Although antiretroviral therapy effectively controls human immunodeficiency virus (HIV) replication, a residual chronic immune activation/inflammation persists throughout the disease. This aberrant immune activation and inflammation are considered an accelerator of non-AIDS-related events and one of the driving forces of CD4⁺ T cell depletion. Unfortunately, HIV-associated immune activation is driven by various factors, while the mechanism of excessive inflammation has not been formally clarified. To date, several clinical interventions or treatment candidates undergoing clinical trials have been proposed to combat this systemic immune activation/inflammation. However, these strategies revealed limited results, or their nonspecific anti-inflammatory properties are similar to previous interventions. Here, we reviewed recent learnings of immune activation and persisting inflammation associated with HIV infection, as well as the current directions to overcome it. Of note, a more profound understanding of the specific mechanisms for aberrant inflammation is still imperative for identifying an effective clinical intervention strategy.

Sepsis is defined as a dysregulated immune response to infection that leads to multiple organ dysfunction. To date, though a growing body of knowledge has gained insight into the clinical risk factors, pathobiology, treatment response, and recovery methods, sepsis remains a significant concern and clinical burden. Therefore, further study is urgently needed to alleviate the acute and chronic outcomes. Berberine (BBR), a traditional Chinese medicine with multiple actions and mechanisms, has been investigated in cellular and rodent animal models of sepsis mainly based on its anti-inflammatory effect. However, the practical application of BBR in sepsis is still lacking, and it is imperative to systematically summarize the study of BBR in sepsis. This review summarized its pharmacological activities and mechanisms in septic-related organ injuries and the potential BBR-based therapeutic strategies for sepsis, which will provide comprehensive references for scientific research and clinical application.

Background: The activation of adenosine-monophosphate-activated protein kinase (AMPK) by berberine (BBR) benefits various inflammatory diseases. Conversely, high mobility group box-1 (HMGB1), a prototypical damage-associated molecular pattern (DAMP), typically exerts opposing effects. This research aims to investigate the relationship between AMPK and HMGB1, elucidating the functions and underlying mechanisms by which BBR alleviates acute lung injury (ALI) caused by lipopolysaccharide (LPS). Methods: Male C57BL/6J mice were intragastrically administered BBR twice daily for three days with a total of 25 and 100 mg/kg/day. On day four, an intraperitoneal injection of 10 mg/kg LPS was administered, and BBR was given two hours before and six hours after this injection, respectively. Eighteen hours post-LPS administration, lung tissues and serum samples were collected to assess indicators of lung tissue injury, inflammation, oxidative stress, and apoptosis. The relationship between AMPK activation, HMGB1 release, and inflammatory activation was investigated in both mice and RAW264.7 cells using protein expression analysis, AMPK silencing, and exogenous HMGB1 introduction. Results: Our findings demonstrate that BBR activates AMPK and inhibits HMGB1 expression, translocation, and release in LPS-induced ALI, resulting in reduced histopathological lung injuries, decreased expression of inflammatory cytokine genes, and diminished oxidative stress and apoptosis. Mechanistic studies revealed that BBR decreases extracellular HMGB1 in LPS-stimulated RAW264.7 cells and inhibits HMGB1-stimulated nuclear factor Kappa B (NF-κB) activation. Concurrently, silencing the activation of AMPK by siRNA and compound C reversed the BBR-reduced extracellular HMGB1 level in LPS-stimulated RAW264.7 cells. Conclusions: Based on these findings, we conclude that BBR effectively inhibits inflammation, oxidative stress, and apoptosis in LPS-induced ALI by modulating the AMPK-HMGB1-NF-κB axis. Consequently, BBR and other AMPK activators may represent promising therapeutic options for managing systemic inflammation and injury during sepsis.

Metabolic dysfunction-associated steatotic liver disease (MASLD), a prevalent metabolic disorder globally, has presented an urgent need for effective therapeutic agents. The complex pathogenesis of MASLD and the failure of numerous clinical trials targeting this disease have prompted the exploration of probiotic intervention as a novel therapeutic strategy. Emerging evidence underscores the pivotal role of the gut-liver axis in MASLD progression, particularly through dysregulation of gut microbiota composition, impaired intestinal barrier integrity, and aberrant bacterial metabolite signaling. Preclinical studies indicate that specific probiotic strains may ameliorate MASLD by restoring microbial homeostasis, fortifying gut barrier function, and attenuating hepatic inflammation via gut-liver crosstalk. Preliminary clinical trials further support the beneficial effects of probiotics in reducing hepatic steatosis and improving metabolic parameters. Future research should prioritize elucidating strain-specific mechanisms, optimizing probiotic formulations, and addressing challenges related to long-term efficacy, safety, and personalized therapeutic regimens. This review comprehensively evaluates current evidence on probiotic applications for MASLD treatment and highlights critical directions for advancing translational research in this field.