.

Assessment of early anthracycline-induced cardiotoxicity and liver injury with T2 and T2* mapping in rabbit models.

OBJECTIVES: To evaluate the early prevalence of anthracycline-induced cardiotoxicity (AIC) and anthracycline-induced liver injury (AILI) using T2 and T2* mapping and to explore their correlations. MATERIALS AND METHODS: The study included 17 cardiotoxic rabbits that received weekly injections of doxorubicin and magnetic resonance imaging (MRI) every 2 weeks for 10 weeks. Cardiac function and T2 and T2* values were measured on each period. Histopathological examinations for two to five rabbits were performed after each MRI scan. The earliest sensitive time and the threshold of MRI parameters for detecting AIC and AILI based on these MRI parameters were obtained. Moreover, the relationship between myocardial and liver damage was assessed. RESULTS: Early AIC could be detected by T2 mapping as early as the second week and focused on the 7th, 11th, and 12th segments of left ventricle. The cutoff value of 46.64 for the 7th segment had the best diagnostic value, with an area under the curve (of 0.767, sensitivity of 100%, and specificity of 52%. T2* mapping could detect the change in iron content for early AIC at the middle interventricular septum and AILI as early as the sixth week (p = 0.014, p = 0.027). The T2* values of the middle interventricular septum showed a significant positive association with the T2* values of the liver (r = 0.39, p = 0.002). CONCLUSION: T2 and T2* mapping showed value one-stop assessment of AIC and AILI and could obtain the earliest MRI diagnosis point and optimal parameter thresholds for these conditions. CLINICAL RELEVANCE STATEMENT: Anthracycline-induced cardiotoxicity could be detected by T2 mapping as earlier as the second week, mainly focusing on the 7th, 11th, and 12th segments of left ventricle. Combined with T2* mapping, hepatoxicity and supplementary cardiotoxicity were assessed by one-stop scan. KEY POINTS: • MRI screening time of cardiotoxicity was as early as the second week with focusing on T2 values of the 7th, 11th, and 12th segments of left ventricle. • T2* mapping could be used as a complement to T2 mapping to evaluate cardiotoxicity and as an effective index to detect iron change in the early stages of chemotherapy. • The T2* values of the middle interventricular septum showed a significant positive association with the T2* values of the liver, indicating that iron content in the liver and heart increased with an increase in the chemotherapeutic drugs.

Use of complementary and alternative medicine in children affected by oncologic, neurologic and liver diseases: a narrative review.

Complementary and alternative medicine (CAM) consist of a broad group of restorative resources often linked to existing local cultures and established health care systems and are also increasingly used in children with some serious illnesses. In this narrative review, we examine the epidemiology of the use, efficacy, and safety of complementary and alternative medicine in pediatric oncology, neurology, and hepatology. We searched for relevant articles published in Pubmed evaluating CAM use and its efficacy in safety in children affected by oncologic, neurologic and liver diseases. CAM is used to improve the success of conventional therapies, but also to alleviate the pain, discomfort, and suffering resulting from the diseases and their treatment, which are often associated with a significant burden of adverse effects. CAM use must be evaluated in children with neurological, oncological and liver diseases.

Nutrition and Mental Well-Being: Exploring Connections and Holistic Approaches.

Quality of life, well-being, and psycho-emotional balance are closely related to the quality of the diet, the level of physical activity, the quality of rest, but also the absence of the consumption of narcotic substances and tobacco, or alcohol abuse. Based on the distribution of a questionnaire that included 30 questions, we aimed to statistically evaluate several factors that influence mental health and vices. It recorded a total of 1719 valid responses, which came from 78.3% female respondents and 21.7% male respondents. After processing the anthropometric data, it was observed that the majority of respondents are of normal weight (63.87%) and come from women in particular (36.13%). Based on the answers recorded, although over 60% of the respondents participating in the study are up to 40 years old, there is an increased tendency towards sedentarism (over 58% of the respondents declaring that they do sports very rarely or not at all), a low tendency regarding optimal consumption of vegetables and fruits, many respondents do not hydrate properly, which is why approximately 60% of respondents feel frequently tired, and over 32% are frequently nervous. The increased level of stress among the respondents and emotional eating are also generated by inadequate rest, reduced physical activity, and a diet that does not help the efficient detoxification of the body.

The effect of Moringa oleifera crude extract on liver cell line, HepG2.

BACKGROUND: The liver plays a crucial role in the body's metabolic and detoxification processes. Given its importance, compromised liver function can negatively impact the body's metabolic and physiological function. Liver diseases can result from several factors, including exposure to toxins, alcohol consumption, and viral infections. Therefore, finding natural remedies for liver protection and treatment is important. Moringa oleifera is a tree known for its various medicinal properties, including hepatoprotective effects. This study aimed to investigate the potential of M. oleifera seed extract in protecting liver cells. METHODS: In this study, dried-seed powder of M. oleifera was extracted using extraction solvents, methanol, and ethanol. HepG2 cells were cultured and treated with different concentrations of the extracts. The antioxidative activity, cell viability, and antiproliferation were assessed using the total antioxidant capacity assay (TAC) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Additionally, liver enzyme activity was determined through alkaline phosphatase and aspartate aminotransferase activity assays. RESULTS: The extracts had varying effects on liver cells depending on the concentration and time of exposure. Lower concentrations (50 mg/l and 100 mg/l) have mild stimulatory effects/minimal impact on metabolic activity, while higher concentrations (200 mg/l and 400 mg/l) tend to decrease metabolic activity, especially at later time points. Moreover, the extracts effectively reduced the levels of the liver enzyme AST, indicating their ability to mitigate liver injury. CONCLUSION: The study concludes that the crude extracts of M. oleifera seeds exhibit potential as a natural remedy for liver diseases. The effects of M. oleifera extract suggest that it has potential as a preventive and therapeutic agent for liver damage. This study highlights the importance of exploring natural remedies for liver protection and treatment.

Yao-Shan of traditional Chinese medicine: an old story for metabolic health.

Type 2 diabetes mellitus, nonalcoholic fatty liver disease (NAFLD), cardio-cerebrovascular diseases (CCVDs), hyperuricemia and gout, and metabolic-related sexual dysfunction are metabolic diseases that affect human health in modern society. Scientists have made great efforts to investigate metabolic diseases using cell models in vitro or animal models in the past. However, the findings from cells or animals are difficult to translate into clinical applications due to factors such as the in vitro and in vivo differences; the differences in anatomy, physiology, and genetics between humans and animals; and the differences in microbiome-host interaction. The Chinese have extensively used the medicated diet of traditional Chinese medicine (TCM) (also named as Yao-Shan of TCM, Chinese Yao-Shan et al.) to maintain or improve cardiometabolic health for more than 2,200 years. These ancient classic diets of TCM are essential summaries of long-term life and clinical practices. Over the past 5 years, our group has made every effort to collect and sort out the classic Yao-Shan of TCM from the ancient TCM literature since Spring and Autumn and Warring States Period, especially these are involved in the prevention and treatment of metabolic diseases, such as diabetes, NAFLD, CCVDs, hyperuricemia and gout, and sexual dysfunction. Here, we summarized and discussed the classic Yao-Shan of TCM for metabolic diseases according to the time recorded in the ancient literature, and revised the Latin names of the raw materials in these Yao-Shan of TCM. Moreover, the modern medicine evidences of some Yao-Shan of TCM on metabolic diseases have also been summarized and emphasized in here. However, the exact composition (in terms of ratios), preparation process, and dosage of many Yao-Shan are not standardized, and their main active ingredients are vague. Uncovering the mystery of Yao-Shan of TCM through modern biological and chemical strategies will help us open a door, which is ancient but now looks new, to modulate metabolic homeostasis and diseases.

Pharmacological Benefits and Underlying Mechanisms of Salvia miltiorrhiza against Molecular Pathology of Various Liver Diseases: A Review.

Salvia miltiorrhiza Bunge, called Danshen in Chinese, is the dried root and rhizome of S. miltiorrhiza, which is part of the mint family, Lamiaceae; it has chiefly been used to treat blood stasis and improve blood flow in cerebrovascular and cardiovascular diseases for over 2000 years. Recent preclinical studies have indicated that S. miltiorrhiza has a wide range of pharmacological properties making it useful for the treatment of diverse liver diseases. S. miltiorrhiza protects the liver from harmful hepatotoxins, reduces hepatic oxidative stress, ameliorates steatosis, and alleviates hepatic inflammation, fibrosis, and cancer. Moreover, several key mechanisms, including apoptosis, AMP-activated protein kinase, mitogen-activated protein kinase, and nuclear factor kappa B, may be involved in the benefits of S. miltiorrhiza in hepatic disorders. In particular, salvianolic acid B and cryptotanshinone, both compounds derived from S. miltiorrhiza, possess therapeutic activities similar to those of S. miltiorrhiza, and thus may play a crucial role in the therapeutic activity of S. miltiorrhiza in liver diseases. Because reports on the pharmacological effects of this herb are scattered, this review aimed to consolidate the available literature to allow the re-evaluation and identification of gaps to guide future research. This review focuses on the role of S. miltiorrhiza in improving the molecular pathology of liver diseases, as reported in in vitro and in vivo studies.

Green Alternatives in Treatment of Liver Diseases: the Challenges of Traditional Medicine and Green Nanomedicine.

Over the last decade, liver diseases have become a global problem, with approximately two million deaths per year. The high increase in the mortality rate of these diseases is mostly related to the limitations in the understanding of the evolutionary clinical cases of liver diseases, the low delivery of drugs in the liver, the non-specific administration of drugs, and the side effects generated at the systemic level by conventional therapeutic agents. Today it is common knowledge that phytochemicals have a high curative potential, even in the prevention and/or reversibility of liver disorders; however, even using these green molecules, researchers continue to deal with the same challenges implemented with conventional therapeutic agents, which limits the pharmacological potential of these friendly molecules. On the other hand, the latest advances in nanotechnology have proven that the use of nanocarriers as a delivery system for green active ingredients, as well as conventional ones, increases the pharmacological potential of these active ingredients due to their physicochemical characteristics (size, Zeta potential, etc.,) moldable depending on the therapeutic objective; in addition to the above, it should be noted that in recent years, nanoparticles have been developed for the specific delivery of drugs towards a specific target (stellar cells, hepatocytes, Kupffer cells), depending on the clinical state of the disease in the patient. The present review addresses the challenges of traditional medicine and green nanomedicine as alternatives in the treatment of liver diseases.

The Role of Selenium Nanoparticles in the Treatment of Liver Pathologies of Various Natures.

The liver is the body's largest gland, and regulates a wide variety of physiological processes. The work of the liver can be disrupted in a variety of pathologies, the number of which is several hundred. It is extremely important to monitor the health of the liver and develop approaches to combat liver diseases. In recent decades, nanomedicine has become increasingly popular in the treatment of various liver pathologies, in which nanosized biomaterials, which are inorganic, polymeric, liposomal, albumin, and other nanoparticles, play an important role. Given the need to develop environmentally safe, inexpensive, simple, and high-performance biomedical agents for theragnostic purposes and showing few side effects, special attention is being paid to nanoparticles based on the important trace element selenium (Se). It is known that the metabolism of the microelement Se occurs in the liver, and its deficiency leads to the development of several serious diseases in this organ. In addition, the liver is the depot for most selenoproteins, which can reduce oxidative stress, inhibit tumor growth, and prevent other liver damage. This review is devoted to the description of the results of recent years, revealing the important role of selenium nanoparticles in the therapy and diagnosis of several liver pathologies, depending on the dose and physicochemical properties. The possibilities of selenium nanoparticles in the treatment of liver diseases, disclosed in the review, will not only reveal the advantages of their hepatoprotective properties but also significantly supplement the data on the role of the trace element selenium in the regulation of these diseases.

Chlorogenic acids: A pharmacological systematic review on their hepatoprotective effects.

BACKGROUND: Liver diseases have a negative impact on global health and are a leading cause of death worldwide. Chlorogenic acids (CGAs), a family of esters formed between certain trans-cinnamic acids and quinic acid, are natural polyphenols abundant in coffee, tea, and a variety of traditional Chinese medicines (TCMs). They are reported to have good hepatoprotective effects against various liver diseases. PURPOSE: This review aims to analyze the available literature on the hepatoprotective effect of CGAs, with particular emphasis on their mechanisms. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. PubMed and Web of Science databases were adopted to retrieve all relevant literature on CGAs for liver disease from 2013 to March 2023. RESULTS: Research has indicated that CGAs play a crucial role in improving different types of liver diseases, including drug-induced liver injury (DILI), alcoholic liver disease (ALD), metabolic (dysfunction)-associated fatty liver disease (MAFLD), cholestatic liver disease (CLD), liver fibrosis, and liver cancer. CGAs display remarkable antioxidant and anti-inflammatory effects by activating erythroid 2-related factor 2 (Nrf2) and inhibiting toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathways. Some important molecules such as AMP-activated protein kinase (AMPK) and extracellular signal-regulated kinases 1 and 2 (ERK1/2), and other key physiological processes like intestinal barrier and gut microbiota have also been discovered to participate in CGAs-provided amelioration on various liver diseases. CONCLUSION: In this review, different studies indicate that CGAs have an excellent protective effect against various liver diseases associated with various signaling pathways.

Unraveling the Antioxidant Capacity of Spatholobi caulis in Nonalcoholic Fatty Liver Disease: A Multiscale Network Approach Integrated with Experimental Validation.

Nonalcoholic fatty liver disease (NAFLD) is a global health problem that is closely associated with obesity and metabolic syndrome. Spatholobi caulis (SC) is a herbal medicine with potential hepatoprotective effects; however, its active compounds and underlying mechanisms have not been fully explored. In this study, we combined a multiscale network-level approach with experimental validation to investigate SC's antioxidant properties and their impact on NAFLD. Data collection and network construction were performed, and active compounds and key mechanisms were identified through multi-scale network analysis. Validation was conducted using in vitro steatotic hepatocyte models and in vivo high-fat diet-induced NAFLD models. Our findings revealed that SC treatment improved NAFLD by modulating multiple proteins and signaling pathways, including AMPK signaling pathways. Subsequent experiments showed that SC treatment reduced lipid accumulation and oxidative stress. We also validated SC's effects on AMPK and its crosstalk pathways, emphasizing their role in hepatoprotection. We predicted procyanidin B2 to be an active compound of SC and validated it using a lipogenesis in vitro model. Histological and biochemical analyses confirmed that SC ameliorated liver steatosis and inflammation in mice. This study presents SC's potential use in NAFLD treatment and introduces a novel approach for identifying and validating active compounds in herbal medicine.

Recent insights into the hepatoprotective potential of medicinal plants and plant-derived compounds.

Liver problems are a worldwide concern, and conventional medicinal therapies are ineffective. Hence, safeguarding the healthy liver is vital for good health and well-being. Infections due to virus, immune problems, cancer, alcohol abuse, and an overdose of drugs are some of the causes of liver diseases. Antioxidants derived from medicinal plants and conventional dietary sources can protect the liver from damages caused by oxidative stress system and various chemicals. Plants and plant-derived phytochemicals are appealing hepatoprotective agents since they have less side effects and still there is a lot of interest shown in using herbal tonics for treating liver disorders. This review therefore primarily focuses on newly discovered medicinal plants and compounds produced from plants that fall under the classifications of flavonoids, alkaloids, terpenoids, polyphenolics, sterols, anthocyanins, and saponin glycosides, all of which have the potential to be hepatoprotective. Hosta plantaginea, Ligusticum chuanxiong, Daniella oliveri, Garcinia mangostana, Solanum melongena, Vaccinium myrtillus, Picrorhiza kurroa, and Citrus medica are some potential plants having hepatoprotective effects. We conclude that these phytochemicals and the plant extracts listed above are used in the future to treat a variety of liver diseases, additional research is still needed to develop safer and more potent phytochemical drugs.

Plants-based medicine implication in the evolution of chronic liver diseases.

Hepatic disorders are considered major health problems, due to their high incidence, increased risk of chronicling or death and the costs involved in therapies. A large number of patients with chronic liver diseases use herbal medicines and dietary supplements in parallel with allopathic treatment. The current review provides a thorough analysis of the studies conducted on the most important species of medicinal plants used in this disease, bioactive compounds and on the activity of herbal medicines in the evolution of chronic liver diseases. However, a negative aspect is that there is frequently a lack of comprehensive data on the progression of the illness and the living standards of patients who are affected when evaluating the effects of these phytocomponents on the evolution of chronic liver disease, the patients' health, and their quality of life. It is essential to take this impairment into account when evaluating the long-term effects of herbal treatments on the health of individuals who suffer from liver illness. Bioactive phytocomponents may be a suitable source for the development of novel medications due to the correlation between traditional uses and medical advances. Additional high-quality preclinical examinations utilizing cutting-edge approaches are needed to assess safety and effectiveness and to detect, categorize, and standardize the active substances and their formulations for the most suitable therapeutic management of liver illnesses.

Improving quality of life in patients with rare autoimmune liver diseases by structured peer-delivered support (Q.RARE.LI): study protocol for a transnational effectiveness-implementation hybrid trial.

BACKGROUND: Psychosocial support is a crucial component of adequate rare disease care, but to date psychosocial support needs of this patient population are insufficiently met. Within Q.RARE.LI, we strive to evaluate the effectiveness of a structured, transdiagnostic, and location-independent psychosocial support intervention in routine care of patients with rare autoimmune liver diseases in five countries and prepare its implementation. METHODS: Within an effectiveness-implementation hybrid trial, we aim to a) investigate the effectiveness of the intervention in routine care in five diverse healthcare systems and b) assess implementation outcomes, examine and prepare the implementation context, and develop country-specific implementation strategies. To assess effectiveness, we will include N = 240 patients with rare autoimmune liver diseases. Within a two-armed randomized controlled trial (allocation ratio 1:1), we will compare structured and peer-delivered psychosocial support in addition to care-as-usual (CAU) with CAU alone. Outcomes will be assessed via electronic database entry prior to intervention, directly after, and at a three-month follow-up. Our primary effectiveness outcome will be mental health-related quality of life at post-assessment. Secondary outcomes include depression and anxiety severity, perceived social support, helplessness, and disease acceptance. Implementation outcomes will be assessed within a mixed-methods process evaluation. In a quantitative cross-sectional survey, we will examine perceived acceptability and feasibility in patients, peer-counselors, and healthcare providers involved in delivery of the intervention. In qualitative focus groups, we will analyze the implementation context and determine barriers and facilitators for implementation with different stakeholders (patients and/or representatives, peer-counselors, healthcare providers, health insurers). Based on these results, we will derive country-specific implementation strategies and develop a concrete implementation plan for each country. DISCUSSION: The intervention is expected to help patients adjust to their disease and improve their mental quality of life. The transdiagnostic and location-independent program has the potential to reach patients for psychosocial support who are usually hard to reach. By preparing the implementation in five countries, the project can help to make low-threshold psychosocial support available to many patients with rare diseases and improve comprehensive healthcare for an often neglected group. TRIAL REGISTRATION: ISRCTN15030282.