Livers, Volume 4, Issue 1 (March 2024) – 11 articles

Heat shock proteins are intracellular proteins expressed in prokaryotes and eukaryotes that help protect the cell from stress. They play an important role in regulating cell cycle and cell death, work as molecular chaperons during the folding of newly synthesized proteins, and also in the degradation of misfolded proteins. They are not only produced under stress conditions like acidosis, energy depletion, and oxidative stress but are also continuously synthesized as a result of their housekeeping functions. There are different heat shock protein families based on their molecular weight, like HSP70, HSP90, HSP60, HSP27, HSP40, etc. Heat shock proteins are involved in many cancers, particularly hepatocellular carcinoma, the main primary tumor of the liver in adults. Their deregulations in hepatocellular carcinoma are associated with metastasis, angiogenesis, cell invasion, and cell proliferation and upregulated heat shock proteins can be used as either diagnostic or prognostic markers. Targeting heat shock proteins is a relevant strategy for the treatment of patients with liver cancer. In this review, we provide insights into heat shock proteins and heat shock protein-like proteins (clusterin) in the progression of hepatocellular carcinoma and their use as therapeutic targets. Full article

Since the end of the 20th century and the establishment of minimally invasive techniques, they have become the preferred operative method by many surgeons. These techniques were applied to liver surgery for the first time in 1991, while as far as transplantation is concerned their application was limited to the living donor procedure. We performed a review of the literature by searching in Pubmed and Scopus using the following keywords: Liver transplantation, Minimally invasive surgery(MIS) living liver donor surgery. Applications of MIS are recorded in surgeries involving the donor and the recipient. Regarding the recipient surgeries, the reports are limited to 25 patients, including combinations of laparoscopic, robotic and open techniques, while in the living donor surgery, the reports are much more numerous and with larger series of patients. Shorter hospitalization times and less blood loss are recorded, especially in centers with experience in a large number of cases. Regarding the living donor surgery, MIS follows the same principles as a conventional hepatectomy and is already the method of choice in many specialized centers. Regarding the recipient surgery, significant questions arise mainly concerning the safe handling of the liver graft. Full article

Herbal-induced liver injury (HILI) continues to increase in prevalence each year due to the ongoing popularity of herbal supplements and complementary and alternative medicines. A detailed literature review of case reports and clinical studies published from March 2021 to March 2023 was performed. We discuss the epidemiology and diagnosis of HILI as well as the current and proposed laws and regulations. The 2021 ACG guidelines and 2022 AASLD practice guidelines for the diagnosis and management of drug and herbal-induced liver injury are discussed. We describe updates to previously reported etiologies of HILI such as ayurveda, ashwagandha, turmeric, kratom, green tea extract, and garcinia cambogia. Newly described supplements resulting in HILI, such as tinospora cordifolia, horse chestnut, alkaline water, and more, are described. We discuss newly and previously identified hepatoprotective herbal supplements as they have been reported in the study of animal models and human liver cells. This review suggests the need for ongoing research on the causes and mechanisms of HILI to ensure its proper diagnosis, prevention, and treatment in the future. The goal of this review is to provide novice and expert readers with knowledge regarding the possible etiologies of HILI and a general overview. Full article

The use of high-dose acetaminophen (AAP) with n-acetylcysteine (NAC) rescue was studied as an anti-cancer treatment in phase I trials with promising signals of anti-tumor efficacy. Correlative analysis suggested that AAP has a free-radical-independent mechanism of anti-tumor activity—in contrast to the well-established mechanism of AAP hepatotoxicity. Subsequent “reverse translational” studies in the pre-clinical setting have identified novel mechanisms of action of high-dose AAP, including modulation of JAK-STAT signaling in both the tumor cell and the tumor immune microenvironment. Importantly, these effects are free-radical-independent and not reversed by concurrent administration of the established AAP rescue agents fomepizole and NAC. By administering high-dose AAP concurrently with fomepizole and NAC, 100-fold higher AAP levels than those of standard dosing can be achieved in mice without detected toxicity and with substantial anti-tumor efficacy against commonly used mouse models of lung and breast cancer that are resistant to standard first-line anti-cancer therapies. With these recent advances, additional clinical trials of high-dose AAP with concurrent NAC and fomepizole-based rescue are warranted. Full article

Non-alcoholic metabolic-associated steatohepatitis (MASH) is a condition characterized by increasingly high prevalence and incidence, and also represents an important unmet medical need when it comes to effective pharmacotherapy. In this work, we aimed to explore the therapeutic possibilities of the synergistic combined use of glycyrrhizinic acid (GA) and phosphatidylcholine (PC) to prevent experimental MASH. Adult C57Bl/6 mice were used to model dietary/toxic MASH and treated orally by either GA (34.3 mg/kg/d) or a GA + PC combination (34.3 + 158.1 mg/kg/d) for 3 months. Animal locomotion, behaviour, short-term memory, physical performance, neuromuscular joint function, blood biochemistry, and oxidative stress marker levels were evaluated, followed by histological examination of the liver, skeletal muscle and sciatic nerve with tissue ammonia and lipid content determination. Real-time polymerase chain reaction was used to measure the relative expression of several pathogenetic transcript markers. GA and PC showed moderate additive synergism in their anti-inflammatory, antioxidant, hypoammonaemic, hypoglycaemic, and pro-cognitive activities. Differential effects of the agents were seen in regard to anxiety- and depression-like behaviour as well as gene expression. Our results indicate partial pharmacological synergism between GA and PC and validate further research of its potential clinical applications. Full article

The hepatokine leukocyte cell-derived chemotaxin-2 (LECT2) promotes insulin resistance and hepatic fibrogenesis. In rodents, acute exercise suppresses circulating LECT2; however, human data are lacking. This study compared circulating LECT2 across populations and explored whether acute exercise impacts circulating LECT2. In Part A (n = 43), data were pooled from three experimental studies, regarding the following groups: healthy individuals, individuals with impaired glycaemic regulation (IGR), and individuals with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (T2DM-MASLD). Generalised linear models assessed differences in circulating LECT2 among groups. Part B (n = 20) involved exercise (30 min, 65% peak oxygen uptake) and control (resting) trials in the healthy and IGR groups. Circulating LECT2 was measured before and at 0, 1, 2 and 3 h post-exercise. Generalised estimating equations assessed differences in LECT2 responses to the trials among groups. In Part A, circulating LECT2 levels were 28.7% and 37.3% higher in the IGR and T2DM-MASLD groups, vs. healthy individuals (p ≤ 0.038), with BMI identified as the main predictor (p = 0.008). In Part B, average circulating LECT2 levels were 6.3% higher after exercise vs. in the control (p < 0.001), with similar responses between groups (p = 0.829). In the combined cohort, circulating LECT2 levels were elevated 1–3 h after exercise vs. control (p ≤ 0.009). LECT2 is elevated in people with dysglycaemia, with BMI as a leading predictor. Contrary to previous rodent work, acute exercise augments, rather than suppresses, circulating LECT2 in humans. Full article

Artificial Intelligence (AI) can be a useful tool in the management of disease processes such as hepatocellular carcinoma (HCC) as treatment decisions are often complex and multifaceted. AI applications in medicine are expanding with the ongoing advances in AI including more sophisticated machine learning and deep learning processes. In preliminary studies, AI algorithms have demonstrated superiority in predicting the development of HCC compared with standard models. Radiomics, a quantitative method used to extract features from medical imaging, has been applied to numerous liver imaging modalities to aid in the diagnosis and prognostication of HCC. Deep learning methodologies can help us to identify patients at higher likelihood of disease progression and improve risk stratification. AI applications have expanded into the field of surgery as models not only help us to predict surgical outcomes but AI methodologies are also used intra-operatively, in real time, to help us to define anatomic structures and aid in the resection of complex lesions. In this review, we discuss promising applications of AI in the management of HCC. While further clinical validation is warranted to improve generalizability through the inclusion of larger and more diverse populations, AI is expected to play a central role in assisting clinicians with the management of complex disease processes such as HCC. Full article

Chronic hepatitis B is still a disease process that affects millions around the world. Serologies used to diagnose and follow the progression (or resolution) of the disease can be confusing for clinicians. Further, throughout years of treatment, there may be nuances in presentation that complicate management even further. In this short communication, we highlight six themes in response to treatment and outcomes, including complications. We have the unique perspective of following many patients over extended periods of time at our institution, which has brought these themes to life in order that they can be shared with other clinicians who may encounter similar situations. Full article

The adenosine A2B receptor (A2BAR) is a member of a family of G-protein coupled receptors (GPCRs), which has a low affinity for adenosine and is now implicated in several pathophysiological conditions. We have demonstrated the beneficial effects of A2BAR activation in enhancing recovery after acute liver injury induced by an acetaminophen (APAP) overdose. While receptor trafficking within the cell is recognized to play a role in GPCR signaling, its role in the mediation of A2BAR effects in the context of APAP-induced liver injury is not well understood. This was investigated here, where C57BL/6J mice were subjected to an APAP overdose (300 mg/kg), and the temporal course of A2BAR intracellular localization was examined. The impact of A2BAR activation or inhibition on trafficking was examined by utilizing the A2BAR agonist BAY 60-6583 or antagonist PSB 603. The modulation of A2BAR trafficking via APAP-induced cell signaling was explored by using 4-methylpyrazole (4MP), an inhibitor of Cyp2E1 and JNK activation. Our results indicate that APAP overdose induced the translocation of A2BAR to mitochondria, which was prevented via 4MP treatment. Furthermore, we demonstrated that A2BAR is localized on the mitochondrial outer membrane and interacts with progesterone receptor membrane component 1 (PGRMC1). While the activation of A2BAR enhanced mitochondrial localization, its inhibition decreased PGRMC1 mitochondria levels and blunted mitochondrial Cyp2E1 activity. Thus, our data reveal a hitherto unrecognized consequence of A2BAR trafficking to mitochondria and its interaction with PGRMC1, which regulates mitochondrial Cyp2E1 activity and modulates APAP-induced liver injury. Full article

Non-alcoholic fatty liver disease (NAFLD) is a common and prevalent disorder affecting 25 percent of the adults in the United States and 32 percent of adults globally. It is one of the common causes of chronic liver disease characterized by steatosis, which can lead to inflammation, fibrosis, and cirrhosis. NAFLD is strongly associated with obesity and insulin resistance. Multiple genetic variants have been consistently found to be associated with NAFLD; one of them is found in the TMC4-MBOAT7 loci. One variant (rs641738 C>T) within MBOAT7 encoding lysophosphatidyl inositol acyltransferase increases the risk for NAFLD development and triggers hepatic inflammation by regulating arachidonic acid levels. This review provides an overview of the MBOAT7 gene, pathogenesis of NAFLD, understanding the regulation of MBOAT7 and mechanistic link between MBOAT7 and NAFLD. It further summarizes pathophysiologically relevant in vivo and in vitro studies on MBOAT7 and challenges in treating complex NAFLD with recent progress made in the treatment of NAFLD. As such, this review provides useful information on MBOAT7 and NAFLD interrelation, which has the potential of deciphering novel therapeutic targets rather than well-known genetic variants such as PNPLA3 and TM6SF2. Full article