Synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies, and multiple system atrophy (MSA), are a group of neurodegenerative diseases characterized by the oligomerization of α-synuclein protein in neurons or glial cells. Various splicing isoforms of α-synuclein have been described, each with different aggregation properties. The α-synuclein gene (SNCA) has been identified as a highly significant genetic risk locus associated with various synucleinopathies across populations. This study aimed to assess the association of SNCA genetic variants with MSA and the levels of SNCA transcripts in peripheral blood mononuclear cells (PBMCs) from MSA and PD patients.

In this retrospective case–control study, 96 MSA patients, 1086 PD patients, and 485 healthy volunteers were included. PCR followed by restriction endonuclease analysis was used to detect four SNCA single-nucleotide polymorphisms (rs356219, rs3756063, rs11931074, and rs356168) in these individuals. In addition, RT-qPCR was performed to detect the levels of α-synuclein transcripts (SNCA mRNA isoforms -140, -126, and -112) in PBMCs of 24 MSA patients (including parkinsonian (MSA-P) and cerebellar (MSA-C) variants), 31 PD patients, and 32 healthy volunteers.

The frequency of the ‘T’ allele (of rs11931074) was significantly higher in MSA patients than in the healthy controls. The level of SNCA-140 mRNA was significantly decreased in MSA and PD patients compared with the controls, while the level of SNCA-112 mRNA was significantly increased in MSA-P patients than in PD patients and the controls. SNCA-112 mRNA/SNCA-140 mRNA and SNCA-112 mRNA/SNCA-126 mRNA ratios were significantly increased in MSA patients than in the controls.

The SNCA rs11931074 polymorphism is associated with MSA. There is a pronounced alteration in the expression of SNCA transcripts in PBMCs of MSA and PD patients.

Preclinical studies of the serotonin 2A (5-HT2A) antagonist deramciclane suggested an anxiolytic profile, which has not been unequivocally established in the clinic. The same receptor profile also indicated that the compound may exhibit antidepressant potential. However, evidence for these effects remains inconclusive. The present study examined the effect of the drug in two preclinical tests with predictive validity for antidepressant activity.

The antidepressant-like activity of deramciclane was assessed in male Sprague-Dawley rats by measuring immobility time in the forced swim test (doses: 1, 5 mg/kg) and ambulation scores in the bilateral olfactory bulbectomized (doses: 5, 10 mg/kg) rat model. In both tests, the clinically effective antidepressant imipramine served as the control condition.

In the forced swim test, there was a statistically significant effect of treatment on immobility time (F2,34 = 5.77; p < 0.01; analysis of variance), which was attributable to the effect of the 5 mg/kg dose (p < 0.01; Bonferroni post-hoc test). Deramciclane at 1 mg/kg was not significantly different from vehicle-treated animals. By contrast, neither dose of deramciclane (5 mg/kg or 10 mg/kg) reversed the hyperactivity of olfactory bulbectomized rats, whereas imipramine was active in both tests.

Deramciclane demonstrates contradictory evidence for antidepressant-like activity in two validated pharmacological tools that identify such potential. The agent is clearly active in the forced swim test but not in the bulbectomized rat model. Further evaluation of the antidepressant-like potential of deramciclane in pharmacological models with predictive validity is warranted, and a more detailed examination of the dose-response relationship may be informative.

Hashimoto’s thyroiditis (HT), an autoimmune disease with a prevalence 2–7 times higher in women than in men, is associated with daytime sleepiness. The present study aimed to test the hypothesis that thyroid function is associated with chronotype and daytime sleepiness in women with HT.

This retrospective cross-sectional study included women with confirmed HT. Demographic, clinical and laboratory data were collected. The reduced Morningness-Eveningness Questionnaire (rMEQ) and the Epworth Sleepiness Scale (ESS) were used to assess chronotype and daytime sleepiness, respectively. Based on rMEQ, women were categorized as having a morning (≥18), intermediate (12–17) or evening (≤11) chronotype. Based on ESS, women were categorized as having normal or increased daytime sleepiness.

Overall, 106 women, aged 43 ± 12 years, were included. Most had normal daytime sleepiness (68.9%), and the majority had an intermediate chronotype (61.3%), while only one had a morning chronotype (0.9%). Age was significantly associated with chronotype (P = 0.026). There was a significant association between chronotype and thyroglobulin antibodies (TgAb, P = 0.012). Free triiodothyronine (fT3) levels were significantly higher in women with an evening chronotype than in those with an intermediate chronotype (P = 0.045; OR = 0.500; 95% CI 0.25–0.98). Daytime sleepiness was significantly associated with TgAb (P = 0.016) and thyroid-stimulating hormone (TSH, P = 0.040). TgAb levels were significantly higher in women with increased daytime sleepiness (P = 0.049, OR = 1.003, 95% CI 1.00–1.01) than in those with normal daytime sleepiness.

Approximately one-third of women have an evening chronotype, and approximately one-third had increased daytime sleepiness. TgAb, fT3, and TSH are associated with daytime sleepiness or chronotype in women with HT. Further investigation is required for the underlying mechanisms.

Liver fibrosis is characterized by the excessive deposition of extracellular matrix, a process primarily driven by activated hepatic stellate cells (HSCs), and currently lacks effective therapy. Cathepsin K (CTSK) exhibits context-dependent roles across organ systems in fibrosis, but its function in liver fibrosis is unclear. This study aimed to investigate the role and underlying mechanisms of CTSK during liver fibrosis.

CTSK expression was analyzed in human fibrotic liver samples via transcriptomic analysis and confirmed in murine fibrosis models. The function of CTSK was investigated in both primary HSCs and LX-2 cells by assessing its effects on cell activation, proliferation, apoptosis, and the underlying signaling pathways following CTSK overexpression. The therapeutic potential was evaluated using an adeno-associated virus serotype 8 to overexpress CTSK in two etiologically distinct murine fibrosis models.

CTSK was upregulated in activated HSCs and fibrotic livers. Furthermore, we discovered that it mediates a negative feedback loop to inhibit the TGF-β/Smad pathway via Smad7/Smurf2-dependent TGF-β receptor-I degradation, thereby suppressing HSC activation and proliferation. CTSK also induced mitochondrial apoptosis through Bax/Bcl-2 imbalance and caspase-3 activation. Together, these actions contribute to the anti-fibrotic effect of CTSK. Notably, adeno-associated virus serotype 8-mediated CTSK overexpression attenuated liver fibrosis across multiple murine models.

Our study demonstrates that elevated CTSK functions as an endogenous protective factor that attenuates liver fibrosis. CTSK mediates negative feedback inhibition of the TGF-β pathway while concurrently promoting the mitochondrial apoptosis pathway. The dual anti-fibrotic mechanisms identify CTSK as a promising therapeutic target for liver fibrosis.

Phenylethanoid glycosides (PhGs) are water-soluble natural compounds widely distributed in the plant kingdom, attracting significant attention from medicinal chemists due to their promising potential in pharmaceutical applications. PhGs exhibit a broad range of activities, including neuroprotective, hepatoprotective, anti-inflammatory, antioxidant, and immunomodulatory effects. This review aims to update the hepatoprotective effects of total PhG extracts and individual PhG compounds, as well as the underlying mechanisms. Additionally, we describe the structural characteristics, representative PhG compounds, and their structure–activity relationships. In brief, total PhG extracts can exert synergistic protection by reducing serum alanine aminotransferase/aspartate aminotransferase levels, suppressing oxidative stress, and attenuating inflammatory responses. Representative PhGs, including acteoside (verbascoside), echinacoside, forsythoside A (also known as forsythiaside A), and cistanoside A, protect against liver injury through modulation of the Nrf2/HO-1, NF-κB, MAPK, and TGF-β/Smad pathways, thereby regulating oxidative stress, inflammation, apoptosis, fibrosis, and lipid metabolism. Structurally, PhGs consist of a phenylethyl alcohol core, cinnamoyl residues, and glycosyl moieties. Structure–activity relationship analyses indicate that caffeoyl substitution, multiple phenolic hydroxyl groups, and optimal glycosylation patterns are key determinants of hepatoprotective efficacy.

For individuals with decompensated advanced chronic liver disease (dACLD), the onset of refractory ascites (RA) represents a dramatic event. In this setting, a relevant proportion of RA patients develop kidney dysfunction, as well as hepatorenal syndrome-acute kidney injury, with limited therapeutic and survival chances. An 81-year-old woman with dACLD-RA was admitted with severe ascites and stage IV chronic kidney dysfunction. On the second day, hepatorenal syndrome-acute kidney injury occurred, requiring standard medical therapy. Intravenous human albumin (HA) and terlipressin administration were compromised by poor venous access and severe respiratory dysfunction. After excluding transjugular intrahepatic portosystemic shunt and transplantation due to age and comorbidities, peritoneal dialysis (PD) was initiated, leading to renal recovery and ascites resolution. Two weeks later, she was readmitted due to the unfeasibility of accessing peripheral veins for the intravenous administration of HA, which was essential to support circulatory function, preserve oncotic balance, and properly manage both RA and chronic kidney dysfunction. A novel PD+HA protocol was therefore started, with intraperitoneal infusion of HA-enriched dialysate to allow a positive albumin gradient from dialysate to blood. Over 12 months, serum albumin levels increased, and clinical stability and improved nutritional status were observed, with no additional hospitalizations or complications. This is the first case describing the application of HA-enriched PD in managing a dACLD patient with RA and kidney dysfunction. HA-enriched PD may represent a promising strategy in complex dACLD care by guaranteeing frequent and small-volume paracentesis and preservation of oncotic pressure without dialytic albumin loss.

Hepatic encephalopathy (HE) is a neurologic complication of advanced liver disease (e.g., cirrhosis) resulting in impaired functioning and reduced quality of life. This condition is associated with a substantial burden for patients and their caregivers and carries a poor prognosis and increased risk of hospitalization and mortality. This narrative review discusses the burden of HE, precipitating risk factors, and clinical considerations for reducing the risk of overt HE (OHE) recurrence in adults with cirrhosis. Key precipitating factors include certain medications, constipation, dehydration, uncontrolled diabetes mellitus, electrolyte imbalances, gastrointestinal bleeding, infection, and sarcopenia, among others. Identification and treatment of precipitating factors are critical steps in the management of HE. Components of ongoing care include patient and caregiver education, nutritional supplementation and sleep management, pharmacotherapy, and nonpharmacologic interventions (e.g., spontaneous portosystemic shunt embolization and liver transplantation in appropriate patients). Clinical guidelines recommend lactulose therapy as secondary prophylaxis after an initial episode of OHE. Rifaximin is recommended as add-on therapy to lactulose when an additional OHE episode occurs. Polyethylene glycol has been investigated as an alternative to lactulose in patients with acute HE and in those with chronic HE and a poor response to lactulose. Oral L-ornithine-L-aspartate may reduce the risk of OHE recurrence in patients with cirrhosis. Investigational agents include nitazoxanide, fecal microbiota transplantation, and the use of artificial intelligence, app-based technology, and wearable devices to facilitate acute and prophylactic management of HE.

Hepatic myelopathy, a rare neurological complication of decompensated chronic liver disease, profoundly impairs quality of life. While liver transplantation represents the only curative treatment for hepatic myelopathy, we report a case in which progressive and severe spastic paraparesis was markedly improved following embolization of a paraspinal vein shunt.