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Rendering Oral Nicotine Pouches Harmless—A Biological Appraisal
No full textSince their introduction to the US market in 2016, oral nicotine pouches have grown in popularity. These small fiber pouches of an appealing taste deliver nicotine to the narrow space between the gum and the lip, precisely at the interface of the mucosa of the vestibulum oris and the oral moisture derived from saliva. This delivery mechanism leads to a systemic effect as the substances bypass gastrointestinal enzymatic degradation and the hepatic first-pass effect. While a portion of the nicotine from these products undergoes enzymatic changes in the liver due to the first-pass effect, some nicotine manages to evade this process. The gut environment appears to influence the first-pass effect within the portal circulation system. Despite their ease of use, these products exhibit variability in nicotine levels and concentrations, potentially leading to poisoning and addiction. The increases in use, marketing, and appeal of nicotine pouches have notably elevated their popularity among younger people. However, it is crucial to note that oral nicotine pouches are not risk-free. Given their potential for overdose, a review of medical literature was conducted to explore whether the microbiota could play a role in influencing nicotine overdose among users of oral nicotine pouches
Leukotriene B4 (LTB4) Aggravates Myocardial Ischemia-Reperfusion Injury through BLT2/JAK1/STAT1 Pathway
No full textBackground: Myocardial ischemia-reperfusion (I/R) injury (MIRI) often occurs as a complication following myocardial infarction, resulting in inflammation and apoptosis of myocardial cells, thereby worsening cardiac dysfunction. Leukotriene B4 (LTB4) serves as an inflammatory mediator known for its regulation of various cellular functions through its receptor, leukotriene B4 receptor 2 (BLT2). This study delved into the precise role of LTB4 in MIRI and the underlying mechanisms. Methods: This study utilized LTB4-deficient mouse models and an in vitro model of cardiomyocytes overexpressing LTB4 subjected to H/R (hypoxia/reoxygenation). LTB4 expression levels were analyzed using enzyme linked immunosorbent assay (ELISA), while activation of the BLT2/janus kinase 1 (JAK1)/signal transducer and activator of transcription 1 (STAT1) pathway was assessed via western blotting. Cardiac function in mice was evaluated through echocardiographic and hemodynamic assessments. Myocardial injury was determined by hematoxylin-eosin (H&E) staining, as well as measurement of lactate dehydrogenase (LDH), creatine phosphokinase (CPK), cardiac troponin-I (CTNI), cardiac troponin-T (CTNT), and creatine kinase MB (CK-MB) levels. Inflammation was assessed by real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) to determine the expression of inflammation-related genes. Terminal deoxynucleotidyl transferase (TDT) dUTP Nick-End Labeling (TUNEL) staining and analysis of apoptosis-related protein levels were employed to assess apoptosis. Additionally, selective BLT2 agonists and antagonists were utilized in targeting experiments to demonstrate that BLT2 acts upstream of JAK1/STAT1. Results: Our findings revealed a significant elevation in LTB4 expression during MIRI (p < 0.01). LTB4-deficient mice demonstrated enhanced cardiac function and markedly reduced activation of the BLT2/JAK1/STAT1 pathway, myocardial injury, inflammation, and cell apoptosis following I/R injury compared to wild-type mice (p < 0.05). Moreover, in vitro experiments indicated that LTB4 overexpression heightened activation of the BLT2/JAK1/STAT1 pathway, exacerbating inflammation and apoptosis in H/R-stimulated cardiomyocytes by activating the BLT2/JAK1/STAT1 pathway (p < 0.05). Conclusion: This study reaffirms the crucial involvement of LTB4 through the BLT2/JAK1/STAT1 signaling pathway in MIRI, potentially by promoting inflammation and apoptosis of myocardial cells. These results offer valuable insights for the exploration of novel therapeutic approaches. Future research should explore interventions aimed at modulating the LTB4/BLT2/JAK1/STAT1 signaling pathway to mitigate MIRI and enhance cardiac function
Lysine-Specific Histone Demethylase 1A Contributes to Cutaneous Psoriatic Lesions by Regulating Ferroptosis
Get PDFBackground: Psoriasis is a prevalent immune-mediated chronic inflammatory skin disorder, and the persistent challenge associated with its high recurrence rates remains. This study aimed to investigate the involvement of lysine-specific histone demethylase 1A (KDM1A) in psoriasis pathogenesis. Methods: An imiquimod-induced psoriasis-like dermatitis mouse model was generated and KDM1A knockdown was conducted using lentivirus. Skin appearance was scored and pathological changes were observed. Oxidative stress, lipid peroxidation, inflammatory response, iron accumulation, and ferroptosis-related proteins in the skin were assessed. Afterward, human HaCaT keratinocytes were treated with proinflammatory cytokines to mimic psoriatic conditions and ferroptosis-related proteins were determined. The ferroptosis inducer erastin was used to treat HaCaT keratinocytes, and its influences on oxidative stress and inflammation were assessed. Results: Imiquimod increased the levels of KDM1A, and KDM1A knockdown ameliorated skin psoriatic lesions in mice and reduced inflammatory infiltration. Oxidative stress, lipid peroxidation, iron accumulation, and iron transport-related proteins in skin were also reduced. In HaCaT keratinocytes, KDM1A knockdown similarly mitigated lipid peroxidation and reduced iron transport-related proteins. Importantly, erastin disrupted the inhibition of oxidative stress and inflammation in keratinocytes induced by KDM1A knockdown. Conclusion: This study highlights the significance of KDM1A in psoriasis pathogenesis and suggests that its regulation of ferroptosis may play a critical role in disease development
Correlation Analysis between Systemic Immune Inflammation Index and Adverse Outcomes in Aneurysmal Subarachnoid Hemorrhage
Get PDFBackground: The prognosis of patients with cerebral hemorrhage is strongly linked to systemic inflammatory responses. This study aimed to investigate the correlation between the systemic immune inflammation index (SII) and adverse outcomes in patients diagnosed with aneurysmal subarachnoid hemorrhage (aSAH). Method: Between February 2020 and September 2022, we conducted a retrospective cohort analysis involving 102 aSAH patients who visited our hospital. We collected baseline and clinical data to assess the relationship between SII and prognosis. Patients were categorized into either the good or poor prognosis group based on the modified Rankin Scale (mRS) score three months post-discharge. Comparative analysis of baseline and clinical data at admission and three months post-discharge was conducted between the two groups. Result: The study included 51 patients in the good prognosis group and 51 patients in the poor prognosis group. Statistically significant differences were observed between the groups in terms of age, the number of patients undergoing craniotomy clipping surgery, the number of patients receiving endovascular embolization treatment, main grade of Fisher at admission, and postoperative complications (p < 0.05). The Area Under Curve (AUC) for predicting adverse outcomes in aSAH using SII was 0.812 (95% confidence interval (CI): 0.730–0.894, p < 0.001), with a sensitivity of 0.863, specificity of 0.627, and an optimal cut-off value of 2214.5. Furthermore, the odds ratio (OR) of SII as an independent influencing factor was 10.586 (95% CI: 3.977–28.177, p < 0.001). Conclusion: The prognosis of aSAH patients at three months post-discharge is associated with their SII at admission. An elevated SII indicates a higher incidence of adverse outcomes in aSAH patients
Pharmacokinetics, MDS, and ADME of Spirooxindole-Pyrrolidines Embedded with Pyrazole Heterocycleas α-Amylase Inhibitor and Potential Cytotoxic Compounds
No full textBackground: Cancer is the second leading cause of death world-wide, surpassed only by heart diseases. Diabetes Mellitus is the most globally recorded disease, and a significant number of patients receive diagnoses for both cancer and diabetes. Diabetic patients are prone to developing liver and pancreatic cancer. The objective of this study to identify spirooxindoles scaffold with a broad spectrum of biological targets, particularly those associated with cancer and diabetes. Methods: New spirooxindole-pyrrolidines analogs were designed, synthesized and isolated through a [3 + 2] cycloaddition reaction (32CA) protocol. Following separation and purification via column chromatography, the target spirooxindole-pyrrolidines analogs underwent screening for anticancer activity against breast cancer cells (MDA-MB-231) and liver carcinoma (HepG2) cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Additionally, molecular docking and investigation of Absorption, Distribution, Metabolism, and Excretion (ADME) pharmacokinetics were conducted for the studied compounds. Results: The compound 8e demonstrated the highest activity against triple-negative breast cancer and liver cancer, with Half maximal inhibitory concentration (IC50) values of 4.1 and 8 μM, respectively. The inhibition potential of α-Amylase ranged from 25.25% to 62.96%. Notably, within this series, compound 8c exhibited the highest activity, showing an inhibition rate of 62.96%. To gain insights into the binding mode of these compounds within the enzymes active site, a molecular docking study was conducted. The results of the docking study identified compound 8c as the most potent within the series, with docking scores of –8.91. Furthermore, a molecular dynamic simulation (MDS) was carried out for the most active compound. The analysis revealed that compound 8c remained highly stable throughout the 50 ns simulation. Conclusions: A new class of spirooxindole analogs has been identified as small molecule inhibitors with potential applications in diabetes and cancer. These compounds exhibit promising characteristics, warranting further in-depth investigations
Hydrogen-Rich Water for the Treatment of Experimental Peri-Implantitis
No full textBackground: Due to its antioxidant and anti-inflammatory effects, hydrogen-rich water has been used to reduce inflammatory responses in many inflammatory diseases. However, its efficacy in treating peri-implantitis remains unclear. This study aims to investigate the efficacy of hydrogen-rich water in reducing inflammatory responses in experimental peri-implantitis. Methods: A ligature-induced experimental peri-implantitis model was established using three Beagle dogs (n = 24 implants). The implants were divided into two groups: a hydrogen-rich water-treated group (n = 12 implants), and a non-treated control group (n = 12 implants). The clinical indices, including the gingival index (GI), modified sulcus bleeding index (mSBI), and probing depth (PD), were examined. Hematoxylin and eosin (H&E) staining was used to assess the inflammatory cell infiltrate in the peri-implant tissue. Additionally, three host-derived pro-inflammatory cytokines, interleukin-1 (IL-1), interleukin-6 (IL-6), and matrix metalloproteinase-8 (MMP-8) were assessed using enzyme-linked immunosorbent assay (ELISA). Furthermore, microbial community profiles were analyzed using high-throughput sequencing (HTS) technology. Results: In terms of the GI, the differences between the control and treated groups at 0, 2, and 4 weeks were not statistically significant (all p > 0.05). However, the GI value in the treated group at 6 weeks was significantly lower than that in the control group (p = 0.005). As for the PD, the differences between the control and treated groups at 0, 2, 4, and 6 weeks were not statistically significant (all p > 0.05). Regarding the mSBI, the difference between the control and treated groups at 0 week was not statistically significant (all p > 0.05), while the mSBI value in the treated group at 2, 4, and 6 weeks was significantly lower than that in the control group (p = 0.008, p = 0.005, p = 0.001). Compared to the non-treated group, the hydrogen-rich water-treated group showed a significantly lower number of inflammatory cells, lower pro-inflammatory cytokines, IL-1, IL-6, and MMP-8 levels (p < 0.05). Additionally, there was a significantly decreased relative abundance of pathogenic bacterial species including Porphyromonas gingivalis, Fusobacterium nucleatum, Fusibacter, and Fretibacterium (p < 0.05). Conclusions: The use of hydrogen-rich water for treating peri-implantitis showed promise and effectiveness within the scope of this study
The Role of Vaginal Microbiota Dysbiosis and Inflammation in Reproduction and Pregnancy Outcomes
Get PDFThe human vagina harbors various types of microorganisms, and the normal female vaginal microbiota is in a dynamic balance ecosystem, with Lactobacillus as the predominant organism. Vaginal microbiota dysbiosis is influenced by disordered hormone regulation, autoimmune imbalance, and pathogen invasion. This dysbiosis not only adversely affects womens health and fertility but also has a negative impact on the development of babies during pregnancy, especially in terms of inflammatory responses and complications. The inflammatory response within the vagina is the first to reflect vaginal microbiota dysbiosis. Therefore, understanding the mechanisms by which host inflammatory responses triggered by changes in the microbiota lead to disease progression is critical for prevention and treatment strategies. In this review, we conducted a search of the PubMed electronic databases for studies published before August 2023 with keywords “vaginal microbiota”, “inflammation”, “reproductive”, “fertility”, and “pregnancy”. We also manually searched relevant references from retrieved manuscripts and review articles. We aim to summarize the research focused on inflammation and complications induced by dysbiosis of the vaginal microbiota and the impact on female fertility and pregnancy outcomes
TGR5 Reduces Lipopolysaccharide-Induced Macrophage Inflammatory Response through Regulating the STAT3 Signaling Pathway
No full textBackground: The immune response mediated by alveolar macrophages is critical in lung injury pathogenesis. Takeda G protein-coupled receptor 5 (TGR5) is implicated in the immune cell-mediated responses. This study explored the effects and underlying mechanisms of TGR5 in the lipopolysaccharide (LPS)-induced inflammatory responses in alveolar macrophages. Methods: Mouse alveolar macrophage (MH-S) cells were exposed to LPS, and TGR5 knockdown cells were established using the Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 (CRISPR/Cas9) method. The changes of inflammation responses and macrophage polarity after TGR5 knockdown in LPS-treated MH-S cells were analyzed by quantitative reverse transcriptase real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). The impact of TGR5 knockdown on protein expression related to the signal transducer and activator of the transcription 3 (STAT3) pathway was assessed through Western blot. Finally, MH-S cells were treated with chenodeoxycholic acid (CDCA, a TGR5 agonist) or cucurbitacin B (CuB, a STAT3 inhibitor), and changed in the expression of STAT3 pathway proteins and the macrophage activation markers inducible nitric oxide synthase (iNOS) and cluster of differentiation 206 (CD206) were detected using Western blot and qRT-PCR. Results: LPS stimulation enhanced inflammation responses in MH-S cells, with TGR5 knockdown exacerbating LPS-induced inflammation. Additionally, TGR5 knockdown promoted LPS-induced M1 polarization of macrophages, increasing Interleukin (IL)-6 expression and the phospho (p)-STAT3/STAT3 ratio in LPS-induced MH-S cells. Treatment with CDCA or CuB reduced IL-6 expression and the p-STAT3/STAT3 ratio, inhibiting M1 polarization of macrophages in TGR5 knockdown MH-S cells. Conclusions: TGR5 inhibits inflammation and promotes macrophage polarization toward the M2 phenotype in LPS-induced MH-S cells. Its effect is achieved, in part, by inhibiting the STAT3 signaling pathway
MiR-342-5p Alleviates Inflammatory Responses in Sepsis-Induced AKI by Targeting PFN1
No full textBackground: The development of several human diseases has been linked to microRNA-342-5p (miR-342-5p). However, its specific function in the inflammatory reactions associated with sepsis-triggered acute kidney injury (AKI) remains unexplored. This study aims to delve into the role of miR-342-5p in the progression of sepsis-induced AKI. Methods: To understand the underlying mechanism of miR-342-5p in sepsis, we established sepsis models through induction with lipopolysaccharide (LPS). The cell proliferation and apoptosis were assessed using the 5-ethynyl-2′-deoxyuridine (EdU) method and flow cytometry, respectively. Bioinformatics analysis was employed to predict the downstream binding target of miR-342-5p, and their interaction was confirmed through a dual-luciferase reporter gene assay. The rescue tests were conducted to further explore the action pathway of miR-342-5p. Results: The administration of LPS significantly decreased the HK2 cell proliferation (p < 0.05), and increased cell apoptosis. Additionally, there was a notable downregulation in miR-342-5p expression accompanied by an elevated level of inflammatory factor (p < 0.05). Furthermore, the overexpression of miR-342-5p effectively attenuated the LPS-induced inflammatory response in HK2 cells (p < 0.05). Profilin-1 (PFN1) emerged as a pivotal player in sepsis pathogenesis, serving as a critical downstream target of miR-342-5p. Interestingly, rescue experiments demonstrated that the stimulatory effects of miR-342-5p mimics were counteracted by the overexpression of PFN1 in sepsis. Conclusions: MiR-342-5p alleviates inflammatory responses in sepsis by targeting PFN1
Methacholine Could Induce Asthma-Like Changes at the Molecular Level
No full textBackground: The typical symptoms of asthma, including airway hyperresponsiveness (AHR) and airway remodeling, induce mechanical stress. Despite its crucial role in tissue development and pathophysiology, the role of mechanical stress in the development of asthma and its impact on the induction of AHR remain unclear. In this study, we aimed to investigate the potential contribution of mechanical stress to asthma by using a mouse model. Methods: Healthy mice were challenged with methacholine (METH) and compared with an allergic airway inflammation model induced by ovalbumin (OVA). Different approaches, including immunofluorescence, immunohistochemical staining, Western blot analysis, and histopathology were employed to detect pathological changes in the lung tissue of the experimental mice. Transcriptome analysis was conducted to identify the genetic changes in AHR-related genes within the lung tissue of mice following METH treatment. Results: METH treatment did not promote allergic phenotypes, but induced asthma-like changes in gene expression profiles. Affected genes were enriched in the immune response and inflammation-related genes, including genes involved in granulocyte migration and inflammatory reactions. Importantly, mechanical force perception ability was significantly enhanced in the OVA-induced allergic airway inflammation mouse lung, evidenced by increased expression of mechanoreceptor proteins. Conclusions: Short-term bronchial constriction without inflammation may not lead to tissue remodeling. However, genes involved in asthma development remain active