Limb-Girdle Muscular Dystrophy type R2 (LGMD-R2) is caused by mutations in the DYSFERLIN (DYSF) gene, leading to progressive muscle weakness and defective membrane repair. In our previous study, we identified a novel five-nucleotide microdeletion in DYSF (c.3014_3018delACCAG; NM_001130455.2) in Taiwanese LGMD patients, which is predicted to cause a frameshift and premature termination, potentially producing a truncated ~ 108 kDa dysferlin protein. To investigate its pathogenic consequences in vivo, we generated a Dysf microdeletion knock-in mouse model (DysfΔ5/Δ5) to recapitulate the patient-relevant genetic lesion and associated muscular dystrophy–like phenotypes. DysfΔ5/Δ5 mice exhibited undetectable dysferlin expression, impaired rotarod performance, and progressive pathological changes, including increased centrally nucleated fibers, and adipocyte infiltration within skeletal muscle tissues. Immunostaining of muscle tissues revealed disrupted sarcoglycan localization; furthermore, a trend toward macrophage accumulation was observed. Proteomic profiling quantified 2,329 proteins in skeletal muscle from DysfΔ5/Δ5 and wild-type mice, revealing a remodeling proteomic signature in DysfΔ5/Δ5 muscle. Gene Ontology enrichment highlighted lipid catabolic/metabolic processes alongside reduced representation of muscle development, sarcomeric organization, and contractile programs, consistent with dystrophic remodeling and fatty/fibrotic replacement. Together, these results indicate that Dysf Δ5/Δ5 mice exhibit muscular dystrophy–like pathological and functional features consistent with dysferlinopathy, providing a useful platform for mechanistic investigation and preclinical proof-of-concept studies.

Background/purpose:Endothelin-1 (ET-1) has been implicated in inflammatory tissue responses, but its role in osteoblast-mediated inflammation during periodontal inflammation remains unclear. This study investigated whether ET-1 induces cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) release in osteoblasts and explored the underlying signaling mechanisms. Materials and methods:Murine osteoblast-like MC3T3-E1 cells were stimulated with ET-1. COX-2 protein and mRNA expression, promoter activity, and PGE2 release were assessed by Western blotting, real-time RT-PCR, luciferase reporter assay, and ELISA, respectively. Pharmacological inhibitors and siRNA knockdown were used to examine the roles of ETA/ETB receptors, Gq/Gi proteins, ERK1/2, p38 MAPK, JNK1/2, and AP-1 signaling. Results:ET-1 increased COX-2 protein and mRNA expression, COX-2 promoter activity, and PGE2 release in MC3T3-E1 cells in a time-dependent manner. Actinomycin D and cycloheximide significantly reduced ET-1-induced COX-2 expression and PGE2 release, indicating transcriptional and translational regulation. Pharmacological blockade or knockdown of ETA and ETB receptors attenuated these responses. Inhibition or silencing of Gq and Gi also suppressed ET-1-induced COX-2 expression and PGE2 release. Moreover, inhibition or knockdown of ERK1/2, p38 MAPK, or JNK1/2 reduced these effects. ET-1 also promoted c-Jun phosphorylation, nuclear accumulation, AP-1 binding activity, and COX-2 promoter transactivation, whereas AP-1 inhibition or c-Jun knockdown reduced COX-2 expression and downstream PGE2 production. Conclusion:ET-1 drives COX-2 expression and PGE2 release in osteoblasts through ETA/ETB dependent Gi/Gq, MAPK, and AP-1 signaling, supporting a potential role of ET-1 in osteoblast-associated inflammatory responses and inflammatory bone microenvironment changes under periodontal inflammatory conditions.

In the original publication [...].

Background: Silica nanoparticles (SiNPs), commonly utilized in industrial and biomedical fields, are known to provoke pulmonary inflammation by elevating cyclooxygenase-2 (COX-2) levels in human pulmonary alveolar epithelial cells (HPAEpiCs). Salvianolic acid A (SAA), a water-soluble polyphenol extracted from Salvia miltiorrhiza (Danshen), possesses well-documented antioxidant and anti-inflammatory activities. Nevertheless, its potential to counteract SiNP-induced inflammatory responses in the lung has not been thoroughly explored. Objective: This study aimed to evaluate the protective role and mechanistic actions of SAA against SiNP-triggered inflammation in both cellular and animal models. Methods: HPAEpiCs were pre-incubated with SAA prior to SiNP exposure to investigate changes in COX-2 expression and prostaglandin E2 (PGE2) secretion. A murine model of SiNP-induced lung inflammation was used for in vivo validation. Key inflammatory signaling proteins, including c-Src, PKC alpha, p42/p44 MAPK, and NF-kappa B p65, were analyzed for phosphorylation status. NF-kappa B promoter activity was also assessed. Pharmacological inhibitors and siRNA-mediated silencing were employed to verify the signaling cascade responsible for COX-2 regulation. Results: SAA treatment markedly suppressed SiNP-induced upregulation of COX-2 and PGE2 in both HPAEpiCs and mouse lung tissues. SAA also reduced the activation (phosphorylation) of c-Src, PKC alpha, p42/p44 MAPK, and NF-kappa B p65, alongside diminishing NF-kappa B transcriptional activity. Functional studies using inhibitors and gene silencing further supported the involvement of these pathways in mediating the observed anti-inflammatory effect. Conclusion: By concurrently targeting several upstream pro-inflammatory signaling pathways, SAA demonstrates robust potential in alleviating SiNP-induced lung inflammation. These results highlight SAA as a promising candidate for therapeutic intervention in environmentally triggered respiratory conditions.

Trichomonas vaginalis (Tv) is the causative agent of trichomoniasis, the most common non-viral sexually transmitted infection worldwide. Despite its high prevalence, the mechanisms underlying Tv-induced inflammatory responses remain poorly understood. Herein, we investigated the signaling pathways mediating Tv-induced inflammation in ectocervical cells (Ects). We initially measured the production of various cytokines using a multiplex immunoassay, revealing a significant increase in IL-6, IL-8, IP-10, and CXCL1 secretion in Ects upon Tv infection. We then assessed the role of autophagy in regulating Tv-induced inflammation in Ects by using autophagy inhibitors and small interfering RNA targeting LC3B (si-LC3B) to block different stages of autophagy. Our findings indicated that Tv-induced autophagic flux mediates the secretion of proinflammatory cytokines in Ects. Additionally, blocking autophagosome formation via si-LC3B increases IL-6 and IP-10 levels while reducing IL-8 secretion. To further identify novel pathways involved in Tv-induced inflammation in Ects, we conducted a time-series proteomic analysis using 2D-LC-MS/MS. Intriguingly, we noticed robust activation of antiviral-related pathways in Ects after 8 h of Tv stimulation. Specifically, the most enriched proteins in these pathways were tetratricopeptide repeats (IFIT) family proteins (IFIT1, IFIT2, and IFIT3). Functional validation revealed that IFIT3 positively regulates downstream IL-8 and IP-10 secretion. Furthermore, we proved that si-LC3B enhanced IFIT expression in Ects upon Tv infection, suggesting that autophagy negatively regulates IFIT expression. Collectively, this study demonstrates that Tv infection induces autophagic flux and IFIT overexpression to modulate inflammatory responses in Ects, providing novel insights into the inflammatory mechanisms governing trichomoniasis.

OBJECTIVE:Periodontitis is a chronic inflammatory disease associated with systemic conditions, including cardiovascular diseases. Porphyromonas gingivalis (Pg), a key periodontal pathogen, contributes to vascular endothelial dysfunction through its virulence factors. This study aimed to investigate the protective effects of Taiwanese green propolis (TGP) against Pg-derived lipopolysaccharide (Pg-LPS)-induced endothelial inflammation, focusing on its modulation of the NLRP3 inflammasome and Nrf2/HO-1 signaling pathways. DESIGN:Human aortic endothelial cells (HAECs) were stimulated with Pg-LPS in the presence or absence of TGP. The expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) was assessed using real-time PCR and ELISA. ROS production was evaluated using fluorescence-based assays, while NF-κB activation and Nrf2 transcriptional activity were analyzed via luciferase reporter assays. Pharmacological inhibitors were used to confirm the involvement of these pathways. RESULTS:TGP significantly reduced Pg-LPS-induced IL-1β, TNF-α, and IL-6 expression in HAECs. It inhibited NF-κB activation, suppressed ROS generation, and attenuated NLRP3 inflammasome activation. Additionally, TGP upregulated HO-1 expression and enhanced Nrf2 transcriptional activity, as evidenced by ARE-driven luciferase reporter assays. Pharmacological inhibition of Nrf2 and HO-1 reversed TGP's anti-inflammatory effects, confirming that the Nrf2/HO-1 axis is critical for its protective function. CONCLUSIONS:These findings demonstrate that TGP exerts anti-inflammatory and cytoprotective effects by suppressing NLRP3 inflammasome activation and enhancing the Nrf2/HO-1 pathway, reducing Pg-LPS-induced endothelial inflammation. This study suggests that TGP could be a promising natural therapeutic agent for mitigating periodontal pathogen-induced systemic inflammation.

Trichomonas vaginalis (TV) is a flagellated parasite that causes trichomoniasis, the most common non-viral sexually transmitted infection (STI), with over 275 million cases annually. TV has been shown to secrete extracellular vesicles (TV-EVs) to regulate intercellular communication between parasites and host immune response; however, the mechanisms by innate immunity against TV-EVs are largely unknown. Herein, we aim to investigate the molecular mechanisms of inflammation induced by TV-EVs and identify novel proteins modulating the immune response in host cells. Firstly, the morphological characteristics of TV-EVs have been analyzed by transmission electron microscope (TEM) and nanoparticle tracking analysis, revealing that the vesicles are round-shaped bilayer membrane structures with size mostly about 100–120 nm. Additionally, the internalization of TV-EVs by host cells has been validated through immunofluorescence and TEM analysis. The multiplex immunoassay identified that TV-EVs induce the secretion of inflammatory cytokines, including CXCL1, IL-6, IL-8 and MIP-1β in THP-1 macrophages and ectocervical cells (Ect). Mechanistically, TV-EVs induce TLR3 overexpression to activate the NF-κB/NLRP3 pathway in THP-1 macrophages. Additionally, TV-EVs activate the PI3K-mediated NF-κB, p38 MAPK and ERK pathways in Ect. Moreover, TV-EV-induced TLR3 overexpression positively regulates the PI3K and NF-κB pathways, while simultaneously suppressing the p38 MAPK and ERK pathways in Ect. Proteomic analysis identified that TV-EVs upregulate MICB and TRAF3IP2, which are also positively regulated by TLR3 and involved in TV-EV-induced inflammatory cascade. Altogether, this study significantly advances our understanding of the immunomodulatory roles of TV-EVs in host cells, paving the way for future treatment of trichomoniasis and TV-associated STIs.

Trichomoniasis, caused by Trichomonas vaginalis (Tv), is the most common nonviral sexually transmitted infection (STI). Bacterial vaginosis (BV) is characterized by a reduction in health-associated Lactobacillus and an overgrowth of anaerobes. Both BV-associated bacteria (BVB) and Tv are linked to adverse gynecologic outcomes. Herein, we aimed to investigate whether interactions between vaginal bacterial species and Tv could modulate Tv pathogenicity and Tv-induced host immune responses. We established a co-culture system to evaluate the interaction between Tv and various vaginal bacteria, including Lactobacillus crispatus, Escherichia coli, Prevotella bivia, and Lactobacillus iners, in the context of polymicrobial infection in ectocervical cells (Ect1). The impact of the interactions between Tv and these bacterial species on Tv adhesion, Tv-induced cytotoxicity in Ect1 cells, and cytokine secretion were assessed. Additionally, the molecular mechanisms governing host inflammation following Tv-bacteria interactions were investigated. Our in vitro model showed that specific BVB, particularly P. bivia, enhanced the expression of Tv ap65 gene and promoted Tv adhesion to host cells. Additionally, Tv pretreated with P. bivia increased cytotoxicity and upregulated IL-6, IL-8, CXCL1, and IP-10 secretion in Ect1 cells. Furthermore, Ect1 cells stimulated with Tv pretreated with P. bivia also activated the PI3K, ERK, and p38 MAPK pathways, triggering epithelial-mesenchymal transition (EMT) events. These results demonstrate that this potential pathobiont enhances Tv pathogenicity, highlighting the impact of the vaginal microbiome on host cells during Tv infection. This study significantly advances our understanding of the complex host-bacteria-parasite interactions in the vaginal ecosystem.

Background: Intestinal parasitic infections are the most common infectious diseases among Southeast Asian migrant workers in Taiwan, especially for infections with Blastocystis hominis. However, little is known about the impact of Blastocystis subtypes (STs) on the gut microbiota. Methods: We retrospectively evaluated the prevalence of intestinal parasites in a teaching hospital in Northern Taiwan in the period of 2015-2019. Blastocystis-positive stool specimens were collected for ST analysis by polymerase chain reaction in 2020. Intestinal microbiota analyses of different Blastocystis STs and Blastocystis-free individuals were conducted by 16S rRNA sequencing. Results: A total of 13,859 subjects were analyzed, of which 1802 cases (13%) were diagnosed with intestinal parasitic infections. B. hominis infections were the most prevalent (n = 1546, 85.7%). ST analysis of Blastocystispositive samples (n = 150) indicated that ST1 was the most common type, followed by ST3, ST4, ST2, ST7, and ST5. Different Blastocystis STs (ST1, ST3, and ST4) were associated with distinct richness and diversity of the microbiota. Taxonomic profiles revealed that Akkermansia muciniphila was significantly enriched for all analyzed Blastocystis STs, whereas Holdemanella biformis was more abundant in the Blastocystis-free group. Additionally, Succinivibrio dextrinosolvens and Coprococcus eutactus were specifically more abundant in ST3 carriers than in non-infected individuals. Conclusion: This study demonstrates that A. muciniphila is positively associated with all Blastocystis STs, while H. biformis was negatively associated with them. Several bacteria were enriched in specific STs, highlighting the need for further microbiota analysis at the ST level to elucidate the pathogenicity of Blastocystis.

Diagnostic markers for myasthenia gravis (MG) are limited; thus, innovative approaches are required for supportive diagnosis and personalized care. Gut microbes are associated with MG pathogenesis; however, few studies have adopted machine learning (ML) to identify the associations among MG, gut microbiota, and metabolites. In this study, we developed an explainable ML model to predict biomarkers for MG diagnosis. We enrolled 19 MG patients and 10 non-MG individuals. Stool samples were collected and microbiome assessment was performed using 16S rRNA sequencing. Untargeted metabolic profiling was conducted to identify fecal amplicon significant variants (ASVs) and metabolites. We developed an explainable ML model in which the top ASVs and metabolites are combined to identify the best predictive performance. This model uses the SHapley Additive exPlanations method to generate both global and personalized explanations. Fecal microbe–metabolite composition differed significantly between groups. The key bacterial families were Lachnospiraceae and Ruminococcaceae, and the top three features were Lachnospiraceae, inosine, and methylhistidine. An ML model trained with the top 1% ASVs and top 15% metabolites combined outperformed all other models. Personalized explanations revealed different patterns of microbe–metabolite contributions in patients with MG. The integration of the microbiota-metabolite features and the development of an explainable ML framework can accurately identify MG and provide personalized explanations, revealing the associations between gut microbiota, metabolites, and MG. An online calculator employing this algorithm was developed that provides a streamlined interface for MG diagnosis screening and conducting personalized evaluations.

This integrative literature review evaluates the effectiveness of power toothbrushes (PTBs) compared to manual toothbrushes (MTBs) across various populations, focusing on plaque removal, gingival health, calculus reduction, and stain removal. PTBs equipped with advanced technologies such as oscillating-rotating and high-frequency sonic mechanisms have been examined for their potential to enhance oral hygiene. Special attention is given to vulnerable groups, including the elderly and individuals with intellectual disabilities, to assess how PTBs meet their specific oral health needs. A comprehensive literature search was conducted in databases including PubMed, Cochrane Library, Embase, and Google Scholar using keywords such as "power toothbrush", "electric toothbrush", "manual toothbrush", "plaque removal", "gingivitis", "calculus", "dental stains", "oral hygiene", "elderly", and "intellectual disabilities". Studies published between 2000 and 2024 were selected based on their relevance to the PTB and MTB comparison, with an emphasis on outcomes related to oral hygiene efficacy. As this review is narrative rather than systematic, it focuses on synthesizing existing knowledge without applying strict inclusion or exclusion criteria. The results indicate that PTBs generally outperform MTBs in reducing plaque, gingivitis, and stains, though the benefits for special populations are less pronounced but still significant. However, practical issues such as user experience and mechanical reliability of PTBs warrant further investigation. In conclusion, this review enhances the understanding of PTB effectiveness, guides consumer choices, and informs future technological advancements in dental care practices.

Mevastatin (MVS) is known for its anti-inflammatory effects, potentially achieved by upregulating heme oxygenase-1 (HO-1), an enzyme involved in cytoprotection against oxidative injury. Nonetheless, the specific processes by which MVS stimulates HO-1 expression in human cardiac fibroblasts (HCFs) are not yet fully understood. In this study, we found that MVS treatment increased HO-1 mRNA and protein levels in HCFs. This induction was inhibited by pretreatment with specific inhibitors of p38 MAPK, JNK1/2, and FoxO1, and by siRNAs targeting NOX2, p47phox, p38, JNK1, FoxO1, Keap1, and Nrf2. MVS also triggered ROS generation and activated JNK1/2 and p38 MAPK, both attenuated by NADPH oxidase or ROS inhibitors. Additionally, MVS promoted the phosphorylation of FoxO1 and Nrf2, which was suppressed by p38 MAPK or JNK1/2 inhibitor. Furthermore, MVS inhibited TNF-α-induced NF-κB activation and vascular cell adhesion molecule-1 (VCAM-1) expression via the HO-1/CO pathway in HCFs. In summary, the induction of HO-1 expression in HCFs by MVS is mediated through two primary signaling pathways: NADPH oxidase/ROS/p38 MAPK, and JNK1/2/FoxO1 and Nrf2. This research illuminates the underlying processes through which MVS exerts its anti-inflammatory effects by modulating HO-1 in cardiac fibroblasts.

Muscular dystrophy (MD) is a genetic disorder that causes progressive muscle weakness and degeneration. Limb-girdle muscular dystrophy (LGMD) is a type of MD that mainly causes muscle atrophy within the shoulder and pelvic girdles. LGMD is classified into autosomal dominant (LGMD-D) and autosomal recessive (LGMD-R) inheritance patterns. Mutations in the Dysferlin gene (DYSF) are common causes of LGMD-R. However, genetic screening of DYSF mutations is rare in Taiwan. Herein, we identified a novel c.2867_2871del ACCAG deletion and a previously reported c.937+1G>A mutation in DYSF from a Taiwanese family with LGMD. The primary symptoms of both siblings were difficulty climbing stairs, walking on the toes, and gradually worsening weakness in the proximal muscles and increased creatine kinase level. Through pedigree analysis and sequencing, two siblings from this family were found to have compound heterozygous DYSF mutations (c. 937+1G>A and c. 2867_2871del ACCAG) within the separated alleles. These mutations induced early stop codons; if translated, truncated DYSF proteins will be expressed. Or, the mRNA products of these two mutations will merit the nonsense-mediated decay, might result in no dysferlin protein expressed. To our knowledge, this is the first report of a novel c.2867_2871del ACCAG deletion in DYSF. Further research is required to examine the effects of the novel DYSF mutation in Taiwanese patients with LGMD.

Objectives To investigate the anticancer effects and underlying mechanisms of surfactin on human oral squamous cell carcinoma (OSCC). Materials and Methods The capacity of surfactin to induce apoptosis, autophagy, and cell cycle arrest of two different human OSCC cell lines was investigated by cell viability, acridine orange staining, and cell cycle regulatory protein expression, respectively. The signaling network underlying these processes were determined by the analysis of reactive oxygen species (ROS) generation, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, endoplasmic reticulum (ER) stress-related protein levels, calcium release, mitogen-activated protein kinases activation, and cell cycle regulatory protein expression through corresponding reagents and experiments under various experimental conditions using specific pharmaceutical inhibitors or small interfering RNAs. Results Surfactin was able to induce apoptosis through NADPH oxidase/ROS/ER stress/calcium-downregulated extracellular signal-regulated kinases 1/2 pathway. Surfactin could also lead to autophagy that shared the common regulatory signals with apoptosis pathway until calcium node. Cell cycle arrest at G(2)/M phase caused by surfactin was demonstrated through p53 and p21 accumulation combined p34(cdc2), phosphorylated p34(cdc2), and cyclin B1 inhibition, which was regulated by NADPH oxidase-derived ROS. Conclusion Surfactin could induce apoptosis, autophagy, and cell cycle arrest in ROS-dependent manner, suggesting a multifaced anticancer agent for OSCC.

Myasthenia gravis (MG) is a neuromuscular junction disease with a complex pathophysiology and clinical variation for which no clear biomarker has been discovered. We hypothesized that because changes in gut microbiome composition often occur in autoimmune diseases, the gut microbiome structures of patients with MG would differ from those without, and supervised machine learning (ML) analysis strategy could be trained using data from gut microbiota for diagnostic screening of MG. Genomic DNA from the stool samples of MG and those without were collected and established a sequencing library by constructing amplicon sequence variants (ASVs) and completing taxonomic classification of each representative DNA sequence. Four ML methods, namely least absolute shrinkage and selection operator, extreme gradient boosting (XGBoost), random forest, and classification and regression trees with nested leave-one-out cross-validation were trained using ASV taxon–based data and full ASV–based data to identify key ASVs in each data set. The results revealed XGBoost to have the best predicted performance. Overlapping key features extracted when XGBoost was trained using the full ASV–based and ASV taxon–based data were identified, and 31 high-importance ASVs (HIASVs) were obtained, assigned importance scores, and ranked. The most significant difference observed was in the abundance of bacteria in the Lachnospiraceae and Ruminococcaceae families. The 31 HIASVs were used to train the XGBoost algorithm to differentiate individuals with and without MG. The model had high diagnostic classification power and could accurately predict and identify patients with MG. In addition, the abundance of Lachnospiraceae was associated with limb weakness severity. In this study, we discovered that the composition of gut microbiomes differed between MG and non-MG subjects. In addition, the proposed XGBoost model trained using 31 HIASVs had the most favorable performance with respect to analyzing gut microbiomes. These HIASVs selected by the ML model may serve as biomarkers for clinical use and mechanistic study in the future. Our proposed ML model can identify several taxonomic markers and effectively discriminate patients with MG from those without with a high accuracy, the ML strategy can be applied as a benchmark to conduct noninvasive screening of MG.

We formerly proved that uremic vascular calcification (UVC) correlates tightly with oxidative elastic lamina (EL) injury and two cell fates (apoptosis and osteocytic conversion) in smooth muscle cells (SMC) of chronic kidney disease (CKD) patients and eliminating p-cresyl sulfate (PCS)-activated intracellular ROS ameliorates the MAPK signaling pathway in a human arterial SMC (HASMC) model. Nonetheless, whether ROS scavenger attenuates PCS-triggered inflammasome activation and eicosanoid inflammation in the UVC process remains unknown. Patients with lower extremity amputation were categorized into CKD and normal control group according to renal function. We used immunohistochemistry stain to analyze UVC in arterial specimens, including oxidative injury (8-hydroxy-2′-deoxyguanosine (8-OHdG) and internal EL disruption), cytosolic phospholipase A2 (cPLA2), cyclooxygenase 2 (COX2), interleukin-1 beta (IL-1β), caspase-1 and NLRP3. To simulate the patho-mechanism of human UVC, the therapeutic effects of ROS scavenger on PCS-triggered inflammatory pathways was explored in a HASMC model. We found CKD patients had higher circulating levels of PCS and an increase in medial arterial calcification than the control group. In CKD arteries, the severity of UVC corresponded with expressions of oxidative EL disruption and 8-OHdG. Furthermore, coupling expressions of cPLA2 and COX2 were accentuated in CKD arteries, indicative of eicosanoid inflammation. Notably, tissue expressions of IL-1β, caspase-1 and NLRP3 were enhanced in parallel with UVC severity, indicative of inflammasome activation. From bedside to bench, ROS scavenger attenuates PCS-activated expressions of cPLA2/COX2, pro-caspase-1 and NLRP3 in the HASMC model. UVC as an inevitable outcome is predictive of death in CKD patients. Nonetheless, UVC remain pharmacoresistant despite the evolution of treatment for mineral-parathyroid hormone-vitamin D axis. Beyond the mineral dysregulation, the stimulation of pro-oxidant PCS alone results in eicosanoid inflammation and inflammasome activation. Concerning the key role of Caspase-1 in pyroptosis, cell fates of HASMC in uremic milieu are not limited to apoptosis and osteogenesis. In view of this, reducing ROS and PCS may act as a therapeutic strategy for UVC-related cardiovascular events in CKD patients.

Obesity is a world-wide problem, especially the child obesity, with the complication of various metabolic diseases. Child obesity can be developed as early as the age between 2 and 6. The expansion of fat mass in child age includes both hyperplasia and hypertrophy of adipose tissue, suggesting the importance of proliferation and adipogenesis of preadipocytes. The changed composition of gut microbiota is associated with obesity, revealing the roles of lipopolysaccharide (LPS) on manipulating adipose tissue development. Studies suggest that LPS enters the circulation and acts as a pro-inflammatory regulator to facilitate pathologies. Nevertheless, the underlying mechanisms behind LPS-modulated obesity are yet clearly elucidated. This study showed that LPS enhanced the expression of cyclooxygenase-2 (COX-2), an inflammatory regulator of obesity, in preadipocytes. Pretreating preadipocytes with the scavenger of reactive oxygen species (ROS) or the inhibitors of NADPH oxidase or p42/p44 MAPK markedly decreased LPS-stimulated gene expression of COX-2 together with the phosphorylation of p47phox and p42/p44 MAPK, separately. LPS activated p42/p44 MAPK via NADPH oxidase-dependent ROS accumulation in preadipocytes. Reduction of intracellular ROS or attenuation of p42/p44 MAPK activation both reduced LPS-mediated COX-2 expression and preadipocyte proliferation. Moreover, LPS-induced preadipocyte proliferation and adipogenesis were abolished by the inhibition of COX-2 or PEG2 receptors. Taken together, our results suggested that LPS enhanced the proliferation and adipogenesis of preadipocytes via NADPH oxidase/ROS/p42/p44 MAPK-dependent COX-2 expression.

The growing increases in the global life expectancy and the incidence of chronic diseases as a direct consequence have highlighted a demand to develop effective strategies for promoting the health of the aging population. Understanding conserved mechanisms of aging across species is believed helpful for the development of approaches to delay the progression of aging and the onset of age-related diseases. Mitochondrial hormesis (or mitohormesis), which can be defined as an evolutionary-based adaptive response to low-level stress, is emerging as a promising paradigm in the field of anti-aging. Depending on the severity of the perceived stress, there are varying levels of hormetic response existing in the mitochondria called mitochondrial stress response. Hydrogen sulfide (H2S) is a volatile, flammable, and toxic gas, with a characteristic odor of rotten eggs. However, H2S is now recognized an important gaseous signaling molecule to both physiology and pathophysiology in biological systems. Recent studies that elucidate the importance of H2S as a therapeutic molecule has suggested its protective effects beyond the traditional understanding of its antioxidant properties. H2S can also be crucial for the activation of mitochondrial stress response, postulating a potential mechanism for combating aging and age-related diseases. Therefore, this review focuses on highlighting the involvement of H2S and its sulfur-containing derivatives in the induction of mitochondrial stress response, suggesting a novel possibility of mitohormesis through which this gaseous signaling molecule may promote the healthspan and lifespan of an organism.

Lung inflammation is a pivotal event in the pathogenesis of acute lung injury. Heme oxygenase-1 (HO-1) is a key antioxidant enzyme that could be induced by kaempferol (KPR) and exerts anti-inflammatory effects. However, the molecular mechanisms of KPR-mediated HO-1 expression and its effects on inflammatory responses remain unknown in human pulmonary alveolar epithelial cells (HPAEpiCs). This study aimed to verify the relationship between HO-1 expression and KPR treatment in both in vitro and in vivo models. HO-1 expression was determined by real time-PCR, Western blotting, and promoter reporter analyses. The signaling components were investigated by using pharmacological inhibitors or specific siRNAs. Chromatin immunoprecipitation (ChIP) assay was performed to investigate the interaction between nuclear factor erythroid-2-related factor (Nrf2) and antioxidant response elements (ARE) binding site of HO-1 promoter. The effect of KPR on monocytes (THP-1) binding to HPAEpiCs challenged with lipopolysaccharides (LPS) was determined by adhesion assay. We found that KPR-induced HO-1 level attenuated the LPS-induced intercellular cell adhesion protein 1 (ICAM-1) expression in HPAEpiCs. KPR-induced HO-1 mRNA and protein expression also attenuated ICAM-1 expression in mice. Tin protoporphyrin (SnPP)IX reversed the inhibitory effects of KPR in HPAEpiCs. In addition, in HPAEpiCs, KPR-induced HO-1 expression was abolished by both pretreating with the inhibitor of NADPH oxidase (NOX, apocynin (APO)), reactive oxygen species (ROS) (N-acetyl-L-cysteine (NAC)), Src (Src kinase inhibitor II (Srci II)), Pyk2 (PF431396), protein kinase C (PKC)α (Gö6976), p38 mitogen-activated protein kinase (MAPK) inhibitor (p38i) VIII, or c-Jun N-terminal kinases (JNK)1/2 (SP600125) and transfection with their respective siRNAs. The transcription of the homx1 gene was enhanced by Nrf2 activated by JNK1/2 and p38α MAPK. The binding activity between Nrf2 and HO-1 promoter was attenuated by APO, NAC, Srci II, PF431396, or Gö6983. KPR-mediated NOX/ROS/c-Src/Pyk2/PKCα/p38α MAPK and JNK1/2 activate Nrf2 to bind with ARE on the HO-1 promoter and induce HO-1 expression, which further suppresses the LPS-mediated inflammation in HPAEpiCs. Thus, KPR exerts a potential strategy to protect against pulmonary inflammation via upregulation of the HO-1.

Abdominal aortic aneurysm (AAA) is a common inflammatory vascular disease. Angiotensin II (Ang II) involves in AAA progression by promoting the proliferation and migration of vascular smooth muscle cells, the degradation of extracellular matrices, and the generation of ROS to lead to vascular inflammation. Carbon monoxide releasing molecule-2 (CORM-2) is known to exert anti-inflammatory and antioxidant activities. However, it remains unclear whether CORM-2 can suppress Ang II-induced vascular inflammation to prevent AAA progression. Therefore, this study aimed to investigate the vasoprotective effects of CORM-2 against Ang II-induced inflammatory responses of human aortic smooth muscle cells (HASMCs) and the underlying mechanisms of those effects. The results showed that Ang II induced inflammatory responses of HASMCs via NADPH oxidase- and mitochondria-derived ROS/NF-κB/IL-6/Jak2/Stat3 pathway which was attenuated by the pretreatment with CORM-2. Additionally, CORM-2 further exhibited anti-inflammatory activities in Ang II-stimulated HASMCs, as indicated by the reduction of monocyte adhesion to HASMCs and migration of HASMCs via the suppression of ICAM-1 and VCAM-1 as well as MMP-2 and MMP-9 levels, respectively. Moreover, Ang II-induced COX-2-mediated PGE2 secretion was also inhibited by the pretreatment with CORM-2. Importantly, our data demonstrated that CORM-2 reversed Ang II-induced IL-6 overexpression dependent on Nrf2 activation and HO-1 expression. Taken together, the present study indicates that CORM-2-induced Nrf2/HO-1 alleviates IL-6/Jak2/Stat3-mediated inflammatory responses to Ang II by inhibiting NADPH oxidase- and mitochondria-derived ROS, suggesting that CORM-2 is a promising pharmacologic candidate to reverse the pathological changes involved in the inflammation of vessel wall for the prevention and treatment of AAA.