While norepinephrine (NE) is the cornerstone of septic shock resuscitation, “macrocirculation–microcirculation decoupling” at high doses remains a critical clinical challenge. This study aimed to explore the quantitative tipping point where the NE dose shifts from a life-saving vasopressor to a microcirculatory toxin in septic intensive care unit patients.

In this prospective observational study (January–September 2025), we used handheld vital microscopy to monitor sublingual microcirculation (microvascular flow index [MFI], total vessel density, perfused vessel density, proportion of perfused vessels [PPV], and heterogeneity index [HI]) in adult septic patients within 24 hours of admission and on Day 3. Beyond standard linear analysis, generalized additive models were employed to identify the dose–response thresholds associated with microcirculatory deterioration, adjusted for Acute Physiology and Chronic Health Evaluation II, interleukin-6, and systemic hemodynamics.

Of 144 screened patients, 66 were analyzed. The NE dose showed strong linear correlations with lactate (r = 0.583, P < 0.001) and HI (r = 0.444, P < 0.001), and negative correlations with MFI (r = −0.492, P < 0.001). Crucially, generalized additive models analysis revealed a significant nonlinear “cliff effect”: when the NE dose exceeds the 0.71–0.80 µg/kg/min threshold (PPV: 0.71 µg/kg/min, HI: 0.72 µg/kg/min, MFI: 0.80 µg/kg/min), microcirculatory perfusion parameters deteriorate abruptly (all P < 0.05). Multivariable Cox regression identified an NE dose of 0.80 µg/kg/min as an independent predictor of increased mortality (hazard ratio = 1.32, 95% confidence interval: 1.28–3.10, P = 0.039).

In patients with septic shock, higher NE doses were associated with impaired microcirculatory perfusion and worse outcomes. These findings support individualized vasopressor titration and suggest that microcirculatory monitoring may help identify patients at risk of vasopressor-associated microvascular dysfunction.

Luteolin is a dietary flavonoid widely distributed in fruits and vegetables. It has attracted substantial preclinical interest due to its pleiotropic hepatoprotective effects against hepatic steatosis, inflammation, fibrosis, and hepatocellular carcinoma. By reviewing data from in vitro and in vivo studies, this review comprehensively synthesizes the full spectrum of liver-directed pharmacology of luteolin, covering metabolic and toxic liver injury, fibrosis, cancer, and viral hepatitis, while critically mapping each mechanism to specific disease contexts and systematically identifying the key challenges limiting its clinical translation. The underlying mechanisms of luteolin action involve activation of Nrf2-mediated antioxidant defense, suppression of NF-κB- and NLRP3-driven inflammatory responses, inhibition of hepatic stellate cell activation via the TGF-β/Smad and STAT3 pathways, and regulation of metabolic homeostasis through liver X receptor (LXR)/SREBP-1c and AMPK signaling. Despite well-characterized mechanisms in preclinical models, several critical gaps hinder its clinical translation: (1) Rigorous randomized controlled trials in well-defined patient populations are scarce, with only one combination supplement study reported. (2) The relative contribution of luteolin metabolites to its overall bioactivity remains poorly understood, even though derivatives such as luteolin-7-diglucuronide exhibit distinct pharmacological properties. Cell-type-specific delivery systems, which show promise in preclinical fibrosis and cancer models, have not been evaluated clinically. (3) Systematic studies on the synergistic effects of luteolin with standard-of-care drugs remain largely exploratory. Overall, luteolin is a promising multi-target nutraceutical for liver diseases, and its clinical translation requires optimized delivery strategies, investigation of metabolite activity, and well-designed human clinical trials.

Apatinib has been shown to be efficacious in the treatment of gallbladder cancer. However, the underlying mechanisms remain unclear. This study aimed to explore pathways related to the antitumor effects of apatinib at the cellular level in gallbladder cancer.

NOZ and GBC-SD gallbladder cancer cells were treated with apatinib at concentrations of 0 μM, 10 μM, or 20 μM. The effect of apatinib on the proliferation of these cells was assessed using MTT and colony formation assays, and the effects of apatinib on cell cycle progression and DNA synthesis were evaluated using flow cytometry. Clinical cancer tissue samples, along with paired adjacent normal tissue samples, were obtained from 10 patients with gallbladder cancer. Immunohistochemistry, western blotting, and quantitative real-time polymerase chain reaction analyses were conducted to elucidate molecular changes induced by apatinib treatment.

Treatment with 20 μM apatinib significantly inhibited the expression of phosphorylated (p)-vascular endothelial growth factor receptor 2 (VEGFR2), p-AKT, and histone deacetylase 1 (HDAC1). Additionally, apatinib treatment led to upregulated expression of p-cyclin-dependent kinase 1, p21, and Bax, and downregulated expression of cell division cycle 25B, B-cell lymphoma 2, Snail, and Slug. Apatinib decelerated DNA replication and induced cell cycle arrest at the G2/M phase, consequently suppressing the proliferation of gallbladder cancer cells.

Apatinib inhibits the proliferation of gallbladder cancer cells, and the mechanism involves VEGFR2/AKT, HDAC1, and downstream genes. These findings provide a basis for further investigation into the molecular mechanisms underlying the inhibitory effect of apatinib in gallbladder cancer.

Disorders of gut–brain interaction (DGBIs) encompass some of the most common gastrointestinal disorders and affect up to 40% of the general population. Despite their inherent heterogeneity and diverse clinical manifestations, many of the underlying pathophysiological mechanisms overlap among different DGBIs. Activation of the gastrointestinal mucosal immune system at a low level (“low-grade inflammation”) and impairments in gut epithelial barrier structure and function have been reported to play a key role in the pathophysiology of multiple DGBIs, but these alterations cannot be detected using routine clinical testing. Confocal laser endomicroscopy (CLE) is an established, readily available technology that can be added to standard gastrointestinal endoscopy, enabling “real-time” microscopic evaluation of the gastrointestinal surface epithelium. CLE has been found to be capable of identifying gastrointestinal mucosal abnormalities that are reflective of epithelial barrier impairment and/or low-grade immune activation. Over the past several years, multiple intriguing studies have utilized CLE as a clinically applicable tool to evaluate the intestinal mucosa in patients with various DGBIs. The aim of this narrative review is to summarize the available literature on the role of CLE in patients with DGBIs and to provide a perspective on the use of this technology in DGBIs.

Liver fibrosis is a central pathological process driving the progression of chronic liver disease, yet effective antifibrotic therapies remain limited. Increasing evidence has identified the mineralocorticoid receptor (MR), a ligand-activated nuclear receptor, as a key regulator of intrahepatic homeostasis and fibrogenesis. MR is expressed across multiple hepatic cell types, including hepatocytes, hepatic stellate cells, macrophages, and liver sinusoidal endothelial cells, where it integrates metabolic, inflammatory, and microvascular signaling. Under pathological conditions, MR activation—mediated by both aldosterone-dependent and ligand-independent mechanisms such as hypoxia and oxidative stress—amplifies core profibrotic pathways, including TGF-β signaling, reactive oxygen species (ROS) generation, and NF-κB–driven inflammation. These molecular mechanisms are executed in a cell-type–specific manner, promoting hepatic stellate cell activation, macrophage-mediated inflammation, hepatocyte metabolic dysfunction, and liver sinusoidal endothelial cell capillarization, thereby forming a self-reinforcing fibrogenic network. Preclinical studies consistently demonstrate that mineralocorticoid receptor antagonists attenuate fibrosis by targeting these interconnected pathways. However, clinical evidence remains limited, with only early-phase trials in metabolic dysfunction-associated steatohepatitis and indirect support from cardiorenal studies. Nonsteroidal mineralocorticoid receptor antagonists, particularly finerenone, exhibit improved receptor selectivity and safety profiles, highlighting their therapeutic potential. Future research should focus on disease-specific patient stratification, validated antifibrotic endpoints, and rigorous safety evaluation to enable effective clinical translation of MR-targeted therapies in liver fibrosis.

Lipid metabolism reprogramming drives malignant proliferation and invasiveness in hepatocellular carcinoma (HCC). Beyond supplying energy and membrane components, lipids function as signaling molecules that modulate tumor cell epigenetics and the microenvironment. Accumulating research has clarified the implications of these metabolic alterations in HCC, providing a rationale for targeted therapies. This review summarizes key alterations in lipid metabolism within HCC and explores their mechanistic contributions to tumor progression. It further examines how lipid metabolic shifts in immune and stromal cells of the tumor microenvironment promote HCC advancement. Finally, we discuss the therapeutic potential of targeting lipid metabolism in liver cancer treatment.

The Asia-Pacific region accounts for a larger share of the hepatitis B burden than any other regions of the world, presenting a challenge to meeting the World Health Organization (WHO) 2030 elimination targets. In this study, we aimed to quantify the burden of chronic hepatitis B (CHB) and project its trends through 2030 using the GBD 2023 framework, thereby identifying gaps and priorities for the Asia-Pacific region to achieve WHO 2030 targets.

Using data from the Global Burden of Disease Study 2023, we analyzed chronic hepatitis B (CHB) prevalence, mortality, and disability-adjusted life years. We evaluated temporal trends (1990–2023) using average annual percent changes and projected the 2024–2030 burden using Bayesian age-period-cohort models.

In 2023, the Asia-Pacific region accounted for 63% of global CHB cases (178.0 million), 66% of deaths (259.1 thousand), and 65% of disability-adjusted life years (8.4 million). Regional prevalence and mortality rates exceeded global averages, although childhood (<5 years) prevalence was comparatively lower (590.3 vs. 1,325.3 per 100,000). East Asia bore the highest absolute burden (99.2 million cases), and South Asia had the largest pediatric caseload. Between 1990 and 2023, Western Asia showed the steepest decline in adult prevalence (−1.99%), whereas Southeast and Central Asia exhibited upward mortality trends. Projections indicate that the Asia-Pacific region is off track to meet the WHO 2030 disease elimination targets, as the prevalence rate in children under five years remains above the 0.1% target threshold and absolute mortality is projected to increase.

The Asia-Pacific region continues to contribute the largest share of the global CHB burden and now faces persistent gaps despite progress. Although substantial progress has been made in reducing prevalence through immunization, the region is currently off track to meet the WHO 2030 targets for both incidence and mortality.