Hepatic encephalopathy, defined as neuropsychiatric dysfunction secondary to liver disease, is a frequent decompensating event in cirrhosis. Its clinical impact is highlighted by a notable increase in patient mortality rates and a concomitant reduction in overall quality of life. Systemically, liver disease, liver function failure, portosystemic shunting, and associated multi-organ dysfunction result in the increase of disease-causing neurotoxins in the circulation, which impairs cerebral homeostasis. Key circulating neurotoxins are ammonia and inflammatory mediators. In the brain, pathophysiology is less well understood, but is thought to be driven by glial cell dysfunction. Astrocytes are the only brain resident cells that have ammonia-metabolizing machinery and are therefore putatively most susceptible to ammonia elevation. Based on a large body of mostly in vitro evidence, ammonia-induced cellular and molecular disturbances include astrocyte swelling and oxidative stress. Microglia, the brain resident macrophages, have been linked to the translation of systemic inflammation to the brain microenvironment. Recent evidence from animal studies has provided novel insights into old and new downstream effects of astrocyte and microglial dysfunction such as toxin clearance disruption and myeloid cell attraction to the central nervous system parenchyma. Furthermore, state of the art research increasingly implicates neuronal dysfunction and possibly even irreversible neuronal cell death. Cell-type specific investigation in animal models highlights the need for critical revision of the contribution of astrocytes and microglia to well-established and novel cellular and molecular alterations in hepatic encephalopathy. In this review, we therefore give a current and comprehensive overview of causes, features, and consequences of astrocyte and microglial dysfunction in hepatic encephalopathy, including areas of interest for future investigation.

Ammonia metabolism plays a crucial role in cancer progression and immune modulation. However, the prognostic relevance and immunological effects of ammonia-induced cell death (ACD) in HNSC remain insufficiently studied. ACD is a newly characterized form of regulated cell death caused by pathological ammonia accumulation, leading to mitochondrial dysfunction, oxidative stress, and DNA damage.

A prognostic model was developed using random survival forests (RSF), with performance evaluated through concordance index (C-index) and survival analysis. Immune landscape profiling was performed using ssGSEA and Tracking Tumor Immunophenotype (TIP) analysis. Single-cell transcriptomic data were also used to examine ACD-associated gene expression in distinct cellular populations.

KM survival analysis revealed that a high ammonia-death signature (ADS) was significantly associated with worse survival outcomes. Multivariate Cox regression identified ADS as an independent predictor of prognosis. Immune profiling showed that high ADS correlated with an immunosuppressive microenvironment, reduced immune infiltration, and impaired immune function. Glutaminase (GLS) was identified as a key ACD-related gene with high diagnostic accuracy and prognostic relevance. Single-cell RNA sequencing analysis demonstrated elevated GLS expression in malignant and stromal cells, with cell-cell communication analysis suggesting its involvement in immune evasion and metabolic reprogramming.

This study establishes ADS as a novel prognostic biomarker in HNSC, linking ammonia metabolism with tumor progression and immune suppression. These findings highlight potential therapeutic targets for metabolic and immunotherapeutic interventions in HNSC.

Hepatic encephalopathy (HE) is a mental and neurological complication induced by acute or chronic hepatic failure. Emerging evidence indicates that the farnesoid X receptor (FXR), a multifunctional nuclear receptor and transcription factor, plays a pivotal role in regulating the expression of key genes associated with ammonia metabolism. However, the effect of FXR activation on HE has remained largely uncharted.

We established mouse models of HE by intraperitoneal injection of thioacetamide (TAA) and partial hepatectomy (PHx). Subsequently, we administered obeticholic acid (OCA) to activate FXR and investigated its effects on HE through comprehensive biochemical, biological, histological and behavioral analysis. Additionally, in vitro experiments were conducted to examine the impact of FXR activation on ammonia stress.

In the animal model of HE, activation of FXR upregulated the expression of key enzymes involved in ammonia metabolism pathway within the liver, thereby enhancing urea cycle functionality, reducing plasma ammonia levels, and mitigating liver injury. Furthermore, FXR activation significantly improved behavioral activities in mice and mitigated inflammation in the brain. Finally, our findings demonstrated that activating FXR could enhance ammonia metabolism and ammonia tolerance of C3A cells.

Our data provide novel evidence demonstrating that the activation of FXR by OCA exerts regulatory control over the expression of enzymes involved in ammonia metabolism, thereby effectively alleviating HE. Consequently, FXR could emerge as a promising novel target for HE treatment.

This study was supported by the National Natural Science Foundation of China No: 81970726 (to W-D Chen), and Henan Provincial Key Project of Medical Science and Technology Research No: SBGJ202102215 (to WL Ye).

Hepatic encephalopathy (HE) following acute liver failure (ALF) is considered as a primary toxic astrocytopathy, but in-depth characterisation of astrocytic contribution to the pathogenesis of this disease is far from complete. Using transmission electron microscopy, confocal fluorescent microscopy, and 3D reconstruction, we found complex morphological alterations of cortical astrocytes in mice with azoxymethane-induced ALF and post-mortem cortical tissue of patients at grade IV of HE. In both mice and post-mortem human tissues astrocytic primary branches demonstrated the territory occupied by astrocytes was increased, confirming astrocytic oedema. Astrocytic primary branches demonstrated swelling, while terminal leaflets showed atrophy quantified by the reduced area occupied by astrocytes, decreased number and the length of leaflets, decreased leaflets volume fraction, and altered astrocyte-to-neurone landscape. In mice these morphological changes develop in parallel with decreased expression of proteins critical for astrocytic modelling and function: the water channel aquaporin 4 (AQP4), the phosphorylated leaflet-associated ezrin, and the actin dynamics regulator, profilin 1 (PFN1). Pathological changes in astrocytes develop in parallel, and are likely causally linked to, the HE-linked neurological decline, manifested by a reduction in EEG power and by excessive glutamate in the brain microdialysates. We propose that HE evokes disease-specific remodelling of astrocytes to a "mixed", oedematic/atrophic phenotype. Concurrence of HE-specific phenotype with alterations in the expression of astrocytic proteins are a likely cause of aberrant astrocyte synaptic support resulting in severe, often fatal brain malfunction in HE.

Hepatic fibrosis involves hepatocyte damage, causing blood ammonia accumulation, which exacerbates liver pathology and crosses the blood-brain barrier, inducing hepatic encephalopathy. It is meaningful to construct a therapeutic platform for targeted ammonia clearance. In this work, a biocompatible water-powered Zn micromotor is constructed as an ammonia chemotaxis platform, which can be actuated by the water splitting reaction and the self-generated Zn2+ gradient. It can propel towards NH3·H2O source through the formation of complex ions [Zn(NH3)1](OH)+ and [Zn(NH3)2](OH)+, representing a generalizable chemotaxis strategy via coordination reaction. In vivo, biomimetic collective behavior allows precise navigation and reduction of the intrahepatic ammonia level, reshaping the pathological microenvironment. This mechanism, operating in a green, zero-waste manner, facilitates integration of these micromotors into the domain of biological regulation. Such environment environment-adaptive platform is favorable for targeted treatment of hepatic fibrosis and hepatic encephalopathy caused by hyperammonemia, which is expected to provide inspiration for future personalized and precision medicine.

Hepatic encephalopathy (HE), an outcome of chronic liver disease is characterized by behavioral impairments. The present study investigated the role of HDAC-mediated transcriptional regulation causing behavioral impairments in the bile duct ligation (BDL) model of HE. Post-BDL surgery in rats, dynamic alterations in liver function tests, liver morphology were observed. In BDL rats, histological staining in brain demonstrated reduced neuronal viability and warped neuronal architecture. Additionally, BDL animals showed impaired spatial learning, memory, and increased anxiety in the open field, Barnes maze, and Y maze tests. Further, the Golgi cox staining revealed a significantly altered spine density and spine clustering patterns of granular neuron in dentate gyrus of BDL rats. Concordantly, a significant downregulation of memory encoding genes was also observed in BDL rats that may account for aberrant behavior. Molecular analysis of modifiers, such as HDAC, showed significant changes in the expression of HDAC3 and HDAC6 in both the cortex and hippocampus of BDL rats. Upregulation of HDAC3 promoted its localization on the promoter of genes like c-Fos, NPAS4, Arc, and others, likely causing their decreased expression. Our findings suggest that increased HDAC3 activity downregulates key synaptic plasticity and memory-related genes, potentially driving neurobehavioral changes in BDL rats.

3D bioprinting of liver tissue with high cell density (HCD) shows great promise for restoring function in cases of acute liver failure, where a substantial number of functional cells are required to perform essential physiological tasks. Direct vascular anastomosis is critical for the successful implantation of these bioprinted vascularized tissues into the host vasculature, allowing for rapid functional compensation and addressing various acute conditions. However, conventional hydrogels used to encapsulate high-density cells often lack the mechanical properties needed to withstand the shear forces of physiological blood flow, often resulting in implantation failure. In this study, a heterogeneous microgel-hydrogel hybrid is developed to carry HCD hepatocytes and support the embedded bioprinting of hierarchical vascular structures. By optimizing the ratio of microgel to biomacromolecule, the covalently crosslinked network offers mechanical integrity and enables direct vascular anastomosis, ensuring efficient nutrient and oxygen exchange. The bioprinted thick, vascularized constructs, containing HCD hepatocytes, are successfully implanted in rats after 85% hepatectomy, leading to swift functional recovery and prolonged survival. This study presents a strategy to enhance regenerative therapy outcomes through advanced bioprinting and vascular integration techniques.

Nicorandil (NIC), an antianginal agent that acts both as an opener of adenosine triphosphate-sensitive potassium (KATP) channels and a nitric oxide donor, has demonstrated protective and curative effects in various diseases. The predominance of these mechanisms varies based on the dose of NIC and the specific organ affected. This study scrutinized the possible beneficial effects of NIC in acetaminophen (APAP)-induced hepatic encephalopathy (HE) model through highlighting the role of KATP channels in mediating these effects. Forty-eight mice were randomly subdivided into four groups: control (saline), APAP model (1 g/kg, i.p.), NIC treatment (15 mg/kg/day p.o. for 14 days), and glibenclamide (GLIB "KATP blocker", 5 mg/kg/day, p.o. 1 h before NIC for 14 days). NIC significantly mitigated APAP-induced liver injury, hyperammonemia, and cognitive deficits, as evidenced by reduced serum alanine aminotransferase, aspartate aminotransferase, ammonia levels, and improved performance in Y-maze and Morris Water Maze tests. Mechanistically, NIC suppressed hippocampal glutamate, activated phosphoserine 473 protein kinase B (p-AKT(Ser473))/mammalian target of rapamycin complex 1 (mTORC1) pathway, lessened the inactive phosphorylation of eukaryotic elongation factor 2 (eEF2), upsurged brain-derived neurotrophic factor (BDNF), leading to reduced neuroinflammation proved by nuclear factor-kappa B and tumor necrosis factor-alpha suppression. Histopathological analyses revealed improved liver and hippocampal morphology, while immunohistochemistry showed reduced astrocyte activation with NIC treatment. These effects were abolished by GLIB pre-treatment, indicating the crucial role of KATP channel. Accordingly, NIC could alleviate APAP-induced liver injury and HE mainly dependent on KATP channel opening, with resultant inhibition of glutamate signaling, activation of p-AKT/mTORC1/eEF2/BDNF trajectory, and abating hippocampal inflammation.

The pathogenesis of hepatic encephalopathy (HE) remains unclear, and the classical theory of ammonia toxicity lacks sufficient justification.

To investigate the potential of bile acids as intervention targets for HE.

This study employed 42 wild-type male SD rats weighing 200 ± 20 g. Using a random number table method, two rats were randomly selected to undergo common bile duct ligation (BDL). The remaining 40 rats were randomly assigned to four groups serving as controls: The vehicle + control diet (VC) group, the thioacetamide (TAA) group, the TAA + total bile acids (TAAT) group, and the TAA + cholestyramine (TAAC) group. Except for the VC group, all rats were intraperitoneally injected with 100 mg/kg TAA solution once daily for ten consecutive days to establish a HE model. Simultaneously, the TAAT and TAAC groups were administered a diet containing 0.3% bile acids (derived from BDL rats) and 2% cholestyramine, respectively, by gavage for ten days. For the BDL rat model group, the common BDL procedure was performed following the aforementioned protocol. After four weeks, laparotomy revealed swollen bile ducts at the ligation site, and bile was collected. Following successful modeling, behavioral tests, including the elevated plus maze and open field test, were conducted to assess the HE status of the rats. Peripheral blood, liver, and cerebral cortex tissue samples were collected, and the total bile acid content in the serum and cerebral cortex was measured using an enzyme cycling method. The levels of inflammatory factors in the serum and cerebral cortex were analyzed using enzyme-linked immunosorbent assay. Liver histological examination was performed using the hematoxylin-eosin double-labeling method. Reverse transcription polymerase chain reaction, western blot, immunohistochemistry, and other techniques were employed to observe the expression of microglial activation marker ionized calcium-binding adaptor molecule-1 and Takeda G protein-coupled receptor 5 (TGR5) protein.

Compared to the VC group, the TAA group exhibited an exacerbation of HE in rats. The total bile acid content, pro-inflammatory factors [interleukin-1β (IL-1β), IL-6], and the anti-inflammatory factor IL-10 in both the serum and cerebral cortex were significantly elevated. Similarly, the expression of the TGR5 receptor in the cerebral cortex was upregulated. To investigate the impact of total bile acids on HE in rats, comparisons were made with the TAA group. In the TAAT group, the severity of HE was further aggravated, accompanied by increased total bile acid content in the serum and cerebral cortex, elevated pro-inflammatory factors (IL-1β, IL-6), reduced levels of the anti-inflammatory factor IL-10, and decreased expression of the TGR5 receptor in the cerebral cortex. In the TAAC group, the severity of HE was alleviated. This group showed reductions in total bile acid content in the serum and cerebral cortex, decreased pro-inflammatory factors (IL-1β, IL-6), increased levels of the anti-inflammatory factor IL-10, and enhanced expression of the TGR5 receptor in the cerebral cortex.

This study demonstrated that the total bile acid content in the serum and cerebral cortex of TAA-induced liver cirrhosis rats was elevated. Furthermore, total bile acids exacerbate the progression of HE in rats. This effect may be attributed to bile acids' involvement in the development of neurological dysfunction by mediating TGR5 expression and regulating neuroinflammation.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects around 30% of the global population. Studies suggest that MASLD is associated with compromised brain health and cognitive dysfunction, initiating a growing interest in exploring the liver-brain axis mechanistically within MASLD pathophysiology. With the prevalence of MASLD increasing at an alarming rate, leaving a large proportion of people potentially at risk, cognitive dysfunction in MASLD is a health challenge that requires careful consideration and awareness. This Review summarises the current literature on cognitive function in people with MASLD and discusses plausible causes for its impairment. It is likely that a multifaceted spectrum of factors works collectively to affect cognition in patients with MASLD. We describe the role of inflammation, vascular disease, and brain ageing and neurodegeneration as possible key players. This Review also highlights the need for future studies to identify the optimal test for diagnosing cognitive dysfunction in patients with MASLD, to examine the correlation between MASLD progression and the severity of cognitive dysfunction, and to evaluate whether new MASLD-targeted therapies also improve brain dysfunction.

The relationship between body composition and the risk of overt hepatic encephalopathy (OHE) following transjugular intrahepatic portosystemic shunt (TIPS) needs to be investigated.

Overall, 571 patients from 5 medical centers were included. To assess body compositions, we evaluated skeletal muscle indices, adipose tissue indices, sarcopenia, and myosteatosis at the third lumbar vertebral level. Univariate and Multivariate logistic regression analyses were performed to identify independent risk factors for post-TIPS OHE. An integrated score was then constructed using stepwise multiple regression analyses, with a cut-off value selected using the best Youden index. Finally, the Akaike information criterion (AIC) was performed to compare the integrated score and independent risk factors on their ability in predicting post-TIPS OHE.

Sarcopenia and all skeletal muscle indices had limited associations with post-TIPS OHE. The index of the subcutaneous adipose tissue (SATI) ( P =0.005; OR: 1.034, 95% CI: 1.010-1.058) and myosteatosis (297 cases, 52.01%, 125 with OHE, 42.09%; P =0.003; OR: 1.973; 95% CI: 1.262-3.084) were both ascertained as independent risk factors for post-TIPS OHE. The integrated score (Score ALL =1.5760 + 0.0107 * SATI + 0.8579 * myosteatosis) was established with a cutoff value of -0.935. The akaike information criterion (AIC) of Score ALL , SATI, and myosteatosis was 655.28, 691.18, and 686.60, respectively.

SATI and myosteatosis are independent risk factors for post-TIPS OHE. However, the integrated score was more significantly associated with post-TIPS OHE than other skeletal muscle and adipose tissue factors.

Porto-systemic shunting (PSS) in patients with Abernethy malformation (AM) or obstruction of the portal vein (OVP) is often associated with normal liver parenchyma and hepatic function. This association provides an interesting natural model for studying the brain functional connectivity changes secondary to PSS but independently from hepatic (dys)function. Because PSS can be eliminated with appropriate interventions, these particular conditions offer a unique physio-pathological model where the same patient can be studied in both "active PSS" and "absent PSS" conditions (pre- and post-cure analyses).

Four children (<18 years) who were evaluated for Abernethy malformation (n = 2) or portal cavernoma (n = 2) and underwent corrective surgery (living-donor liver transplantation for AM, or Meso-Rex bypass for OPV, respectively) were included in the study. Brain magnetic resonance imaging and resting-state functional magnetic resonance imaging (rest-fMRI) were acquired in all patients before and after the corrective surgery. A functional connectome analysis was performed before ("active PSS" condition) and after ("absent PSS"-physiological condition) the cure of PSS.

As a result of the cancelation of PSS, rest-fMRI connectomics revealed a statistically significant (p < 0.05 family-wise error) improvement in global brain functional connectivity in both groups following each surgical procedure.

In this clinical model of isolated PSS (with absence of hepatic dysfunction), brain functional connectivity was altered even in young patients and in the absence of hyperammonemia; moreover, specific interventions to cancel out PSS consequently significantly improved brain functional connectivity.

The purpose of this study was to examine the protective and therapeutic effects of okra (Abelmoschus esculentus [AE]) seed extract, with its known antioxidant, immunomodulatory, and anti-inflammatory properties, in an acetaminophen (paracetamol, N-acetyl- para-aminophenol)-induced model of hepatotoxicity and subsequent acute non-traumatic brain damage.

Forty male Wistar rats were randomly divided into five equal groups, control, paracetamol (P), okra seed extract (AE), okra seed extract + paracetamol (P + AE), and okra seed extract + paracetamol + N-acetyl cysteine (NAC) (P + AE + N). AE was administered by oral gavage through a gastric tube at 600 mg/kg/day for seven days. On the eighth day of the procedure, a single 1 g/kg dose of paracetamol and 300 mg/kg NAC were injected via the intraperitoneal route 1.5 h after AE administration. Rat tissue specimens were subsequently subjected to biochemical and histopathological analyses. Levels of markers such as S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), and matrix membrane metalloproteinase-9 (MMP-9) were investigated from rat serum specimens. Malondialdehyde (MDA) and superoxide dismutase (SOD) were also measured to determine oxidant-antioxidant status.

S100B, NSE, MMP-9, MDA levels, and SOD enzyme activities were examined using biochemical methods. MDA levels were significantly lower in the P + AE group and MMP-9 levels in the AE, P + AE, and P + AE + N groups compared to the P group. Histopathological examination results supported the biochemical findings.

Okra seed extract exhibits a protective and therapeutic effect against non-traumatic brain damage resulting from acute paracetamol intoxication. We think that this benefit of AE derives from its antioxidant property.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic hepatic disorder worldwide in both adults and children. It is well established that MASLD represents the hepatic manifestation of the metabolic syndrome whose definition includes the presence of obesity, type 2 diabetes (T2D), dyslipidemia, hypertension and hypercoagulability. All these conditions contribute to a chronic inflammatory status which may impact on blood brain barrier (BBB) integrity leading to an impaired function of central nervous system (CNS).

Since the mechanisms underlying the brain-liver-gut axis derangement are still inconclusive, the present narrative review aims to make a roundup of the most recent studies regarding the cognitive decline in MASLD also highlighting possible therapeutic strategies to reach a holistic advantage for the patients.

Due to its ever-growing prevalence, the MASLD-related mental dysfunction represents an enormous socio-economic burden since it largely impacts on the quality of life of patients as well as on their working productivity. Indeed, cognitive decline in MASLD translates in low concentration and processing speed, reduced memory, sleepiness but also anxiety and depression. Chronic systemic inflammation, hyperammonemia, genetic background and intestinal dysbiosis possibly contribute to the cognitive decline in MASLD patients. However, its diagnosis is still underestimated since the leading mechanisms are multi-faceted and unexplained and do not exist standardized diagnostic tools or cognitive test strategies. In this scenario, nutritional and lifestyle interventions as well as intestinal microbiota manipulation (probiotics, fecal transplantation) may represent new approaches to counteract mental impairment in these subjects. In sum, to face the "mental aspect" of this multifactorial disease which is almost unexplored, cognitive tools should be introduced in the management of MASLD patients.

Liver cirrhosis is the terminal stage of various acute and chronic liver diseases and ranks 11th among the most common causes of death worldwide. In recent years, with the progress of clinical research, there has been increasing support from evidence-based medicine for the treatment of liver cirrhosis with integrated traditional Chinese and Western medicine. In 2023, the Chinese Association of Integrative Medicine, the China Association of Chinese Medicine, and the Chinese Medical Association jointly released the first evidence-based guideline in this field, the Guidelines for Integrated Traditional Chinese and Western Medicine Diagnosis and Treatment of Liver Cirrhosis. By combining the latest research at home and abroad, this article provides a detailed interpretation of the highlights in the guideline, including traditional Chinese medicine etiology and pathogenesis, diagnostic progress, disease and syndrome combination, stage-based diagnostic mode, and treatment strategies of integrated traditional Chinese and Western medicine. The aim is to enhance understanding of this guideline among health workers and promote the improvement of the diagnosis and treatment of liver cirrhosis with integrated traditional Chinese and Western medicine.

A devasting stage of chronic hepatic dysfunction is strictly correlated with neurological impairment, signifying hepatic encephalopathy (HE). HE is a multifactorial condition; therefore, hyperammonemia, oxidative stress, neuroinflammation, and mitochondrial dysfunction interplay in HE's progressive development. Cilostazol (Cilo) has shown promising neuroprotective and hepatoprotective effectiveness in different neuronal and hepatic disorders; however, its efficiency against HE hasn't yet been explored. This study aimed to investigate the protective role of Cilo against thioacetamide (TAA)-induced HE in rats targeting mitochondrial dysfunction via modulation of Adenosine monophosphate-activated protein kinase (AMPK)/Silent information regulator 1 (SIRT1) dependent pathways. Rats were allocated into three groups: the normal control group, the TAA group received (100 mg/kg, three times per week, for six weeks) to induce HE, and the Cilo group received (Cilo 100 mg/kg/day for six weeks, oral gavage) concurrently with TAA. Cilo counteracted HE indicated in the enhancement of cognitive impairment and the motor performance of rats (P < 0.0001), modulation AMPK/SIRT1signaling pathway causing reduction of NF-kB p65 (P < 0.0001) evoked inflammation along with histopathological alterations and glial fibrillary acidic protein (GFAP) immunoreactivity (P < 0.0001), restoration nuclear factor E2-related factor 2 (Nrf2) (P < 0.0001) antioxidant effects, reduction of Bax and elevation of Bcl2 immunoreactivity (P < 0.0001) in addition to boosting mitochondrial biogenesis by upregulation of PTEN-induced kinase-1 (PINK-1)/Parkin (P < 0.0001)and restoration of Brain-derived neurotrophic factor (BDNF) (P = 0.0002)/tropomyosin-related kinase B (TrkB) (P < 0.0001)/cAMP response element-binding (CREB) (P < 0.0001) neuroprotective axis. Collectively, Cilo activates the SIRT1 trajectory to abridge mitochondrial dysfunction invigorated in the HE rat model via restoration of mitochondrial hemostasis.

Hepatoencephalopathy (HE) is a liver disease that can lead to brain pathology and the impairment of human cognitive abilities. The objective assessment of HE disease severity is difficult due to the lack of reliable diagnostic markers. This paper examines the background to the emergence of HE markers and provides a brief overview of research results indicating the diagnostic value of potential markers isolated from a wide range of metabolites analyzed. It has been suggested that metabolites of the glutamate-glutamine (Glu-Gln) cycle, α-ketoglutarate (αKG), and α-ketoglutaramate (αKGM) can act as such markers of HE. The informative value of these markers was revealed during a comparative analysis of the distribution of αKG and αKGM in samples of the blood plasma and tissues (liver, kidneys, and brain) of rats exposed to the strong hepatotoxin thioacetamide (TAA). A comparative analysis of the balance of αKG and αKGM, as well as their ratio (αKG/αKGM) in the examined samples of blood plasma and animal tissues in these models, revealed their diagnostic value for assessing the severity of HE and/or monitoring the recovery process.

Hepatic Encephalopathy (HE) is a frequent complication of chronic liver disease. Type C HE mainly appears in episodes; only seldom chronic persistent forms occur. HE can lead to hospitalization and it has a huge impact on the health related quality of life. Symptoms of HE comprise alterations of the mental status and HE was associated with structural brain alterations. After the resolution of HE episodes alterations of the mental status seem to be reversible. However, cognitive impairment was described to persist in some patients in between HE episodes questioning the full reversibility of functional and structural alterations of HE. The causative treatment of chronic liver disease and subsequent HE episodes is liver transplantation. After liver transplantation functional and structural alterations caused by HE seem to be reversible, however, neurological complications in the first weeks after liver transplantation are frequent, especially in patients with a history of HE before transplantation. Furthermore, in patients in the long term after liver transplantation cognitive dysfunction was described. The underlying causes discussed are residual HE, side effects of immunosuppressive therapy and cerebrovascular disease besides others. It is an important question for patients and caregivers whether HE is a fully reversible episodic phenomenon or if it leads to persistent structural and functional brain alterations even after liver transplantation.

Development of overt hepatic encephalopathy (oHE) is a particularly feared complication when considering treatment with transjugular intrahepatic portosystemic shunt (TIPS). However, the pathophysiology of HE, in particular after TIPS-insertion, is complex and valid predictors remain scarce. We aimed to investigate whether systemic inflammation markers (SIM) are linked to minimal (mHE) and overt HE (oHE) development before and after TIPS. 62 prospectively recruited patients undergoing TIPS-insertion were included and monitored for oHE occurrence two years thereafter. Patients underwent psychometric testing including the portosystemic encephalopathy syndrome test (PSE), yielding the psychometric hepatic encephalopathy score (PHES), and Animal Naming Test (ANT) before TIPS (baseline) and during structured follow-up 1, 3, 6 and 12 months afterwards. SIM (IL-6, TNF-α and IL-1β) were measured at corresponding timepoints. Patients were predominantly male (64.5%) with a median age of 58 years and MELD of 11. The majority (75.8%) received a TIPS for treatment of refractory ascites. 67.9% presented with mHE before TIPS. No link between the investigated SIM and PHES or ANT at baseline or during any follow-up was documented. 19 (30.6%) patients developed oHE during follow-up. Neither baseline SIM levels nor test results were significantly associated with risk for oHE. We demonstrated a significant decline of all SIM during follow-up, which did not translate to an ameliorated risk for oHE. In patients undergoing TIPS-insertion, the selected SIM have neither a strong link to post-TIPS-oHE development nor to subclinical changes in psychometric tests for mHE.

Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals widely used in various products, including food packaging, textiles, and firefighting foam, owing to their unique properties such as amphiphilicity and strong CF bonds. Despite their widespread use, concerns have arisen due to their resistance to degradation and propensity for bioaccumulation in both environmental and human systems. Emerging evidence suggests a potential link between PFAS exposure and neurotoxic effects, spanning cognitive deficits, neurodevelopmental disorders, and neurodegenerative diseases. This review comprehensively synthesizes current knowledge on PFAS neurotoxicity, drawing insights from epidemiological studies, animal experiments, and mechanistic investigations. PFAS, known for their lipophilic nature, tend to accumulate in lipid-rich tissues, including the brain, breaching biological barriers such as the blood-brain barrier (BBB). The accumulation of PFAS within the central nervous system (CNS) has been implicated in a spectrum of neurological maladies. Neurotoxicity induced by PFAS manifests through a multitude of direct and indirect mechanisms. A growing body of research associated PFAS exposure with BBB disruption, calcium dysregulation, neurotransmitter alterations, neuroinflammation, oxidative stress, and mitochondrial dysfunction, all contributing to neuronal impairment. Despite notable strides in research, significant lacunae persist, necessitating further exploration to elucidate the full spectrum of PFAS-mediated neurotoxicity. Prospective research endeavors should prioritize developing biomarkers, delineating sensitive exposure windows, and exploring mitigation strategies aimed at safeguarding neurological integrity within populations vulnerable to PFAS exposure.

In our study, the protective effect of dodder plant extract against encephalopathy induced by cholestatic liver disease model was investigated.

Spraque Dawley rats were used in the study. For the cholestatic liver disease model, the bile duct ligation (BDL) was applied. The groups were determined as control, Cuscuta sp. (CUS), BDL and BDL + CUS. Double ligation was performed in the bile duct in the BDL groups. For the applications, saline (SF) was administered to the control and BDL groups for 28 days while 250 mg/kg of Cuscuta sp. extract was given by oral gavage to the CUS and BDL + CUS groups. At the end of the experiment, cognitive evaluations were made by applying new object recognition and Morris water maze tests. After these tests, blood-brain barrier (BBB) measurements were made in half of the groups. In the other half of the groups, brain tissue samples were taken by decapitation and transforming growth factor-beta (TGF-β), 8-hydroxydeoxyguanosine (8-OHdG) and sodium-potassium adenosine triphosphatase (Na+/K+-ATPase) measurements were made in the tissues. Histological examinations of the tissues were also performed.

Cognitive performance was low, and BBB permeability was found to be increased in the group with bile duct ligation. In addition, TGF-β and 8-OHdG levels were increased in tissues, while Na+/K+-ATPase enzyme activity was suppressed. Treatment with Cuscuta sp. increased cognitive performance and decreased BBB permeability. Other biochemical parameters examined were significantly (p<0.05-0.001) reversed and supported by histological findings.

Our findings in the study suggest that dodder plant may be beneficial for the protection of cognitive performance and brain tissue in encephalopathy caused by cholestasis.

Ammonia is thought to be a cytotoxin and its increase in the blood impairs cell function. However, whether and how this toxin triggers cell death under pathophysiological conditions remains unclear. Here we show that ammonia induces a distinct form of cell death in effector T cells. We found that rapidly proliferating T cells use glutaminolysis to release ammonia in the mitochondria, which is then translocated to and stored in the lysosomes. Excessive ammonia accumulation increases lysosomal pH and results in the termination of lysosomal ammonia storage and ammonia reflux into mitochondria, leading to mitochondrial damage and cell death, which is characterized by lysosomal alkalization, mitochondrial swelling and impaired autophagic flux. Inhibition of glutaminolysis or blocking lysosomal alkalization prevents ammonia-induced T cell death and improves T cell-based antitumour immunotherapy. These findings identify a distinct form of cell death that differs from previously known mechanisms.

Hepatic encephalopathy (HE) is one of the most prevalent and severe hepatic and brain disorders in which escalation of the oxidative, inflammatory and apoptotic trajectories pathologically connects acute liver injury with neurological impairment. Mirabegron (Mira) is a beta3 adrenergic receptor agonist with proven antioxidant and anti-inflammatory activities. The current research pointed to exploring Mira's hepato-and neuroprotective impacts against thioacetamide (TAA)-induced HE in rats. Rats were distributed into three experimental groups: the normal control group, the TAA group, received TAA (200 mg/kg/day for three consecutive days) and the Mira-treated group received Mira (10 mg/kg/day; oral gavage) for 15 consecutive days and intoxicated with TAA from the 13th to the 15th day of the experimental period. Mira counteracted hyperammonemia, enhanced rats' locomotor capability and motor coordination. It attenuated hepatic/neurological injuries by its antioxidant, anti-apoptotic as well as anti-inflammatory potentials. Mira predominantly targeted cyclic adenosine monophosphate (cAMP)/phosphorylated extracellular signal-regulated kinase (p-Erk1/2)/peroxisome proliferator-activated receptor gamma (PPARγ) dependent pathways via downregulation of p S536-nuclear factor kappa B p65 (p S536 NF-κB p 65)/tumor necrosis alpha (TNF-α) axis. Meanwhile, it attenuated nuclear factor erythroid 2-related factor (Nrf2) depletion in parallel with restoring of the neuroprotective defensive pathway by upregulation of cerebral cAMP/PPAR-γ/p-ERK1/2 and p-CREB/BDNF/TrkB besides reduction of GFAP immunoreactivity. Mira showed anti-apoptotic activity through inhibition of Bax immunoreactivity and elevation of Bcl2. To summarize, Mira exhibited a hepato-and neuroprotective effect against TAA-induced HE in rats via shielding antioxidant defense and mitigation of the pathological inflammatory and apoptotic axis besides upregulation of neuroprotective signaling pathways.

Emerging research suggests that hyperammonemia may enhance the probability of hepatic encephalopathy (HE), a condition associated with elevated levels of circulating ammonia in patients with cirrhosis. However, some studies indicate that blood ammonia levels may not consistently correlate with the severity of HE, highlighting the complex pathophysiology of this condition.

A systematic review and meta-analysis through PubMed, Scopus, Embase, Web of Science, and Virtual Health Library were conducted to address this complexity, analyzing and comparing published data on various laboratory parameters, including circulating ammonia, blood creatinine, albumin, sodium, and inflammation markers in cirrhotic patients, both with and without HE.

This comprehensive review, which included 81 studies from five reputable databases until June 2024, revealed a significant increase in circulating ammonia levels in cirrhotic patients with HE, particularly those with overt HE. Notably, significant alterations were observed in the circulating creatinine, albumin, sodium, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFα) in HE patients.

These findings suggest an association between ammonia and HE and underscore the importance of considering other blood parameters such as creatinine, albumin, sodium, and pro-inflammatory cytokines when devising new treatment strategies for HE.

Inter-organ communication through hormones, cytokines and extracellular vesicles (EVs) has emerged to contribute to the physiological states and pathological processes of the human body. Notably, the liver coordinates multiple tissues and organs to maintain homeostasis and maximize energy utilization, with the underlying mechanisms being unraveled in recent studies. Particularly, liver-derived EVs have been found to play a key role in regulating health and disease. As an endocrine organ, the liver has also been found to perform functions via the secretion of hepatokines. Investigating the multi-organ communication centered on the liver, especially in the manner of EVs and hepatokines, is of great importance to the diagnosis and treatment of liver-related diseases. This review summarizes the crosstalk between the liver and distant organs, including the brain, the bone, the adipose tissue and the intestine in noticeable situations. The discussion of these contents will add to a new dimension of organismal homeostasis and shed light on novel theranostics of pathologies.

Hepatic encephalopathy is a common and serious complication of decompensated cirrhosis. It can considerably contribute to economic burden and impaired quality of life. However, its pathogenesis remains unclear.

In this study, we aimed to visually analyse the research status and development trends in hepatic encephalopathy pathogenesis using bibliometrics and knowledge mapping. Information regarding publications between 1978 and 2022 were obtained from the Web of Science Core Collection. CiteSpace was used to analyse and present data by year, author, institution, country, journal, reference, and keyword.

A total of 1578 publications on hepatic encephalopathy pathogenesis in patients with cirrhosis were retrieved from Web of Science Core Collection. A gradual increasing trend in annual publications has occurred. The collaborative network analysis results suggest the United States of America, the University of London, and Bajaj, Jasmohan S as the most influential country, institution, and author, respectively, in this research field. Notably, China appeariiuis to be the most promising country. Research on 'hepatology' garners the most significant papers in the field. Combined with reference co-citation and keyword co-occurrence analyses, we found that ammonia metabolism, gut microbiota, sarcopenia, and trace elements will become future research frontiers that are likely to be explored for a considerable length of time.

Future research directions in HE pathogenesis may target modulating the ammonia metabolism, the gut microbiota, sarcopenia, and trace elements.

Transjugular intrahepatic portosystemic shunt (TIPS) is a commonly performed procedure in patients with liver cirrhosis to treat portal hypertension-related conditions, including variceal bleeding and refractory ascites. However, while the increased risk of hepatic encephalopathy (HE) after TIPS is important to consider when determining whether a patient is a good candidate for TIPS, currently there is no widely used method to predict the development of post-TIPS HE, although the model for end-stage liver disease (MELD) score is used to predict post-TIPS mortality. We conducted a systematic review and meta-analysis to evaluate sarcopenia as a risk factor for HE and mortality in patients undergoing TIPS.

A comprehensive search strategy was used to identify reports of post-TIPS HE and mortality in sarcopenia vs. non-sarcopenia patients with liver cirrhosis who received TIPS in March 2023. Open Meta Analyst was used to compute the results.

Twelve studies with 2056 patients met inclusion criteria and were included in the final meta-analysis. Sarcopenia was associated with a significantly higher post-TIPS HE rate than non-sarcopenia (risk ratio [RR]: 1.68, 95% CI: 1.48-1.92, p < 0.00001, I2 = 65%), as well as a significantly higher post-TIPS mortality rate (RR: 1.73, 95% CI: 1.14-2.64, p < 0.00001, I2 = 87%).

Patients with sarcopenia have a significantly increased risk of post-TIPS HE and mortality. Presence of sarcopenia should be considered when weighing the risks and benefits of performing TIPS in patients with cirrhosis. Further studies are needed to determine the clinical utility of important risk factors such as sarcopenia on post-TIPS outcomes.

Acute liver failure (ALF) is a complex syndrome that impairs the liver's function to detoxify bilirubin, ammonia, and other toxic metabolites. Bioartificial liver (BAL) aims to help ALF patients to pass through the urgent period by temporarily undertaking the liver's detoxification functions and promoting the recovery of the injured liver. We genetically modified the hepatocellular cell line HepG2 by stably overexpressing genes encoding UGT1A1, OATP1B1, OTC, ARG1, and CPS1. The resulting SynHeps-II cell line, encapsulated by Cytopore microcarriers, dramatically reduced the serum levels of bilirubin and ammonia, as demonstrated both in vitro using patient plasma and in vivo using ALF animal models. More importantly, we have also completed the 3-dimensional (3D) culturing of cells to meet the demands for industrialized rapid and mass production, and subsequently assembled the plasma-cell contacting BAL (PCC-BAL) system to fulfill the requirements of preclinical experiments. Extracorporeal blood purification of ALF rabbits with SynHeps-II-embedded PCC-BAL saved more than 80% of the animals from rapid death. Mechanistically, SynHeps-II therapy ameliorated liver and brain inflammation caused by high levels of bilirubin and ammonia and promoted liver regeneration by modulating the nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways. Also, SynHeps-II treatment reduced cerebral infiltration of neutrophils, reduced reactive oxygen species (ROS) levels, and mitigated hepatic encephalopathy. Taken together, SynHeps-II cell-based BAL was promising for the treatment of ALF patients and warrants clinical trials.

Non-alcoholic fatty liver disease (NAFLD) currently affects 25% of the global adult population. Cognitive impairment is a recently recognised comorbidity impeding memory, attention, and concentration, affecting the patients' activities of daily living and reducing their quality of life. This systematic review provides an overview of the evidence for, and potential pathophysiological mechanisms behind brain dysfunction at a neurobiological level, in preclinical NAFLD. We performed a systematic literature search for animal models of NAFLD studying intracerebral conditions using PubMed, Embase and Scopus. We included studies that reported data on neurobiology in rodent and pig models with evidence of steatosis or steatohepatitis assessed by liver histology. 534 unique studies were identified, and 30 studies met the selection criteria, and were included. Findings of neurobiological changes were divided into five key areas: (1) neuroinflammation, (2) neurodegeneration, (3) neurotransmitter alterations, (4) oxidative stress, and (5) changes in proteins and synaptic density. Despite significant heterogeneity in the study designs, all but one study of preclinical NAFLD reported changes in one or more of the above key areas when compared to control animals. In conclusion, this systematic review supports an association between all stages of NAFLD (from simple steatosis to non-alcoholic steatohepatitis (NASH)) and neurobiological changes in preclinical models.

Although the liver is the largest metabolic organ in the body, it is not alone in functionality and is assisted by "an organ inside an organ," the gut microbiota. This review attempts to shed light on the partnership between the liver and the gut microbiota in the metabolism of macronutrients (i.e., proteins, carbohydrates, and lipids). All nutrients absorbed by the small intestines are delivered to the liver for further metabolism. Undigested food that enters the colon is metabolized further by the gut microbiota that produces secondary metabolites, which are absorbed into portal circulation and reach the liver. These microbiota-derived metabolites and co-metabolites include ammonia, hydrogen sulfide, short-chain fatty acids, secondary bile acids, and trimethylamine N-oxide. Further, the liver produces several compounds, such as bile acids that can alter the gut microbial composition, which can in turn influence liver health. This review focuses on the metabolism of these microbiota metabolites and their influence on host physiology. Furthermore, the review briefly delineates the effect of the portosystemic shunt on the gut microbiota-liver axis, and current understanding of the treatments to target the gut microbiota-liver axis.

The use of probiotics to regulate the intestinal microbiota to prevent and treat a large number of disorders and diseases has been an international research hotspot. Although conventional probiotics have a certain regulatory role in nutrient metabolism, inhibiting pathogens, inducing immune regulation, and maintaining intestinal epithelial barrier function, they are unable to treat certain diseases. In recent years, aided by the continuous development of synthetic biology, engineering probiotics with desired characteristics and functionalities to benefit human health has made significant progress. In this article, we summarise the mechanism of action of conventional probiotics and their limitations and highlight the latest developments in the design and construction of probiotics as living diagnostics and therapeutics for the detection and treatment of a series of diseases, including pathogen infections, cancer, intestinal inflammation, metabolic disorders, vaccine delivery, cognitive health, and fatty liver. Besides we discuss the concerns regarding engineered probiotics and corresponding countermeasures and outline the desired features in the future development of engineered live biotherapeutics.

The mechanism of hepatic encephalopathy is complex and has not been conclusively established. Recent studies support lower serum 25-Hydroxy Vitamin D [25(OH) D] levels in patients with hepatic encephalopathy. This study aimed to evaluate the association between serum 25(OH) D and hepatic encephalopathy in patients with decompensated cirrhosis of liver.

A total of 70 cirrhosis patients (35 cases of hepatic encephalopathy and 35 patients without encephalopathy as control, mean age 53.07 ± 12.99 years, 67 % male) were recruited for this study. Assessment of the severity of cirrhosis was done by using a model for end-stage liver disease(MELD) and Child Turcotte Pugh (CTP) scores, and assessment of the severity of hepatic encephalopathy was done according to West Haven criteria. Serum 25 (OH) D level was measured by Chemiluminescent Microparticle Immuno Assay(CMIA).

The mean serum 25(OH) D level among hepatic encephalopathy patients was significantly lower in comparison to the control group without encephalopathy (18.76 ± 8.84 nmol/L vs 31.19 ± 13.9 nmol/L, P<0.0001). 91.4 % of hepatic encephalopathy patients had moderate to severe 25(OH)D deficiency as compared to 51.4 % in the control group. There was a significant correlation observed between the severity of the 25 (OH) D deficiency and the severity of liver disease (r =  - 0.35, P = 0.002). No statistically significant difference in serum 25(OH) D levels was found among patients with different hepatic encephalopathy grades (P = 0.416).

A significant association was found between a low serum 25(OH) D leveland hepatic encephalopathy. It requires further large-scale multicenter studies to establish it as a risk factor and predictor of hepatic encephalopathy.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that is observed primarily in patients with liver disease. The pathophysiology is complex and involves many factors including ammonia toxicity, dysregulation of central nervous system activity, and excess inflammatory cytokines. Symptoms of HE range from subclinical to debilitating. HE can be difficult to treat and represents a large burden to patients, their caregivers, and the health-care system because of associated resource utilization. This review article provides an overview of the current understanding of the pathophysiology behind HE and where the current research and treatments are pointing toward.

Minimal hepatic encephalopathy (MHE) is an early stage of hepatic encephalopathy (HE) and is highly prevalent. The efficacy of L-ornithine L-aspartate (LOLA) for the treatment of HE is well known but its role in MHE remains uncertain. The objectives of the current study were to evaluate the efficacy of LOLA for the treatment of MHE in patients with cirrhosis.

The Cochrane Library, PubMed, EMBASE, Web of Science and Ovid databases were searched. Only randomized controlled trials (RCTs) that compared the efficacy of LOLA with placebo or no intervention for the treatment of MHE in patients with cirrhosis were included from inception to January 2023. The primary outcomes were reversal of MHE and development of overt hepatic encephalopathy (OHE).

Overall, six RCTs comprising 292 patients were included. Compared with placebo or no intervention, LOLA was more effective in reversing MHE (RR = 2.264, 95 % CI = 1.528, 3.352, P = 0.000, I2 = 0.0 %) and preventing progression of OHE (RR = 0.220, 95 % CI = 0.076, 0.637, P = 0.005, I2 = 0.0 %). Based on subgroup analyses, oral LOLA treatment appeared more likely to reverse MHE (RR = 2.648, 95 % CI = 1.593, 4.402, P = 0.000, I2 = 0.0 %), intravenous LOLA treatment yielded a similar probability of reversing MHE (RR = 1.669, 95 % CI = 0.904, 3.084, P = 0.102, I2 = 0.0 %). LOLA did not show a superior possibility in reducing mortality (RR = 0.422, 95 % CI = 0.064, 2.768, P = 0.368, I2 = 0.0 %) and ammonia levels (SMD = 0.044, 95 % CI = -0.290, 0.379, P = 0.795, I2 = 0.0 %) compared with placebo or no intervention.

LOLA has significant beneficial effects on reversal of MHE and prevention of OHE in patients with cirrhosis compared with placebo or no intervention.

Hepatic encephalopathy (HE) is a neurological condition linked to liver failure. Acute HE (Type A) occurs with acute liver failure, while chronic HE (Type C) is tied to cirrhosis and portal hypertension. HE treatments lag due to gaps in understanding its development by gender and age. We studied how sex and age impact HE and its severity with combined liver toxins. Our findings indicate that drug-induced (thioacetamide, TAA) brain edema was more severe in aged males than in young males or young/aged female rats. However, adding alcohol (ethanol, EtOH) worsens TAA's brain edema in both young and aged females, with females experiencing a more severe effect than males. These patterns also apply to Type A HE induced by azoxymethane (AZO) in mice. Similarly, TAA-induced behavioral deficits in Type C HE were milder in young and aged females than in males. Conversely, EtOH and TAA in young/aged males led to severe brain edema and fatality without noticeable behavioral changes. TAA metabolism was slower in aged males than in young or middle-aged rats. When TAA-treated aged male rats received EtOH, there was a slow and sustained plasma level of thioacetamide sulfoxide (TASO). This suggests that with EtOH, TAA-induced HE is more severe in aged males. TAA metabolism was similar in young, middle-aged, and aged female rats. However, with EtOH, young and aged females experience more severe drug-induced HE as compared to middle-aged adult rats. These findings strongly suggest that gender and age play a role in the severity of HE development and that the presence of one or more liver toxins may aggravate the severity of the disease progression.

Hepatic encephalopathy is a neuropsychiatric complication of liver disease which is partly associated with elevated ammonemia. Urea hydrolysis by urease-producing bacteria in the colon is often mentioned as one of the main routes of ammonia production in the body, yet research on treatments targeting bacterial ureases in hepatic encephalopathy is limited. Herein we report a hydroxamate-based urease inhibitor, 2-octynohydroxamic acid, exhibiting improved in vitro potency compared to hydroxamic acids that were previously investigated for hepatic encephalopathy. 2-octynohydroxamic acid shows low cytotoxic and mutagenic potential within a micromolar concentration range as well as reduces ammonemia in rodent models of liver disease. Furthermore, 2-octynohydroxamic acid treatment decreases cerebellar glutamine, a product of ammonia metabolism, in male bile duct ligated rats. A prototype colonic formulation enables reduced systemic exposure to 2-octynohydroxamic acid in male dogs. Overall, this work suggests that urease inhibitors delivered to the colon by means of colonic formulations represent a prospective approach for the treatment of hepatic encephalopathy.

Hepatic encephalopathy (HE) is a formidable complication in patients with decompensated cirrhosis, often necessitating the administration of rifaximin (RFX) for effective management. RFX, is a gut-restricted, poorly-absorbable oral rifamycin derived antibiotic that can be used in addition to lactulose for the secondary prophylaxis of HE. It has shown notable reductions in infection, hospital readmission, duration of hospital stay, and mortality. However, limited data exist about the concurrent use of RFX with broad-spectrum antibiotics, because the patients are typically excluded from studies assessing RFX efficacy in HE. A pharmacist-driven quasi-experimental pilot study was done to address this gap. They argue against the necessity of RFX in HE during broad-spectrum antibiotic treatment, particularly in critically ill patients in intensive care unit (ICU). The potential for safe RFX discontinuation without adverse effects is clearly illuminated and valuable insight into the optimization of therapeutic strategies is offered. The findings also indicate that RFX discontinuation during broad-spectrum antibiotic therapy was not associated with higher rates of delirium or coma, and this result remained robust after adjustment in multivariate analysis. Furthermore, rates of other secondary clinical and safety outcomes, including ICU mortality and 48-hour changes in vasopressor requirements, were comparable. However, since the activity of RFX is mainly confined to the modulation of gut microbiota, its potential utility in patients undergoing extensive systemic antibiotic therapy is debatable, given the overlapping antibiotic activity. Further, this suggests that the action of RFX on HE is class-specific (related to its activity on gut microbiota), rather than drug-specific. A recent double-blind randomized controlled (ARiE) trial provided further evidence-based support for RFX withdrawal in critically ill cirrhotic ICU patients receiving broad-spectrum antibiotics. Both studies prompt further discussion about optimal therapeutic strategy for patients facing the dual challenge of HE and systemic infections. Despite these compelling results, both studies have limitations. A prospective, multi-center evaluation of a larger sample, with placebo control, and comprehensive neurologic evaluation of HE is warranted. It should include an exploration of longer-term outcome and the impact of this protocol in non-critically ill liver disease patients.

In the example of a rat model with chronic hepatoencephalopathy (HE), changes in the organ morphology of rats affect the balance of metabolites of the tricarboxylic acid (TCA) cycle and metabolites of the glutamine-glutamate (Gln-Glu) cycle, namely α-ketoglutarate (αKG) and α-ketoglutaramate (αKGM), as well as the enzymes associated with them, ω-amidase (ωA) and glutamine transaminase (GTK). This model of rats was obtained as a result of 2-22 weeks of consumption by animals of hepatotoxin thioacetamide (TAA) added to drinking water at a concentration of 0.4 g/L. The control (n = 26) and TAA-induced (n = 55) groups of rats consisted of 11 cohorts each. The control cohorts consisted of 2-4 rats, and the TAA-induced cohorts consisted of 4-7 individuals. Every two weeks, samples of blood plasma, liver, kidney, and brain tissues were taken from the next cohort of rats (a total of 320 samples). By the end of the experiment, irreversible morphological changes were observed in the organs of rats: the weight of the animals was reduced up to ~45%, the weight of the kidneys up to 5%, the brain up to ~20%, and the weight of the liver increased up to ~20%. The analysis revealed: (i) a decrease in the activity of ωA and GTK in the tissues of the brain, kidneys, and liver of rats with chronic HE (by ~3, 40, and 65% and ~10, 60, and 70%, respectively); and (ii) the appearance of a significant imbalance in the content of metabolites of the Gln-Glu cycle, αKG, and αKGM. It is indicative that a ~1.5-12-fold increase in the level of αKG in the blood plasma and tissues of the organs of rats with chronic HE was accompanied by a synchronous, ~1.2-2.5-fold decrease in the level of αKGM. The data obtained indicate an essential involvement of the Gln-Glu cycle in the regulation of energy metabolism in rats under conditions of chronic HE. Attention is focused on the significance of the αKG/αKGM ratio, which can act as a potential marker for diagnosing the degree of HE development.

Paracetamol, or acetaminophen (N-acetyl-para-aminophenol, APAP), is an analgesic and antipyretic drug that is commonly used worldwide, implicated in numerous intoxications due to overdose, and causes serious liver damage. APAP can cross the blood-brain barrier and affects brain function in numerous ways, including pain signals, temperature regulation, neuroimmune response, and emotional behavior; however, its effect on adult neurogenesis has not been thoroughly investigated. We analyze, in a mouse model of hepatotoxicity, the effect of APAP overdose (750 mg/kg/day) for 3 and 4 consecutive days and after the cessation of APAP administration for 6 and 15 days on cell proliferation and survival in two relevant neurogenic zones: the subgranular zone of the dentate gyrus and the hypothalamus. The involvement of liver damage (plasma transaminases), neuronal activity (c-Fos), and astroglia (glial fibrillar acidic protein, GFAP) were also evaluated. Our results indicated that repeated APAP overdoses are associated with the inhibition of adult neurogenesis in the context of elevated liver transaminase levels, neuronal hyperactivity, and astrogliosis. These effects were partially reversed after the cessation of APAP administration for 6 and 15 days. In conclusion, these results suggest that APAP overdose impairs adult neurogenesis in the hippocampus and hypothalamus, a fact that may contribute to the effects of APAP on brain function.