Frontiers in Pharmacology最新文献

• Frequent substantial modifications for initiating new trial parts slow down development and reduce transparency. • Combining healthy volunteers and patients in a single early-phase trial raises safety, feasibility, and regulatory concerns. • A multi-stakeholder consensus in Germany identified regulatory pathways to enable seamless transitions within integrated protocols for non-ATMP (advanced therapy medicinal product), non-oncology trials. • The EMA FIH (first-in-human) guideline supports predefined transitions if scope, safety thresholds, and decision rules are clearly described. • The German guardrail concept clarifies when transitions do not require a substantial modification, enhancing planning certainty. • Actionable recommendations are provided on protocol design, decision criteria, and governance structures to enable early inclusion of patients without compromising safety or compliance. • First positive experience has been gained with the presented framework in Germany.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a major global health concern, affecting more than one-third of the adult population worldwide. Notably, Latin America exhibits the highest regional prevalence, with recent estimates of 44.4%. This elevated burden is attributed to the convergence of risk factors that render the population particularly vulnerable. These include high rates of obesity and type 2 diabetes mellitus (T2DM), widespread adoption of energy-dense and nutrient-poor dietary patterns, low levels of physical activity, increased alcohol consumption, and underlying genetic predispositions. Despite its growing impact, MASLD remains significantly underdiagnosed in this region. This is largely due to the limited access to gold-standard diagnostic modalities, such as liver biopsy and magnetic resonance imaging, which are costly, invasive, and often unavailable in routine clinical settings. The lack of accessible diagnostic infrastructure delays early identification and intervention, contributing to disease progression and an increased healthcare burden. Consequently, there is an urgent need to establish cost-effective, non-invasive screening strategies capable of identifying individuals at risk and facilitating timely clinical decision-making. This review synthesizes the current epidemiological data on MASLD in Mexico and Latin America and examines the most validated diagnostic and screening tools currently available.

The gut-brain axis is a bidirectional pathway linking the gastrointestinal microbiota to neurological functions. While its significance in the pathogenesis of gastrointestinal conditions is well-documented, emerging evidence indicates that dysbiosis of the gut microbiota could also be implicated in various neuropsychiatric disorders, specifically major depressive disorder (MDD). MDD represents a debilitating illness that accounts for a significant portion of global disability. Although numerous medications have been developed to manage depression, they are frequently plagued by variable efficacy and unpleasant adverse effects. The inconsistency of antidepressant effects highlights the complexity and poorly understood pathophysiology underlying this condition. Recent studies suggest that MDD may involve disruptions in the gut-brain axis via gut dysbiosis, induction of inflammation, metabolic disturbances of neuroactive substances, and dysregulation of the hypothalamic-pituitary-adrenal axis, along with the autonomic and enteric nervous systems. Given the direct and indirect connections between the microbiota and these physiological processes, probiotics are increasingly being explored as a prospective therapeutic option for MDD. Multiple probiotic formulations have shown promise in both preclinical and clinical settings, demonstrating effectiveness in attenuating symptoms associated with MDD. This review provides an overview of the pathophysiologic attributes of MDD, with particular focus on disturbances along the gut-brain axis, and investigates current findings regarding the role of probiotics in addressing these challenges. We conclude by identifying persistent gaps in the literature and proposing directions for future studies.

Background: Neuroinflammation plays a central role in neurodegenerative diseases such as Alzheimer's and Parkinson's, along with depression, anxiety, and infectious diseases including COVID-19. Harmine and harmaline, β-carboline alkaloids from Banisteriopsis caapi, exhibit immunomodulatory, anti-inflammatory, and neuroprotective properties. In this study, we aimed not only to investigate the anti-inflammatory and neuroprotective effects of β-carbolines and B. caapi extract on a lipopolysaccharide (LPS)-induced neuroinflammation model using SH-SY5Y cells and their impact on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor expression but also to compare cytokine levels in plasma from intensive care unit (ICU) and non-ICU COVID-19 patients, thereby providing clinical context for the inflammatory response.

Methods: SH-SY5Y cells were treated with LPS and incubated with harmine, harmaline, or B. caapi extract. Cell viability was assessed using the MTT assay. Cytokine expression was quantified by ELISA, and receptor gene expression was analyzed using RT-qPCR. Plasma was obtained from the Hospital das Clínicas of the University of São Paulo Medical School (HCFMUSP) biobank.

Results: IL-6 was high in ICU patients; LPS increased IL-6 and TNF-α cytokine levels in cells, whereas harmine and harmaline significantly reduced both cytokines. B. caapi extract decreased LPS-induced NF-κB and TNF-α but did not affect IL-6. Harmine also reduced NF-κB expression. None of the treatments altered TMPRSS11D or furin, and harmaline showed no effect on ACE2. In contrast, the extract upregulated ACE2, whereas harmine induced a modest increase. Only harmine and harmaline reduced TMPRSS2 expression.

Conclusion: β-carbolines and B. caapi extract attenuate LPS-induced cytokine production in SH-SY5Y cells, supporting their anti-inflammatory and neuroprotective potential. The extract and β-carbolines also modulate ACE2 and TMPRSS2 expressions, suggesting relevance to mechanisms associated with neuro-COVID.

Background: Acute methanol intoxication is life-threatening and typically presents with severe metabolic acidosis and central nervous system injury. Intracranial hemorrhage associated with methanol poisoning is uncommon and may be clinically occult, potentially delaying diagnosis and intervention.

Case: We report a case of high-dose oral methanol poisoning presenting with profound metabolic acidosis and coma. Emergent cranial CT revealed basal ganglia hemorrhage. The patient underwent intermittent hemodialysis and received supportive pharmacotherapy. Owing to obstructive hydrocephalus and neurological deterioration, frontal burr-hole drilling and ventricular drainage were performed. Although metabolic derangements partially improved, the patient remained comatose after 1 week of hospitalization. The family requested transfer to another hospital for further management; however, the patient died during inter-hospital transport.

Conclusion: Cerebral hemorrhage secondary to methanol poisoning can be insidious and may occur within hours to days after ingestion. Early neuroimaging and timely intervention are crucial when neurological deterioration or hydrocephalus is suspected.

Alcohol use disorder (AUD) remains a significant problem in the United States, resulting in over 178,000 alcohol-related deaths annually. A central problem in treating AUD is the high rate of relapse to alcohol use even after protracted periods of abstinence. Stress is a major contributor to the chronic relapsing and compulsive nature of AUD, and it alters neurocircuitry mediating craving and drug seeking. Chronic alcohol use dysregulates the neuropeptides orexin (OX)/hypocretin and dynorphin (DYN), which contribute to alcohol seeking and relapse. OX neurons originate exclusively in the hypothalamus and co-express DYN. Although OX and DYN are localized in the same synaptic vesicles and co-released when the hypothalamus is stimulated, they play opposing roles in reward, motivation, and substance use. OX, via OX receptor (OXR) signaling, promotes reward-seeking behavior, whereas DYN, acting through κ-opioid receptors (KOPs), increases depressive-like states and plays a key role in mediating aversive effects of stress. OX neurons densely innervate the paraventricular nucleus of the thalamus (PVT), a brain region that is involved in the regulation of reward function, stress, anxiety, and drug-directed behavior. In individuals with AUD, chronic alcohol use damages the thalamus, resulting in volume reductions and cognitive deficits. Therefore, lasting changes in PVT OX/DYN transmission and their interaction following chronic alcohol use may underlie stress-induced alcohol craving and relapse. Although their opposing roles in the PVT are established, implications of their interaction, particularly under conditions of stress, are limited in the context of alcohol use and reinstatement. This review synthesizes evidence from preclinical evidence and complementary clinical observations that implicate the co-transmission of OX and DYN in the PVT, with an emphasis on the posterior PVT (pPVT), which receives the most OX afferents, during the stress-induced reinstatement of alcohol seeking. We also discuss the potential of targeting OXRs and KOPs pharmacologically to reduce stress-induced alcohol craving and reinstatement. This review will help disentangle individual vs. interactive contributions of OX and DYN, and elucidate how their modulation within stress- and reward-related circuits may reveal novel insights for preventing relapse in individuals with AUD.

Introduction: In recent years, the incidence and mortality rates of gastric cancer (GC) have continued to rise, making it a major public health concern that poses a severe threat to human health. Although significant progress has been made in the treatment of GC in recent years, the overall median survival time for patients remains short. This situation is primarily attributed to the high metastatic potential and recurrence rate of tumors, as well as the generally low sensitivity of patients to radiotherapy and chemotherapy. Therefore, the development of safe, effective, and sustainable therapeutic strategies has become an urgent and critical issue in global medical research. Chinese herbal medicine, with its unique advantages such as low cost, minimal risk of drug resistance, and fewer adverse effects, has accumulated extensive clinical experience in the treatment of GC, demonstrating broad application prospects.

Methods: We systematically searched databases including PubMed, Web of Science, Scopus, and ISI using the following keywords: "gastric cancer/tumor," "natural products," "natural extracts," "traditional Chinese medicine extracts," "traditional Chinese medicine formulas," and "ferroptosis." A comprehensive review and analysis of the existing relevant literature were conducted.

Results: Currently, the management of gastric cancer (GC) primarily relies on surgical resection, complemented by a range of therapeutic modalities including radiotherapy, chemotherapy, targeted therapy, and immunotherapy. However, the overall median survival rate for patients with GC remains unsatisfactory. In recent years, accumulating evidence has indicated that Chinese herbal medicine may play a significant role in the treatment of GC through the regulation of ferroptosis. Emerging studies have further demonstrated that Chinese herbal medicine not only induces ferroptosis in tumor cells and suppresses tumor proliferation but also enhances the therapeutic efficacy of radiotherapy, targeted therapy, and immunotherapy, thereby improving overall treatment outcomes. This article reviews recent advances in research on Chinese herbal medicine-mediated modulation of ferroptosis in GC and discusses the potential molecular mechanisms underlying ferroptosis in this malignancy, aiming to provide a theoretical foundation for the development of precise diagnostic approaches and targeted therapeutic strategies.

Conclusion: Studies indicate that Chinese herbal medicines targeting ferroptosis hold promising potential in GC therapy, not only laying a theoretical foundation for elucidating the pathogenesis of GC and establishing ferroptosis-targeted Chinese herbal medicine intervention strategies, but also opening new avenues for the clinical prevention and treatment of GC.

Background: Hypertriglyceridemia (HTG) and mixed dyslipidemia are significant risk factors for cardiovascular diseases. Despite the widespread use of traditional therapies, many patients continue to experience elevated triglycerides and residual cardiovascular risk. Small interfering RNA (siRNA) therapies represent a novel approach to lipid-lowering treatment.

Methods: A systematic review and meta-analysis were conducted on randomized controlled trials comparing siRNA versus placebo for hypertriglyceridemia or mixed dyslipidemia. The search included PubMed, Cochrane Library, Web of Science, and Embase databases from inception to 1 October 2025, limited to English-language publications. Data extraction was performed independently by two authors.

Results: Eight RCTs involving 2,671 participants met the inclusion criteria. siRNA therapies significantly reduced triglycerides (TG) (MD, -52%; 95%, -57.9 to -46.2), non-high-density lipoprotein cholesterol (non-HDL-C) (MD, -21.9%; 95%, -26 to -17.7), very low-density lipoprotein cholesterol (VLDL-C) (MD, -49.5%; 95%, -60.1 to -38.9), apolipoprotein B (apoB) (MD, -12.6%; 95%, -16.4 to -8.8), and remnant cholesterol (MD, -64.8%; 95%, -81.7 to -47.9)compared with placebo. The reduction in TG was particularly notable. Subgroup analysis revealed that ANGPTL3-targeted therapies resulted in more substantial reductions in low-density lipoprotein cholesterol (MD, -13.2%; 95% CI, -20.1 to -6.2), while APOC3-targeted therapies had a neutral effect on LDL-C levels (MD, 0.6%; 95% CI, -5.7-6.9) (p for interaction = 0.00001). On the other hand, APOC3-targeted therapies significantly increased high-density lipoprotein cholesterol levels (MD, 40.9%; 95% CI, 31.6-50.2), whereas ANGPTL3-targeted therapies led to a reduction in HDL-C levels (MD, -20.2%; 95% CI, -25.4 to -14.9) (p for interaction = 0.00001). No significant differences were observed in the risk of adverse events between siRNA therapy and placebo (RR, 1.02; 95% CI, 0.96-1.09).

Conclusion: siRNA therapies demonstrate significant efficacy in reducing triglycerides and improving lipid profiles in patients with HTG and mixed dyslipidemia. APOC3-targeted treatments primarily reduce triglycerides while increasing HDL-C, whereas ANGPTL3-targeted therapies offer broader lipid modulation, including substantial reductions in LDL-C. Both therapies demonstrate favorable safety profiles.

KRAS is one of the most frequently mutated oncogenes in non-small cell lung cancer (NSCLC), particularly in lung adenocarcinoma, with mutation rates ranging from 15% to 25%. Historically considered "undruggable," KRAS has recently become a viable therapeutic target with the development of selective KRAS G12C inhibitors such as sotorasib (AMG510) and adagrasib (MRTX849). These inhibitors have demonstrated promising clinical efficacy; however, their effectiveness is frequently limited by the emergence of resistance mechanisms. This review provides a comprehensive analysis of KRAS G12C structural biology, its role in oncogenic signaling, and the challenges associated with targeted therapy. We discuss the mechanisms of intrinsic and acquired resistance, current monotherapy limitations, and the rationale for combination strategies aimed at overcoming resistance. Additionally, we explore future therapeutic perspectives, including novel inhibitors, combination regimens, and emerging precision medicine approaches, to optimize treatment outcomes for patients with KRAS G12C-mutant NSCLC.

Ganoderic acid A (GAA), a major bioactive triterpenoid from Ganoderma lucidum, is known for its anti-inflammatory effects; however, its precise molecular targets in sepsis-related liver injury (SRLI) remain unclear. Integrating network pharmacology and transcriptomic analysis, we identified Tumor Necrosis Factor-alpha (TNFα) as a primary candidate target. Subsequent biophysical validation using surface plasmon resonance (SPR) and molecular dynamics (MD) simulations confirmed that GAA directly binds to TNFα. Functionally, this interaction inhibits the TNFα/NF-κB signaling axis, thereby suppressing macrophage M1 polarization and ameliorating liver injury in vitro and in vivo. This study identifies TNFα as a primary candidate target of GAA, providing a mechanistic basis for its hepatoprotective effects and therapeutic potential.