Benign prostatic hyperplasia is a common pathological condition in aging men. Although its pathophysiology is not yet fully understood, dysfunctions in the nitric oxide (NO) and hydrogen sulfide (H2S) signaling pathways may be critically involved. In the present review, we address the physiological roles of these gasotransmitters in the prostate and discuss how their modulation may be a valuable therapeutic strategy in benign prostatic hyperplasia. Reduced NO bioavailability, decreased expression of soluble guanylate cyclase, and increased oxidative stress are associated with prostatic smooth muscle hypercontractility, increased cell proliferation, and impaired prostatic blood flow, contributing to the development of benign prostatic hyperplasia. Similarly, reductions in H2S-synthesizing enzymes, including cystathionine γ-lyase, have been observed during the aging process, suggesting a link between impaired H2S signaling and benign prostatic hyperplasia progression. Considering the critical roles of both the NO and H2S pathways in benign prostatic hyperplasia pathogenesis, the pharmacological modulation of these signaling cascades has emerged as a key therapeutic approach. Phosphodiesterase 5 inhibitors and NO donors improved benign prostatic hyperplasia and benign prostatic hyperplasia-related symptoms in clinical and preclinical studies, mainly by reducing prostate smooth muscle tone and prostatic cell proliferation. On the other hand, the therapeutic role of H2S in benign prostatic hyperplasia is less explored, although recent data suggest a promising effect. Novel therapeutic strategies to treat benign prostatic hyperplasia experimentally have been emerging and include soluble guanylate cyclase stimulators/activators, the inhibition of multidrug resistance proteins or DNA methylation, and hybrid molecules that release both NO and H2S; however, more comprehensive clinical studies to assess their efficacy in humans are needed.
FactsMost evidence on exhaled nitric oxide measurement in patients with connective tissue diseases associated with interstitial lung disease is focused on systemic sclerosis.In systemic sclerosis, the alveolar nitric oxide concentration may serve as a marker of interstitial lung disease and may reflect inflammatory activity, with potential implications for disease monitoring and therapeutic decision-making.Alveolar nitric oxide concentration may contribute to the phenotypic characterization of interstitial lung diseases and help distinguish those associated with connective tissue disease from other subsets.Open QuestionsThe potential influence of factors such as smoking, obesity, and the presence of pulmonary hypertension on exhaled nitric oxide should be further investigated in patients with connective tissue disease-associated interstitial lung disease.The levels and clinical value of the alveolar nitric oxide concentration in patients with interstitial lung disease secondary to connective tissue diseases other than systemic sclerosis warrant further investigation.Standardization of the methodology for determining alveolar nitric oxide concentration, as well as comparison of results obtained using the same device and analytical model, appears fundamental.The minimum clinically important difference in the alveolar nitric oxide concentration in patients with connective tissue disease-associated interstitial lung disease still needs to be defined. Connective tissue diseases are a group of different conditions frequently associated with interstitial lung disease, a complication with significant morbidity and mortality implications. Given its high incidence and clinical impact, an early and accurate diagnosis of interstitial lung disease is crucial. High-resolution computed tomography of the chest and pulmonary function tests is essential for diagnosing and monitoring interstitial lung disease, but in recent years, many studies have been conducted to identify new potential biomarkers. Among these, nitric oxide in exhaled air has drawn much attention, mainly because it is non-invasive, rapid and relatively low in cost. In this narrative review, we summarize published evidence regarding exhaled nitric oxide assessment in interstitial lung disease associated with connective tissue disease in adults, starting from the role of the molecule and the measurement technique. Most of the published studies have focused on interstitial lung disease associated with systemic sclerosis, which is the subject of the central part of the review. Under these conditions, measurements of exhaled nitric oxide levels, particularly its alveolar concentration, have been shown to correlate with the presence of interstitial lung disease and to predict its progression and response to treatment. Although most evidence is related to interstitial lung disease associated with systemic sclerosis, the results are also becoming available for other interstitial lung diseases associated with connective tissue disease. Despite promising results, exhaled nitric oxide measurement is not yet part of routine clinical practice. Further studies are needed to validate its role and integrate it into the clinical management of patients with interstitial lung disease associated with connective tissue disease.
FactsCardiovascular disease, Alzheimer's disease, and multiple sclerosis share a neurocardiac basis linked by cellular metabolism and diabetes, indicating the presence of common pathological pathways.Current care remains symptomatic and prevention focused, and interventions targeting shared pathways such as oxidative stress, senescence, and autophagy are lacking.Apolipoprotein E (APOE), glucagon-like peptide-1 (GLP-1) agonism, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mitochondrial dynamics, and the gut microbiome are key modulators of the neurocardiac axis and are highly interdependent.Understanding the interactions among ferroptosis, pyroptosis, and apoptosis under comorbid conditions is essential for clinical translation.Open questionsIs oxidative stress a primary driver or a consequence of autophagy dysregulation that links cardiac dysfunction to cognitive decline?Are GLP-1 receptor agonists neuroprotective independent of glycemic control, and what is the optimal timing and disease stage?Which microbial metabolites influence mitochondrial dynamics and senescence, and can microbiome targeting improve both cardiac and cognitive outcomes?Is combined inhibition of ferroptosis and pyroptosis superior to single-pathway blockade, and how can strategies for different comorbidity profiles be chosen?How can APOE genotypes and individual metabolic states guide personalized therapies that simultaneously reduce cardiovascular risk and neurodegeneration? Cardiovascular disease and cognitive loss have a neurocardiac basis. Poor vascular perfusion can impair cognitive function in both Alzheimer's disease and multiple sclerosis. However, a treatment gap exists because current approaches do not adequately address the shared underlying cellular mechanisms responsible for cognitive dysfunction in these conditions. Current treatments for cognitive impairment in diseases such as cardiovascular disease, Alzheimer's disease, multiple sclerosis, and diabetes often fail to fully address the shared underlying cellular mechanisms. Consequently, the prevailing precision treatment strategy, which focuses on managing symptoms and preventing disease progression, is insufficient. This highlights the urgent need for innovative approaches capable of targeting these common cellular pathways across these diverse conditions. Novel investigations into oxidative stress, cellular senescence, programmed cell death with apoptosis, ferroptosis, pyroptosis, and autophagy, cellular metabolism with apolipoprotein E and glucagon-like peptide-1 receptor agonism, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae), mitochondrial dynamics, and the gut microbiome offer the potential to address the risk factors and clinical treatments for cardiovascular disease and cognitive loss. These pathways are exquisitely dependent upon one another and require in-depth knowledge of the modulatory cellular mechanisms for effective translation to clinical care.
JOURNAL/mgres/04.03/01612956-202612000-00006/figure1/v/2026-07-23T200825Z/r/image-tiff Hypertension is a prevalent chronic condition and serves as a significant risk factor for numerous cardiovascular and cerebrovascular disorders. Gut microbiota dysbiosis has been considered to contribute to the pathogenesis of hypertension. It has been reported that a large majority of gut microbiota possess genes encoding hydrogenases. These hydrogenases are involved in the alteration of gut microbiota in non-infectious colitis, suggesting a potential link between microbial hydrogen metabolism and disease onset. This study aims to explore the relationship between hydrogenase expression patterns in the gut microbiome and the incidence of hypertension. In this study, publicly available gut microbiome metagenomic data were used to comprehensively analyze the expression patterns of hydrogenases in the gut microbiota of hypertensive patients. Compared with the control group, a 2.3-fold increase in electron bifurcating [FeFe] group A3 hydrogenases (P = 0.0299), a 55.6% decrease in [NiFe] group 1d hydrogenases (P = 0.0097), increased hydrogen-sensing hydrogenases and decreased hydrogen-uptake hydrogenases in the hypertension group. The main difference between the two groups is reflected in the abundance of [NiFe] hydrogenase subtypes. After eliminating the effects of factors such as age, sex, and lifestyle, significant differences in the abundance of [FeFe] group A3, [NiFe] group 1d, and [NiFe] group 1c were observed between the two groups, suggesting that these three indicators could serve as potential biomarkers for diagnosing the onset of hypertension. Additionally, Mendelian randomization analysis showed a protective effect of hydrogen metabolism against hypertension (odds ratio = 0.72, 95% confidence interval: 0.61-0.85, P < 0.001). Our study advances the understanding of microbiome-mediated mechanisms in hypertension by demonstrating an association between hydrogenase expression dynamics and blood pressure regulation, providing a foundation for future microbiome-based diagnostic and therapeutic strategies.
FactsPhotodynamic therapy (PDT) kills cancer cells via the generation of reactive oxygen species but can also trigger harmful protumorigenic effects.Cyclooxygenase-2 (COX-2) overexpression and prostaglandin E2 secretion limit PDT efficacy in many tumors.Combining indomethacin (IMC) COX-2 inhibitor with photosensitizer reduces inflammation and enhances PDT treatment.IMC-conjugated photosensitizers show promising targeted, improved tumor accumulation, and effective cancer phototherapy.Open QuestionsHow can PDT-induced protumorigenic inflammation be effectively minimized?Can IMC conjugation with photosensitizers inhibit inflammation and improve the accumulation of photosensitizers in cancer cells?What design strategies best optimize IMC-conjugated photosensitizers? Photodynamic therapy is a non-invasive treatment that directly kill cancer cells through the generation of reactive oxygen species. However, photodynamic therapy can also paradoxically trigger harmful protumorigenic effects, such as overexpression cyclooxygenase-2 and secretion of prostaglandin E2 in various type of tumors, limiting the overall therapeutic efficacy of photodynamic therapy. The inhibition of prostaglandin E2 secretion using nonselective cyclooxygenase inhibitors such as indomethacin, a widely used anti-inflammatory drug, with photodynamic therapy offers a promising approach for reducing light-induced inflammation and enhancing the effectiveness of photodynamic therapy. In addition, indomethacin and other cyclooxygenase-2 inhibitors have been conjugated with other therapeutic agents to develop tumor-targeted drug delivery systems. Their ability to selectively target and accumulate in cancer cells makes them attractive for delivering a wide range of photosensitizers directly to diseased tissues. Given the considerable progress in this area, this review outlines the photodynamic therapy application of various indomethacin-conjugated photosensitizers for the treatment of cyclooxygenase-2 overexpressed tumor cells, aiming to improve light-mediated effectiveness and reduce off-target effects. Finally, we highlight and discuss future perspectives and challenges in the development of indomethacin-conjugated photodynamic therapy agents.
JOURNAL/mgres/04.03/01612956-202612000-00012/figure1/v/2026-07-23T200825Z/r/image-tiff After knee cartilage injury, the self-repair capability is limited, making it prone to progression into osteoarthritis. Recently, gas signaling molecules such as nitric oxide and oxygen, along with reactive oxygen species and other factors associated with oxygen metabolism, have increasingly demonstrated critical roles in the field of knee cartilage injury and repair. However, there are few reports on the evolving research hotspots in this field. Based on the Web of Science Core Collection database, this study conducted a bibliometric and visualization analysis of 245 publications related to the roles of gas molecules and other factors associated with knee cartilage injury and repair. The results reveal a clear evolutionary trend in the research hotspots of this field, characterized by a transition from basic mechanism exploration to translational application transformation. (1) Basic mechanism exploration stage: The keyword co-occurrence network identified a tightly-knit cluster comprising core nodes such as "nitric oxide," "chondrocytes," "apoptosis," "reactive oxygen species," "oxidative stress," and "hypoxia." Co-citation analysis revealed that classic studies had demonstrated that nitric oxide mediates chondrocyte injury and matrix degradation through the inducible nitric oxide synthase-nitric oxide-apoptosis signaling pathway. Subsequent research further clarified the dual regulatory roles of oxygen and reactive oxygen species, confirming the significance of the hypoxia-inducible factor pathway in cartilage metabolism. Burst detection revealed that core literature from this period, such as studies on inducible nitric oxide synthase inhibition and hypoxic culture, maintained a high citation rate for 5-8 years, thereby forming a long-term, stable knowledge foundation in the field. (2) Translational application transformation stage: Emerging translational and biomaterial-related nodes, including "graphene oxide," "cartilage tissue engineering," and "nanomedicine," together with gas-based interventions such as "ozone therapy," have surged and formed strong interdisciplinary connections with "osteoarthritis" and "cartilage repair." This shift illustrates a change in perspective from "injury mechanisms" to "repair interventions." Co-citation analysis confirmed that the most significant recent literature focuses on the relationship between reactive oxygen species, cartilage aging, and osteoarthritis, as well as on nanoscale drug delivery systems for directly clearing nitric oxide and reactive oxygen species. Burst detection revealed that "synergistic intervention of materials and gases" has emerged as the most active frontier hotspot. These findings suggest that gas signaling molecules and oxygen metabolism-related factors are core mediators regulating knee cartilage injury and repair. Research hotspots have shifted from exploring the inducible nitric oxide synthase-nitric oxide-apoptosis signaling pathway and oxidative stress in cartilage injury to translational applications in nanomedicine and biomaterials for cartilage repair. Future research may benefit from elucidating the mechanisms underlying multi-factor interactive networks and promoting the clinical translation of gas-targeted regulatory strategies.
JOURNAL/mgres/04.03/01612956-202612000-00004/figure1/v/2026-07-23T200825Z/r/image-tiff Radiotherapy is the primary treatment of glioblastoma, but its efficacy is often limited by tumor cell resistance to radiation. Radiotherapy mainly has its cytotoxic effect through the formation of reactive oxygen species and the damage to DNA. Nevertheless, to overcome the effects of reactive oxygen species-mediated oxidative damage and endoplasmic reticulum stress, tumor cells may activate the repair mechanisms to stress and improve antioxidant defenses. This study innovatively proposes the use of the calcium ionophore ionomycin as a radiosensitizer in glioblastoma. We used U87MG and U251 cell lines as well as subcutaneous xenograft mice as models, and conducted a combined intervention of ionomycin and radiotherapy. Mechanistically, ionomycin selectively disrupted endoplasmic reticulum calcium homeostasis, inducing severe and sustained endoplasmic reticulum stress. When combined with radiotherapy, this led to a marked surge in intracellular reactive oxygen species, and significantly enhanced apoptosis. In vitro , the combination treatment synergistically reduced cell viability, clonogenicity, and proliferation compared with either monotherapy. In vivo , ionomycin combined with radiotherapy substantially suppressed tumor growth and increased intratumoral reactive oxygen species levels and apoptosis. These findings indicate that ionomycin converts repairable adaptive stress into irreversible lethal damage by amplifying reactive oxygen species through an endoplasmic reticulum stress-reactive oxygen species vicious cycle, thereby overcoming antioxidant defenses and enhancing glioblastoma radiosensitivity.
