Protective Role Research Articles

Activation of the IKK2/NF-κB pathway in VSMCs inhibits calcified vascular stiffness in CKD.

IKK2/NF-κB pathway-mediated inflammation in vascular smooth muscle cells (VSMCs) has been proposed to be an etiologic factor in medial calcification and stiffness. However, the role of the IKK2/NF-κB pathway in medial calcification remains to be elucidated. In this study, we found that chronic kidney disease (CKD) induces inflammatory pathways through the local activation of the IKK2/NF-κB pathway in VMSCs associated with calcified vascular stiffness. Despite reducing the expression of inflammatory mediators, complete inhibition of the IKK2/NF-κB pathway in vitro and in vivo unexpectedly exacerbated vascular mineralization and stiffness. In contrast, activation of NF-κB by SMC-specific IκBα deficiency attenuated calcified vascular stiffness in CKD. Inhibition of the IKK2/NF-κB pathway induced cell death of VSMCs by reducing anti-cell death gene expression, whereas activation of NF-κB reduced CKD-dependent vascular cell death. In addition, increased calcification of extracellular vesicles through the inhibition of the IKK2/NF-κB pathway induced mineralization of VSMCs, which was significantly reduced by blocking cell death in vitro and in vivo. This study reveals that activation of the IKK2/NF-κB pathway in VSMCs plays a protective role in CKD-dependent calcified vascular stiffness by reducing the release of apoptotic calcifying extracellular vesicles.

The role of cytokines and chemokines in the maintenance of chronic pain-a pilot study.

The immune system is believed to be important in the initiation and maintenance of chronic pain. The aim was to investigate whether patients with chronic painful polyneuropathy (PP) differ in cytokine profiles of serum and/or cerebrospinal fluid (CSF) compared with pain-free controls. Thirty-nine patients (16 women and 23 men, mean age, 69.2 ± 12.7 years, range 41-92 years) with PP (mean duration 43 ± 48.3 months) were phenotyped with quantitative sensory testing and electroneurography, and serum and CSF samples were analyzed by 40-multiplexed, bead-based cytokine immunoassays. Results were compared with 36 age- and gender-matched patients with normal pressure hydrocephalus and absence of abnormal CSF findings. Compared with controls, patients with PP had lower concentrations of several proinflammatory and anti-inflammatory chemokines and cytokines in CSF, and others showed the same tendency, among these were tumor necrosis factor-α (14.1 ± 10.0 vs 23.9 ± 16.4 pg/mL, P < 0.005), interleukin (IL)-2 (0.6 ± 0.4 vs 1.2 ± 0.6 pg/mL, P < 0.0001), IL-6 (4.7 ± 6.8 vs 7.3 ± 9 pg/mL, P = 0.001), and IL-10 (7.5 ± 6.8 vs 16.8 ± 19.2 pg/mL, P < 0.01), whereas no differences were observed in serum. Results suggest that (1) inflammatory mediators play a minor role in the maintenance of chronic pain in contrast to initiation of acute pain, (2) chemokines/cytokines are downregulated in chronic pain, or (3) chemokines/cytokines have a protective role for nerve regeneration that is disturbed in patients with chronic pain.

Associations of Inflammation, Oxidative Stress and Prognosis with IL-37 Expression in Sepsis Rats with Lung Injury

This study aimed to investigate the role of interleukin-37 (IL-37) expression in lung tissues of sepsis-induced acute lung injury (ALI) rats and its impact on ALI, along with the underlying mechanisms. Sprague-Dawley (SD) rats were categorized into three groups: Control, sepsis-induced ALI (via cecal ligation and puncture, CLP), and sepsis-induced ALI with antibiotics (CLP+An). ALI models were established, and lung tissue injuries were assessed through hematoxylineosin staining. mRNA levels of IL-1α, IL-1β, IL-37, and tumor necrosis factor-α (TNF-α) were measured via RT-PCR, while IL-37 protein levels in lung tissues were determined using Western blotting. Additionally, bronchoalveolar lavage fluid (BALF) and blood samples were collected to assess inflammatory factors through ELISA. In the CLP group, there was an increase in pro-inflammatory factors (IL-1α, IL-1β, and TNF-α) in lung tissues and serum. However, in the CLP+An group, these factors decreased, IL-37 expression increased, and oxidative stress levels decreased. IL-37 demonstrated an inhibitory effect on the release of pro-inflammatory factors (IL-1α, IL-1β, and TNF-α) in sepsis rats, leading to a reduction in lung tissue inflammation. Furthermore, IL-37 exhibited a protective role by reducing oxidative stress in sepsis-induced lung tissues. These findings highlight IL-37 as a potential therapeutic target for mitigating ALI in sepsis.

The longitudinal impact of pre- and postnatal maternal depression and anxiety on children's cognitive and language development.

We investigated the longitudinal associations among maternal pre- and postnatal depression, maternal anxiety, and children's language and cognitive development followed from 15 to 61 months. Furthermore, we assessed the protective role of children's early print experiences with books against the adverse effect of maternal depression on language development. Data for mothers and children (51.7% boys, 95% White, N = 11,662) were from the Avon Longitudinal Study of Parents and Children. Prenatal maternal depression held an adverse association with child language (β = -.16, p = .002). Moreover, the risk was greater for girls than boys (β = .19, p = .02). In addition, prenatal depression was significantly and negatively associated with child verbal intelligence quotient (β = -.11, p = .02) and performance intelligence quotient (β = -.12, p = .01). In contrast, postnatal depression or anxiety were not unique predictors of child outcomes. Importantly, children's early experiences with books, as measured by the reported frequency of parent-child shared reading, moderated the negative association between maternal depression and child language development (β = .30, p < .001). Although modest in size, these findings inform models of child risk and resilience related to maternal psychopathology. The results also have implications for clinical programs as well as for prevention and intervention studies focusing on at-home early literacy. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Exposure to community violence as a mechanism linking neighborhood disadvantage to amygdala reactivity and the protective role of parental nurturance.

Emerging literature links neighborhood disadvantage to altered neural function in regions supporting socioemotional and threat processing. Few studies, however, have examined the proximal mechanisms through which neighborhood disadvantage is associated with neural functioning. In a sample of 7- to 19-year-old twins recruited from disadvantaged neighborhoods (354 families, 708 twins; 54.5% boys; 78.5% White, 13.0% Black, 8.5% other racial/ethnic group membership), we found that exposure to community violence was related to increased amygdala reactivity during socioemotional processing and may be one mechanism linking neighborhood disadvantage to amygdala functioning. Importantly, parenting behavior appeared to modulate these effects, such that high parental nurturance buffered the effect of exposure to community violence on amygdala reactivity. These findings elucidate the potential impact of exposure to community violence on brain function and highlight the role parents can play in protecting youth from the neural effects of exposure to adversity. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

دور تعدد الأشكال لجين APE1 Asp148Glu على خطر الإصابة بسرطان الدم النخاعي الحاد في المرضى العراقيين

ابيضاض الدم النخاعي الحاد هو أكثر أنواع امراض الدم الخبيثة شيوعًا عند البالغين. يعد انتشار الخلايا الطافرة الغير مسيطر عليها للأسلاف النخاعية الغير متمايزة سمة مميزة لهذا المرض. يمكن إصلاح تلف الحمض النووي عن طريق مجموعة متنوعة من الأنظمة  الأنزيمية الموجودة في الخلايا حقيقية النواة. تتشكل الخلايا الطافرة عندما لا يمكن إصلاح تلف الحمض النووي بواسطة آليات إصلاح الخلية. إحدى آليات إصلاح الحمض النووي هي مسار إصلاح استئصال القاعدة ، التي تكون المسئولة عن تصحيح الأضرار الصغيرة الناتجة عن التلف ألتأكسدي أو والقلوية أو المثيلة. اشتملت الدراسة على 70 مريضًا مصابًا بسرطان الدم النخاعي الحاد - 37 أنثى و 33 ذكرًا - بالإضافة إلى 30 فردًا سليمًا كمجموعة سيطرة. تم استخدام مجموعة استخلاص الحمض النووي gSYNCTM لاستخراج الحمض النووي من عينات الدم الكاملة من مجموعات الدراسة. تم استخدام طريقة PCR-RFLP لتحديد تعدد الأشكال Asp148 Glu للجين APE1   في التحليل الجيني ، تبين أن الزيادة في النمط الجيني T/T وأليل T في تعدد الأشكال في كودون APE1 148 يلعب دورًا وقائيًا في مرض ابيضاض الدم النخاعي الحادAML ، وأن الزيادة في النمط الجيني G / G يمكن أن تترافق مع خطر الإصابة بسرطان الدم الحاد. . أظهرت النتائج أن النمط الجيني المتغاير لجين APE1 ، Asp 148 Glu (T / G)  وأليل G كانت أعلى بشكل ملحوظ (P &lt;0.05) في مرضى AML مقارنة بمجموعة السيطرة . في تسلسل المنطقة التي تم دراستها ، وجد أن هناك موقعًا للتغاير يقع بين GATC و GAGC ، حيث يمثل التغيير في النيوكليوتيدات T إلى G موقع تقييد الإنزيم القاطع. حيث ارتبط النمط الجيني متعدد الأشكال 148 Glu&gt; Asp من جين APE1 مع تطور AML في المرضى العراقيين. أثبتت الدراسة أن حاملي النمط الجيني  T / T لديهم مخاطر أقل لتطور مرض ابيضاض الدم النخاعي الحادAML ، في حين أن حاملي الأليلات G لديهم مخاطر متزايدة.

Cultural mechanisms linking mothers' familism values to externalizing behaviors among Midwest U.S. Latinx adolescents.

This study was designed to examine associations among parents' familism values, adolescents' cultural resources, and externalizing behavior among Latinx youth in the Midwestern United States. Participants were 267 Latinx adolescents (M age = 15.58 years; SD = 1.28 years; 45% girls; 82.8% Mexican American) and their mothers/mother figures who completed individually administered interviews comprised of standardized measures. Structural equation modeling was used to test several alternative mediational models in which youth ethnic identity and familism values served as potential cultural mechanisms linking parents' familism values to lower levels of youth externalizing behavior. Results showed that mothers' familism values were positively associated with youth ethnic identity which was positively associated with youth familism values; in turn, youth familism values were inversely associated with externalizing behavior. The findings did not differ by youth gender or nativity (U.S.-born vs. foreign-born youth). These findings provide support for cultural resilience perspectives by highlighting the protective role of ethnic identity and familism values among U.S. Latinx adolescents. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Extracellular vesicles from Candida albicans modulate immune cells function and play a protective role in fungal keratitis

Fungal keratitis (FK) is a highly blinding infectious corneal disease caused by pathogenic fungi. Candida albicans (C. albicans) is one of the main pathogens of fungal keratitis. Extracellular vesicles (EVs), lipid bilayer compartments released by almost all living cells, including fungi, have garnered attention for their role in pathogenic microbial infection and host immune responses in recent years. Studies have reported that pretreating the host with fungal EVs can reduce the inflammatory response of the host when attacked by fungi and reduce the lethality of fungal infection. However, there are no studies that have evaluated whether C. albicans EVs can modulate the inflammatory response associated with C. albicans keratitis. Our study revealed that C. albicans EVs could activate the polymorphonuclear cells (PMNs) and promote their secretion of proinflammatory cytokines and nitric oxide (NO), enhance their phagocytic and fungicidal abilities against C. albicans. C. albicans EVs also induced a proinflammatory response in RAW264.7 cells, which is characterized by increased production of inflammatory cytokines and elevated expression of the chemokine CCL2. Similarly, stimulation of C. albicans EVs to RAW264.7 cells also enhanced the phagocytosis and killing ability of cells against C. albicans. Besides, in vivo experiments, after receiving subconjunctival injection of C. albicans EVs, C57BL/6 mice were infected with C. albicans. The results demonstrated that pre-exposure to C. albicans EVs could effectively diminish the severity of keratitis, reduce fungal load and improve prognosis. Overall, we conclude that C. albicans EVs can modulate the function of immune cells and play a protective role in C. albicans keratitis.

Abstract 6682: Bile acid profiles and racial disparities in colorectal cancer: Exploring the protective role of secondary bile acid derivatives

Abstract Background: Colorectal cancer (CRC) is the third leading cause of cancer death in the United States, with diet and gut microbiota-derived bile acids implicated as long-term risk factors. The interplay between bile acids and immune cell differentiation, particularly of macrophages and T-cells, is a crucial aspect of the CRC microenvironment. Given the high-animal-fat diets' influence on the microbiome’s production of hydrophobic secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid (LCA), this study investigates the potential immunomodulatory effects of their lower concentrations and their isomers in possibly fostering M2-like macrophage expansion. Methods: Clinical samples were obtained during colonoscopies with no tumor findings at Rush University Medical Center, Chicago. RNA was extracted from colonoscopy biopsies for NanoString RNA expression analysis, while bile acids were isolated from both lyophilized stool and frozen serum samples. To explore the immunological effects of secondary bile acids, the macrophage RAW 264.7 cell line, alongside peritoneal macrophages and bone marrow-derived macrophages (BMDMs) from C57BL/6J mice, were treated with LCA and LCA isomers. Following the bile acid treatment, LPS (100 ng/mL) or IL-4 (40 ng/ml) was added to elicit pro-inflammatory or anti-inflammatory states, respectively. After 48 hours, conditioned media were collected for enzyme-linked immunosorbent assay (ELISA), while cells were analyzed by flow cytometry and rt-qPCR. Results: Contrary to initial hypotheses, the levels of DCA and LCA levels were not significantly different between African American and non-Hispanic White subjects. Notably, allo-isomers and oxo-derivatives of these bile acids, which may promote Treg and M2-like macrophage expansion, were substantially lower in African American subjects. Ex vivo treatments with isoalloLCA and IsoLCA led to notable changes in the M2 macrophage differentiation and shifts in PGE2 production upon exposure to inflammatory or anti-inflammatory stimuli, suggesting a nuanced alteration in the macrophage-mediated inflammatory response. Conclusion: This study highlights a significant ethnic variation in bile acid profiles, with a potential impact on immune modulation and CRC risk. The reduced presence of certain bile acid isomers in African American subjects may influence the risk of CRC through altered macrophage differentiation and function. These findings emphasize the need for personalized dietary and therapeutic strategies to modulate the bile acid metabolome, potentially reducing CRC disparities. Citation Format: Hanchu Dai, Patricia G. Wolf, Lisa Tussing-Humphreys, Ece Mutlu, Jason M. Ridlon, Rex Gaskins. Bile acid profiles and racial disparities in colorectal cancer: Exploring the protective role of secondary bile acid derivatives [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6682.

Protective role of kallistatin in oxygen-glucose deprivation and reoxygenation in human umbilical vein endothelial cells.

Ischemia-reperfusion (IR) injury is implicated in various clinical diseases. Kallistatin attenuates oxidative stress, and its deficiency has been associated with poor neurological outcomes after cardiac arrest. The present study investigated the antioxidant mechanism through which kallistatin prevents IR injury. Human umbilical vein endothelial cells (HUVECs) were transfected with small interfering RNA (siRNA) targeting the human kallistatin gene (SERPINA4). Following SERPINA4 knockdown, the level of kallistatin expression was measured. To induce IR injury, HUVECs were exposed to 24 h of oxygen-glucose deprivation and reoxygenation (OGD/R). To evaluate the effect of SERPINA4 knockdown on OGD/R, cell viability and the concentration of kallistatin, endothelial nitric oxide synthase (eNOS) and total NO were measured. SERPINA4 siRNA transfection suppressed the expression of kallistatin in HUVECs. Exposure to OGD/R reduced cell viability, and this effect was more pronounced in SERPINA4 knockdown cells compared with controls. SERPINA4 knockdown significantly reduced kallistatin concentration regardless of OGD/R, with a more pronounced effect observed without OGD/R. Furthermore, SERPINA4 knockdown significantly decreased eNOS concentrations induced by OGD/R (P<0.01) but did not significantly affect the change in total NO concentration (P=0.728). The knockdown of SERPINA4 resulted in increased vulnerability of HUVECs to OGD/R and significantly affected the change in eNOS level induced by OGD/R. These findings suggest that the protective effect of kallistatin against IR injury may contribute to its eNOS-promoting effect.

A Conditional Process Analysis of Microaffirmations, Microaggressions, and Mental Health Among Thai Sexual Minorities

ABSTRACT Sexual orientation (SO) microaggressions contribute to mental health issues among sexual minorities. Microaffirmations may mitigate these effects, with internalized heterosexism and SO concealment proposed as mediators. A community sample of 307 Thai sexual minorities completed measures assessing SO microaggressions, microaffirmations, internalized heterosexism, SO concealment, and mental health concerns. Serial mediation analysis using Hayes’ PROCESS macro model 6 tested indirect effects through proposed mediators. Conditional process analysis using PROCESS model 85 examined the moderating role of microaffirmations. These models tested hypothesized moderated serial mediation relationships among study variables. SO microaggressions had a total effect on mental health concerns, directly and indirectly through increased SO concealment. The internalized heterosexism → SO concealment sequence mediated this relationship. Microaffirmations moderated the direct microaggressions-mental health link, reducing this association at higher levels of microaffirmations. The full model accounted for 31.6% of the variance (R2 = 0.316) in mental health concerns. The Johnson-Neyman technique identified 0.613 as the microaffirmations value above which the effect of SO microaggressions on mental health was no longer significant. Findings elucidate mechanisms linking SO microaggressions to mental health issues and microaffirmations’ protective role among Thai sexual minorities. These results could inform efforts to mitigate minority stress impacts.

On the Edge of Psychopathology: Strong Relations Between Reversed Self-compassion and Symptoms of Anxiety and Depression in Young People.

Self-compassion is assumed to have a protective role in the etiology of emotional problems in adolescents. This assumption is primarily based on correlational data revealing negative correlations between the total score on the Self-Compassion Scale (SCS) and symptom measures of anxiety and depression. Recently, however, the SCS has been criticized because this scale not only consists of items measuring compassionate self-responding (i.e., self-kindness, common humanity, and mindfulness), but also includes 'reversed' items measuring uncompassionate self-responding (i.e., self-criticism, isolation, and overidentification), which would undermine the validity of the scale as an index of a protective construct. The present article used two methods to demonstrate that compassionate (positive) and uncompassionate (negative) self-responding have differential effects on emotional problems in youths. In the first part, a meta-analysis based on 16 relevant studies demonstrated a modest protective effect of positive self-compassion on anxiety/depression and a large (and significantly stronger) vulnerability effect of negative self-compassion on such emotional symptoms. In the second part, network analyses were conducted on three previously collected data sets and these analyses again showed that negative self-compassion is more closely connected to young people's symptoms of anxiety and depression than positive self-compassion. It is argued that the observed differential effects should not be discarded as a subversive fallacy, but rather offer an opportunity for studying the role of self-compassion in adolescents' emotional psychopathology in a more sophisticated way, taking into account both protection and vulnerability.

Polyphenols in obesity and weight management: Are they worth further research? An umbrella review.

Polyphenols are widely known for their putative antioxidant and anti-inflammatory effects and their potential protective role in several diseases such as type 2 diabetes, cardiovascular disease and cancer. They have also attracted significant interest as 'anti-obesity' agents, although with mechanisms of action that have been exclusively demonstrated in animal and invitro studies. This umbrella review aims to evaluate current evidence surrounding the role of polyphenols in obesity and weight management and to establish the usefulness of these agents in combatting obesity. A search of systematic reviews and meta-analyses of randomised controlled trials was carried out. Nine systematic reviews (of which eight included a meta-analysis) were included. Evidence of polyphenols' effects on reducing bodyweight is mixed, and where the effects are significant, they are numerically small and unlikely to be of help in reducing bodyweight or preventing weight gain. Future research should focus on establishing the anti-inflammatory and antioxidant effects of polyphenols through well-designed randomised controlled trials. Such research could be more valuable and cost-effective since it has shown potential to improve human health.

Functional roles of CD26/DPP4 in lipopolysaccharide-induced lung injury.

Acute respiratory distress syndrome (ARDS) is characterized by dysregulated inflammation and increased permeability of lung microvascular cells. CD26/Dipeptidyl peptidase-4 (DPP4) is a type II membrane protein that is expressed in several cell types and mediates multiple pleiotropic effects. We previously reported that DPP4 inhibition by sitagliptin attenuates lipopolysaccharide (LPS)-induced lung injury in mice. The current study characterized the functional role of CD26/DPP4 expression in LPS-induced lung injury in mice, isolated alveolar macrophages, and cultured lung endothelial cells. In LPS-induced lung injury, inflammatory responses (bronchoalveolar lavage fluid (BALF) neutrophil numbers and several pro-inflammatory cytokine levels) were attenuated in Dpp4 knockout (Dpp4 KO) mice. However, multiple assays of alveolar capillary permeability were similar between the Dpp4 KO and wild-type mice. TNF-α and IL-6 production was suppressed in alveolar macrophages isolated from Dpp4 KO mice. In contrast, in cultured mouse lung microvascular endothelial cells (MLMVECs), reduction in CD26/DPP4 expression by siRNA resulted in greater ICAM-1 and IL-6 expression after LPS stimulation. Moreover, the LPS-induced vascular monolayer permeability in vitro was higher in MLMVECs treated with Dpp4 siRNA, suggesting that CD26/DPP4 plays a protective role in endothelial barrier function. In summary, this study demonstrated that genetic deficiency of Dpp4 attenuates inflammatory responses but not permeability in LPS-induced lung injury in mice, potentially through differential functional roles of CD26/DPP4 expression in resident cellular components of the lung. CD26/DPP4 may be a potential therapeutic target for ARDS and warrants further exploration to precisely identify the multiple functional effects of CD26/DPP4 in ARDS pathophysiology.

Anterior cruciate ligament injury should not be considered a contraindication for medial unicompartmental knee arthroplasty: Finite element analysis.

The research objective of this study is to use finite element analysis to investigate the impact of anterior cruciate ligament (ACL) injury on medial unicompartmental knee arthroplasty (UKA) and explore whether patients with ACL injuries can undergo UKA. Based on the morphology of the ACL, models of ACL with diameters ranging from 1 to 10mm are created. Finite element models of UKA include ACL absence and ACLs with different diameters. After creating a complete finite element model and validating it, four different types of loads are applied to the knee joint. Statistical analysis is conducted to assess the stress variations in the knee joint structure. A total of 11 finite element models of UKA were established. Regarding the stress on the ACL, as the diameter of the ACL increased, when a vertical load of 750N was applied to the femur, combined with an anterior tibial load of 105N, the stress on the ACL increased from 2.61 MPa to 4.62 MPa, representing a 77.05% increase. Regarding the equivalent stress on the polyethylene gasket, a notable high stress change was observed. The stress on the gasket remained between 12.68 MPa and 14.33 MPa in all models. the stress on the gasket demonstrated a decreasing trend. The equivalent stress in the lateral meniscus and lateral femoral cartilage decreases, reducing from the maximum stress of 4.71 MPa to 2.61 MPa, with a mean value of 3.73 MPa. This represents a reduction of 44.72%, and the statistical significance is (P < 0.05). However, under the other three loads, there was no significant statistical significance (P > 0.05). This study suggests that the integrity of the ACL plays a protective role in performing medial UKA. However, this protective effect is limited when performing medial UKA. When the knee joint only has varying degrees of ACL injury, even ACL rupture, and the remaining structures of the knee joint are intact with anterior-posterior stability in the knee joint, it should not be considered a contraindication for medial UKA.

Deciphering the multi-functional role of Indian propolis for the management of Alzheimer's disease by integrating LC-MS/MS, network pharmacology, molecular docking, and in-vitro studies.

The conventional one-drug-one-disease theory has lost its sheen in multigenic diseases such as Alzheimer's disease (AD). Propolis, a honeybee-derived product has ethnopharmacological evidence of antioxidant, anti-inflammatory, antimicrobial and neuroprotective properties. However, the chemical composition is complex and highly variable geographically. So, to leverage the potential of propolis as an effective treatment modality, it is essential to understand the role of each phytochemical in the AD pathophysiology. Therefore, the present study was aimed at investigating the anti-Alzheimer effect of bioactive in Indian propolis (IP) by combining LC-MS/MS fingerprinting, with network-based analysis and experimental validation. First, phytoconstituents in IP extract were identified using an in-house LC-MS/MS method. The drug likeness and toxicity were assessed, followed by identification of AD targets. The constituent-target-gene network was then constructed along with protein-protein interactions, gene pathway, ontology, and enrichment analysis. LC-MS/MS analysis identified 16 known metabolites with druggable properties except for luteolin-5-methyl ether. The network pharmacology-based analysis revealed that the hit propolis constituents were majorly flavonoids, whereas the main AD-associated targets were MAOB, ESR1, BACE1, AChE, CDK5, GSK3β, and PTGS2. A total of 18 gene pathways were identified to be associated, with the pathways related to AD among the topmost enriched. Molecular docking analysis against top AD targets resulted in suitable binding interactions at the active site of target proteins. Further, the protective role of IP in AD was confirmed with cell-line studies on PC-12, in situ AChE inhibition, and antioxidant assays.

Roles of Plasminogen Activator Inhibitor-1 in Heterotopic Ossification Induced by Achilles Tenotomy in Thermal Injured Mice.

Heterotopic ossification (HO) is the process by which ectopic bone forms at an extraskeletal site. Inflammatory conditions induce plasminogen activator inhibitor 1 (PAI-1), an inhibitor of fibrinolysis, which regulates osteogenesis. In the present study, we investigated the roles of PAI-1 in the pathophysiology of HO induced by trauma/burn treatment using PAI-1-deficient mice. PAI-1 deficiency significantly promoted HO and increased the number of alkaline phosphatase (ALP)-positive cells in Achilles tendons after trauma/burn treatment. The mRNA levels of inflammation markers were elevated in Achilles tendons of both wild-type and PAI-1-deficient mice after trauma/burn treatment and PAI-1 mRNA levels were elevated in Achilles tendons of wild-type mice. PAI-1 deficiency significantly up-regulated the expression of Runx2, Osterix, and type 1 collagen in Achilles tendons 9weeks after trauma/burn treatment in mice. In in vitro experiments, PAI-1 deficiency significantly increased ALP activity and mineralization in mouse osteoblasts. Moreover, PAI-1 deficiency significantly increased ALP activity and up-regulated osteocalcin expression during osteoblastic differentiation from mouse adipose-tissue-derived stem cells, but suppressed the chondrogenic differentiation of these cells. In conclusion, the present study showed that PAI-1 deficiency promoted HO in Achilles tendons after trauma/burn treatment partly by enhancing osteoblast differentiation and ALP activity in mice. Endogenous PAI-1 may play protective roles against HO after injury and inflammation.

Protective role of forsythoside B in Kawasaki disease-induced cardiac injury: Inhibition of pyroptosis via the SIRT1–NF-κB–p65 signaling pathway

Kawasaki disease (KD), an acute exanthematous febrile pediatric illness involving systemic non-specific inflammatory reactions in small- and medium-sized arteries, poses a significant risk of coronary artery and myocardial inflammatory injury. Developing new KD treatments with improved safety and fewer side-effects is highly desirable. Forsythoside B (FTS-B), extracted from the Forsythia suspensa plant, exerts anti-inflammatory activity by inhibiting NF-κB, which is regulated by SIRT1, the reduced expression of which is strongly associated with cardiovascular disease. However, it has yet to be established whether FTS-B influences KD-related inflammatory damage. In this study, we investigated the effects of FTS-B on inflammation in cellular and murine models of KD. Our findings revealed that KD is associated with cardiac dysfunction and inflammatory injury to myocardial and human coronary artery endothelial cells (HCAECs), resulting in a pyroptosis-feedback loop. Both cellular and KD models were characterized by reduced SIRT1 expression and increased NF-κB p65 expression. Contrastingly, the rates of pyroptosis in both murine model myocardial tissues and HCAECs were significantly alleviated in response to FTS-B treatment. Also in both models, we detected an increase of SIRT1 expression and a decrease in the expression of p65. Further examination of the protective mechanism of FTS-B using the SIRT1-specific inhibitor, EX 527, revealed that this inhibitor blocked the palliative effects of FTS-B on inflammatory injury-induced pyroptosis. These results highlight the potential utility of the SIRT1–NF-κB–p65 pathway as a therapeutic target for KD treatment and demonstrate that FTS-B can alleviate KD-induced cardiac and HCAEC inflammatory injury via inhibition of pyroptosis.

Quercetin improves diabetic kidney disease by inhibiting ferroptosis and regulating the Nrf2 in streptozotocin-induced diabetic rats

Diabetic kidney disease (DKD) is a leading factor in end-stage renal disease. The complexity of its pathogenesis, combined with the limited treatment efficacy, necessitates deeper insights into potential causes. Studies suggest that ferroptosis-driven renal tubular damage contributes to DKD's progression, making its counteraction a potential therapeutic strategy. Quercetin, a flavonoid found in numerous fruits and vegetables, has demonstrated DKD mitigation in mouse models, though its protective mechanism remains ambiguous. In this study, we delved into quercetin’s potential anti-ferroptotic properties, employing a DKD rat model and high glucose (HG)-treated renal tubular epithelial cell models. Our findings revealed that HG prompted unusual ferroptosis activation in renal tubular epithelial cells. However, quercetin counteracted this by inhibiting ferroptosis and activating NFE2-related factor 2 (Nrf2) expression in both DKD rats and HG-treated HK-2 cells, indicating its renal protective role. Further experiments, both in vivo and in vitro, validated that quercetin stimulates Nrf2. Thus, our research underscores quercetin’s potential in DKD treatment by modulating the ferroptosis process via activating Nrf2 in a distinct DKD rat model, offering a fresh perspective on quercetin’s protective mechanisms.

Perceived Community Belonging as a Moderator: Effects of Childhood Abuse on Health and Well-Being Among Middle-Aged and Older Canadians

ABSTRACT This study examined the moderating role of perceived community belonging in the relationship between childhood abuse and health and well-being outcomes among Canadian individuals aged 55 and older. Using data from the 2014 Canadian General Social Survey (n = 14,416), multiple linear regression models revealed that women who experienced either childhood physical or sexual abuse reported poorer self-rated general and mental health, as well as lower life satisfaction, compared to those without such histories. The most pronounced effects were observed among women who experienced both types of abuse. For men, a similar pattern was evident only for those who experienced childhood physical abuse. Notably, among women, a strong sense of community belonging lessened the negative effects of both types of childhood abuse on all examined outcomes. These findings underscore the protective role of perceived community belonging against the consequences of childhood abuse for older women. They illuminate the crucial role of gerontological social workers and scholars in promoting community integration and support. Focusing on these areas, especially for those with traumatic histories, can potentially improve their overall health and well-being.