AbstractHost-parasite interactions are likely to involve eco-evolutionary feedbacks. Parasites can impose strong selection on host immune traits. Evolution of these traits can suppress parasite abundance, which alters the strength of selection. Such eco-evo feedbacks can be hard to document in natural settings, where long-term interactions may have converged on relatively stable equilibria. However, when a species disperses into an unoccupied habitat, it can experience altered parasite abundance (e.g., enemy release) or encounter new parasite genotypes. These perturbations may be followed by observable eco-evolutionary dynamics as the newly assembled host-parasite communities interact and evolve. To test this hypothesis, we experimentally founded nine whole-lake populations of threespine stickleback and tracked changes in the prevalence of a parasite (Schistocephalus solidus) and a heritable host immune trait (fibrosis) for 7 years. In native source lakes, among-population differences in tapeworm prevalence and fibrosis were relatively stable across years, suggesting there are alternative eco-evolutionary equilibria. In contrast, the experimentally founded populations initially exhibited enemy release, followed by strong year-to-year fluctuations in infection and fibrosis. In lakes with high initial infection rates, fibrosis subsequently increased in severity, suppressing infections. Conversely, low fibrosis was followed by increased parasite prevalence. This temporal autocorrelation between parasite prevalence and immune traits weakened over time. These results are consistent with the existence of transient eco-evolutionary dynamics between host and parasite in newly founded populations.

Transforming growth factor-β (TGF-β) contributes to fibrosis, immunosuppression, and tumor progression, but systemic TGF-β inhibition is limited by toxicity and lack of selectivity. This exploratory proof-of-concept study evaluated novel peptides designed to target the TGF-β receptor I/II complex and examined their effects on canonical and noncanonical TGF-β signaling in vitro. Peptides 2_5 and 2_6, selected by in silico docking of receptor-ligand interface-derived sequences, were tested in human embryonic kidney 293T (HEK293T) cells at 20 and 50 μM, with the TGF-β receptor I inhibitor SD-208 as a reference. Total and phosphorylated SMAD2, SMAD3, extracellular signal-regulated kinase 1/2 (ERK1/2), and c-Jun N-terminal kinase (JNK) were assessed by Western blotting and densitometry. Peptide 2_5 showed the strongest activity, reducing total ERK1/2 by 65% at 50 μM and phosphorylated ERK1/2 by 90.4% and 83.4% at 20 and 50 μM, respectively; SD-208 reduced total and phosphorylated ERK1/2 by 64.3% and 54.5%, respectively. Peptide 2_5 also reduced total SMAD2 by 81% at 50 μM, whereas its effect on SMAD2 phosphorylation was inconsistent. Peptide 2_6 showed minimal effects, JNK was largely unaffected, and SMAD3 results were inconclusive because of weak signals. These preliminary findings suggest that peptide 2_5 may differentially modulate TGF-β signaling, with a stronger effect on ERK1/2 than on SMAD2; however, receptor targeting and pathway selectivity require confirmation in fully replicated quantitative studies.

Chronic hepatitis D represents the most severe form of viral hepatitis and is associated with higher rates of advanced fibrosis, cirrhosis and hepatocellular carcinoma than hepatitis B monoinfection. It is caused by the hepatitis D virus (HDV), a defective RNA virus that requires co-infection with hepatitis B (HBV) for hepatocyte entry and propagation. Accurate prediction of liver disease sequelae and treatment response using currently available serological biomarkers remains challenging. This article reviews peripheral biomarkers in HDV, including novel biomarkers of HBV activity, exploring their potential clinical utility and areas for future development. Peripheral biomarkers capable of risk stratifying patients with HDV, monitoring or predicting treatment response and elucidating the natural history of infection (including the complex relationship with HBV), would enable individualised care and early identification of those at greater risk of developing advanced liver disease. Establishing the role of these biomarkers in larger, ethnically diverse populations both on existing treatments and in the context of emerging antiviral therapies will be imperative going forward.

Aging-related cardiac dysfunction constitutes a major and growing global health challenge with limited effective treatment options. While adiponectin receptor activation has demonstrated cardioprotective potential, its translation into a viable therapy for the senescent heart remains unrealized. In this study, we developed CardiAdip (CAD), an agonist with improved predicted binding affinity for adiponectin receptors. In d-galactose (d-gal)-induced senescent H9c2 cardiomyocytes, CAD attenuated senescence-associated phenotypes and reduced stress-responsive signaling. In naturally aged mice (24 months), oral administration of CAD significantly improved cardiac function, alleviated myocardial hypertrophy and fibrosis, and suppressed molecular hallmarks of cardiac aging. Transcriptomic and molecular analyses indicated that these benefits were mediated through the restoration of mitochondrial-endoplasmic reticulum homeostasis and the alleviation of oxidative stress in aged myocardium. To enable effective systemic administration, we reformulated CAD into a stable aqueous dispersion (CAD-cluster) via exosome-assisted nonencapsulative dispersion. This approach expanded the administration route to intravenous injection and significantly enhanced systemic exposure. Remarkably, intravenous administration of CAD-cluster achieved therapeutic efficacy comparable to high-dose oral CAD while requiring a markedly reduced cumulative dose. Together, these findings identify CAD as an effective therapeutic candidate for aging-related cardiac dysfunction and support nonencapsulative exosome-assisted dispersion as a practical strategy to improve the translational feasibility of poorly soluble membrane-targeted small molecules.

Berberine (BBR), the core alkaloid of the traditional Chinese medicine Coptis chinensis (Huanglian), exhibits a notable pharmacological paradox: it possesses an oral bioavailability of less than 1% yet exerts broad therapeutic effects across the full spectrum of liver diseases, from metabolic dysfunction-associated steatotic liver disease (MASLD) through fibrosis to hepatic malignancies. This review constructs an integrated mechanistic framework to interpret BBR's holistic pharmacological characteristics, which distinguish it from conventional single-target drugs. In MASLD, BBR engages a convergent AMPK-SIRT-Nrf2 network to ameliorate insulin resistance, lipid dysregulation, oxidative stress, and hepatic inflammation. Combined with the complementary actions of its bioactive metabolites, it achieves parent-metabolite coordinated efficacy that embodies the holistic principle of traditional Chinese medicine. In liver fibrosis, BBR may block hepatic stellate cell activation via the TGF-β1/Smad3 pathway and eliminate activated HSCs through multiple programmed cell death pathways, particularly ferroptosis, which may overcome apoptosis resistance. In hepatic malignancies, BBR suppresses tumor progression, metastasis, and chemoresistance via apoptotic, ferroptotic, and immunomodulatory mechanisms. Current clinical evidence validates its metabolic benefits in MASLD, whereas clinical data regarding fibrosis and hepatic malignancies remain insufficient. Improving its poor bioavailability through structural modification and nanocarrier delivery is critical for clinical translation. This review provides a modern pharmacological rationale for the clinical application of Coptis chinensis-based formulas against progressive liver diseases.

A multidimensional diagnosis-based comorbidity index (MDCI) and a drug comorbidity index (DCI) have demonstrated superior discrimination of mortality risk compared to the Charlson Comorbidity Index (CCI) in smaller specific populations. We aimed to evaluate performance of these indices in an entire population according to age, sex, and to estimate comorbidity-adjusted life expectancy (CALE), i.e. life expectancy conditional on age and comorbidity. Open cohort study of all adults residing in Sweden in 2006-2022. Discrimination of mortality risk at one year of follow-up was assessed through the C-index. CALE was estimated using parametric survival models based on age and comorbidity. 10 079 529 individuals were included. The MDCI (C-index 0.882 [95% CI 0.882-0.882]) and DCI (C-index 0.871 [95% CI 0.870-0.871]) improved discrimination of mortality risk compared to the CCI (C-index 0.811 [95% CI 0.811-0.812]). For each age above 40 the combination of MDCI and DCI clearly separated risk of death within levels of CCI and identified a wider range of CALE than CCI. At age 70 CALE based on the combination of MDCI and DCI varied from 7.0 to 17.9 years at the 5th and 95th percentile in men, and from 8.9 to 20.2 years in women. CALE based on CCI varied from 11.0 to 16.1 years in men and 11.7 to 18.4 years in women. Comprehensive comorbidity indices improved discrimination of mortality risk over the CCI in all age groups in men and women and identified a wider range of comorbidity-adjusted life expectancy in individuals of the same age.

Obesity is a global health problem linked to the development of metabolic syndrome and comorbidities such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Pleiotrophin (PTN) is a cytokine known for its role in tissue regeneration and energy metabolism. However, its function in hepatic metabolism and its role in MASLD progression remain to be elucidated. Here, we investigated the contribution of PTN to hepatic metabolism using male and female wild-type (Ptn+/+) and PTN-deficient (Ptn-/-) mice fed a standard or high-fat diet (HFD) for 6 months, as well as primary hepatocytes and Huh7 cells. Ptn-deletion protected both sexes against HFD-induced body weight gain, fasting hyperglycemia, hyperinsulinemia, insulin resistance and metainflammation. Furthermore, PTN deficiency prevented hepatic steatosis, reduced triacylglyceride accumulation and protected against liver fibrosis. Mechanistically, PTN deficiency was associated with increased AMPK activation, reduced ACC abundance and phosphorylation, constitutively low DGAT2 expression and altered AKT signalling. In vitro, PTN directly promoted lipid accumulation and triacylglyceride synthesis in primary hepatocytes and Huh7 cells, supporting a direct role for PTN in regulating hepatocyte lipid metabolism. Our results highlight PTN as a key modulator of hepatic lipid metabolism, systemic inflammation and extracellular matrix remodelling during obesity. These findings identify PTN as a promising therapeutic target for MASLD, MASH and related metabolic disorders, and point to a sexual dimorphism in adaptive metabolic strategies, with females demonstrating a greater degree of protection against the liver-damaging effects of diet-induced obesity.