[This corrects the article DOI: 10.3389/fgene.2022.931785.].

BACKGROUND:Sepsis, a dysregulated host response to infection, frequently leads to catastrophic intestinal barrier failure, a key driver of mortality. Magnolol, a bioactive compound from Magnolia officinalis, has shown pleiotropic therapeutic effects, but its role in sepsis-induced intestinal injury remains unclear. Here, we investigate the protective mechanisms of magnolol in sepsis, focusing on its modulation of inflammatory signaling. METHODS:We employed both in vitro (LPS-stimulated Caco-2 cells) and in vivo (cecal ligation and puncture model of sepsis) systems. The effects of magnolol on cellular viability, apoptosis, inflammatory cytokine production, and intestinal barrier integrity were assessed using a combination of molecular and histological techniques, including Western blot, immunofluorescence, ChIP, and Co-IP assays. RESULTS:Magnolol potently mitigated LPS- and sepsis-induced cellular damage, apoptosis, and inflammation, while preserving intestinal barrier function. Mechanistically, we identify magnolol as a direct transcriptional activator of peroxisome proliferator-activated receptor gamma (PPARG). Magnolol treatment robustly reversed the LPS-mediated suppression of PPARG transcriptional activity (P < 0.001). This activation was crucial for its protective effects, as CRISPR-Cas9-mediated knockdown of PPARG abrogated magnolol's benefits. Furthermore, magnolol restored the physical interaction between PPARG and its co-activator p300/CBP, which was disrupted by LPS. Crucially, activation of PPARG by magnolol led to the dual inhibition of the pro-inflammatory JAK-STAT and NF-κB signaling pathways. CONCLUSION:Our study delineates a novel protective mechanism for magnolol in sepsis, demonstrating that it functions as a potent PPARG agonist to suppress the inflammatory cascade driven by the JAK-STAT and NF-κB pathways. These findings establish magnolol as a promising, mechanistically defined therapeutic candidate for treating sepsis-induced intestinal injury.

BACKGROUND:Neuregulin 4 (Nrg4), a secretory peptide predominantly derived from brown adipose tissue (BAT), has been verified to play roles in multiple metabolic disorders. Nevertheless, the role of Nrg4 in the pathogenesis of PCOS remains largely unelucidated. METHODS:Female C57BL/6 J mice were randomly divided into NC, PCOS, AAV-Luc, and AAV-Nrg4 group. Mice in the AAV-Luc group received AAV-Luc injection, while those in the AAV-Nrg4 group received AAV-Nrg4 injection into the BAT in the scapular region. One week after virus injection, the PCOS model was established. The weight, intraperitoneal glucose tolerance test and serum sex hormone were detected at the eighth week after virus injection. Then, the mice were sacrificed. The expression of Nrg4 in BAT was detected. The histological morphology of the ovaries and and WAT were observed. The expression of steroid synthasesin the ovaries, inflammatory factors and adiponectin in WAT were detected. Further, the expression of macrophage polarization markers in WAT were measured. Finally, the ErbB4/PI3K/AKT signaling pathway related proteins were detected. RESULTS:In PCOS mice, overexpression of Nrg4 in BAT led to reduction of body weight, improvement of glucose tolerance, restoration of the estrous cycle, and decrease in serum testosterone estrogen and luteinizing hormone levels. This treatment also reduced the levels of pro-inflammatory factors. Additionally, Nrg4 overexpression suppressed the expression of CYP17A1 and StAR in ovarian tissue and enhanced the expression of CYP19A1. Finally, the ErbB4/PI3K/AKT signaling pathway was intensely activated in WAT. CONCLUSION:Nrg4 can improve WAT inflammation and ovarian steroidogenesis and follicular development in PCOS mice.

Aims: The present work aimed to examine impact of tanshinone IIA on intestinal barrier in sepsis and to explore the underpinning mechanisms. Materials and Methods: Sepsis induction in Sprague-Dawley (SD) rats was conducted via cecal ligation and puncture (CLP), with subsequent intraperitoneal injection of tanshinone IIA. Intestinal permeability was examined 12 h post-operation using the fluorescein isothiocyanate dextran method. Blood and distal ileum tissue samples were collected for Enzyme-Linked Immunosorbent Assay (ELISA) analysis of oxidative stress and inflammatory markers. Histopathologic examination was performed using hematoxylin and eosin staining and the Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) assay. Immunofluorescence and immunoblot were performed for protein detection. In vitro, Caco-2 cells were administered lipopolysaccharide (LPS) followed by tanshinone IIA treatment, and pregnane X receptor (PXR) and cytochrome P450-3A4 (CYP3A4) protein levels were assessed. Results: In sepsis model rats, tanshinone IIA dose-dependently reversed the increased intestinal permeability, bacterial shift rate, ileum Chiu's score, apoptosis level of ileal mucosa, the elevated serum and ileal Malondialdehyde (MDA), Interleukin-1 beta (IL-1β), and Tumor Necrosis Factor-alpha (TNF-α) amounts, and the enhanced ileal expression levels of Proto-oncogene c-Fos (c-Fos) and tryptase proteins. In addition, tanshinone IIA restored the decreased serum and ileal Superoxide Dismutase (SOD) levels and reversed the reduced ileal expression levels of claudin-1, Junctional Adhesion Molecule (JAM), occludin, and ZO-1. In vitro, tanshinone IIA restored PXR and CYP3A4 levels following LPS stimulation. Conclusion: Tanshinone IIA exerts a protective effect in murine CLP-induced sepsis. The underlying mechanism may involve activation of the PXR-CYP3A4 pathway in murine intestinal epithelial cells.

ETHNOPHARMACOLOGICAL RELEVANCE:Enhanced apoptosis of intestinal epithelial cells during sepsis results in impaired barrier function, facilitating the influx of bacteria and endotoxins into the bloodstream, which worsens the organism's damage. Therefore, addressing intestinal injury in sepsis may represent a novel approach to treatment. Shenling Baizhu Powder (SLBZP), a classical traditional Chinese medicine formula, has been widely used for the treatment of Inflammatory diseases including sepsis. However, its potential mechanisms of action in sepsis-induced intestinal injury remain unclear. AIM OF THE STUDY:This study aimed to investigate whether SLBZP and its betulin ameliorate intestinal barrier function and cellular death in sepsis mice and LPS-induced IEC-6 cells through GADD45B/TAOK1/p38 MAPK pathway. MATERIALS AND METHODS:Network pharmacology and Gene Expression Omnibus (GEO) database were used to identify the potential active ingredients and epigenetic regulators of SLBZP. High-performance liquid chromatography coupled with mass spectrometry (HPLC/MS) was used to measure the betulin present in SLBZP. Besides, the animal model of sepsis was developed by using a cecal ligation and puncture (CLP) to investigate the protective roles of SLBZP and betulin on intestinal injury in sepsis. Furthermore, the determination of cell viability, inflammation, and apoptosis of LPS-induced IEC-6 cells treated by betulin was performed by Cell counting Kit-8 (CCK-8), ELISA, Tunel staining, and flow cytometry assays. Meanwhile, the underlying mechanism was investigated through IHC, qMSP, and Western blot assays, respectively. RESULTS:Through network and GSE202261 analysis, three epigenetic regulators including GADD45B, MAP3K7, and PRKAA1 were screened from the "drug-component-target" network. The betulin and the GADD45B had a good binding ability in molecular docking. Animal experiments indicated that SLBZP and betulin could inhibit inflammation, ameliorate intestinal injury, and reduce cell apoptosis in mice. Moreover, the intestinal cytotoxicity of LPS-treated IEC-6 cells was significantly inhibited after betulin treatment, as accompanied by an increase in DNA methylation level in the TAOK1 promoter. Importantly, we found that the overexpression of GADD45B and TAOK1, or p38 MAPK inhibitor reversed the anti-apoptosis effect induced by the betulin. CONCLUSIONS:SLBZP and betulin may exert anti-inflammatory and anti-apoptosis effects against sepsis-associated intestinal barrier injury, possibly via the GADD45B/TAOK1/p38 MAPK pathway.

BackgroundsAspirin has been shown to enhance endometrial receptivity (ER) during the window of implantation in patients with polycystic ovary syndrome (PCOS). However, the underlying mechanisms remain unclear. This study aimed to elucidate the mechanisms by which aspirin improves ER through metabolic analysis of uterine lavage fluid.MethodsA PCOS rat model was established using letrozole. Body weight and estrous cycles were monitored, and the number of implanted embryos was assessed across groups. We evaluated endometrial ultrastructure, ovarian and endometrial histomorphometry. Serum levels of estradiol(E2) and progesterone(P)were measured. Moreover, through ultra-performance liquid chromatography-mass spectrometry, the study of uterine lavage fluid metabolites revealed the potential mechanism of action of aspirin.ResultsCompared with the model group, aspirin treatment significantly increased embryo implantation rates, improved endometrial morphology and hormone levels. Metabolomic analysis identified 48 differential metabolites, among which five-2, 6-dihydroxypurine, gluconolactone, Oxaceprol, PC (18:1/18:1), and PC (20:3e/17:1)-were identified as potential biomarkers for aspirin-mediated improvement of ER in PCOS rats. Pathway analysis revealed that aspirin primarily modulates the pentose phosphate pathway, arginine and proline metabolism, and glycerophospholipid metabolism.ConclusionsAspirin may enhance glucose metabolism, alleviate insulin resistance, promote angiogenesis, and improve vascular permeability and endometrial receptivity. These effects are likely mediated through the regulation of biomarkers involved in the pentose phosphate pathway, arginine and proline metabolism, and glycerophospholipid pathways in uterine lavage fluid.

Core/shell structured nanoparticles (NPs) are a novel category of functional materials that have garnered widespread attention due to their advantageous preparation methods, unique characteristics, and multifunctional application prospects, which have shown significant performance in materials chemistry and many other fields, such as electronics, biomedical, pharmaceutical, optics, and catalysis. Although some reviews about core/shell NPs have been published, there is still an intense requirement for an extensive review about the updated literature and new reported core/shell nanomaterials. Colloidal quantum dots (QDs) and noble metal NPs have a very small size, which results in the large surface-to-volume ratio and under-coordinated chemical bonds. As a result, the effort on the design of core–shell structure has been essential for colloidal QDs and noble metal NPs. In this review, the core–shell structures dominated by traditional QDs and CsPbX3 perovskite QDs, as well as noble metal nanocrystals (NCs) were summarized. The applications of the above core–shell structure NCs in medical or biological fields such as sensing, biological imaging, medical diagnostics and therapeutics, immunological diagnosis were discussed. The main objective of this review is to provide a better basis for the synthesis, properties, and biomedical applications of QDs or noble metal core/shell NPs, which is beneficial for the further development of QDs, noble metal NPs, and other NPs.

Objectives: To investigate whether the protective actions of ginsenoside Rb1 (Rb1) on astrocytes are mediated through the Gs-type G-protein-coupled receptor (GPCR-Gs). Methods: Primary astrocyte cultures derived from neonatal mouse brain were used. Astrocyte injury was induced via oxygen-glucose deprivation/re-oxygenation (OGD/R). Cell morphology, viability, lactate dehydrogenase (LDH) leakage, apoptosis, glutamate uptake, and brain-derived neurotrophic factor (BDNF) secretion were assessed to gauge cell survival and functionality. Western blot was used to investigate the cyclic adenosine monophosphate (cAMP) and protein kinase B (Akt) signaling pathways. GPCR-Gs-specific inhibitors and molecular docking were used to identify target receptors. Results: Rb1 at concentrations ranging from 0.8 to 5 μM did not significantly affect the viability, glutamate uptake, or BDNF secretion in normal astrocytes. OGD/R reduced astrocyte viability, increasing their LDH leakage and apoptosis rate. It also decreased glutamate uptake and BDNF secretion by these cells. Rb1 had protective effects of astrocytes challenged by OGD/R, by improving viability, reducing apoptosis, and enhancing glutamate uptake and BDNF secretion. Additionally, Rb1 activated the cAMP and Akt pathways in these cells. When the GPCR-Gs inhibitor NF449 was introduced, the protective effects of Rb1 completely disappeared, and its activation of cAMP and Akt signaling pathways was significantly inhibited. Conclusion: Rb1 protects against astrocytes from OGD/R-induced injury through GPCR-Gs mediation.

Irritable bowel syndrome (IBS) is a persistent functional gastrointestinal disorder characterised by abdominal pain and altered patterns of defecation. This study aims to clarify an increase in the expression and interaction of protein disulfide-isomerase A3 (PDIA3) and Signal Transducer and Activator of Transcription 3 (STAT3) within the membrane of dendritic cells (DCs) from individuals with IBS. Mechanistically, the heightened interaction between PDIA3 and STAT3 at the DC membrane results in reduced translocation of phosphorylated STAT3 (p-STAT3) into the nucleus. The reduction of p-stat3 to nuclear transport subsequently increased the levels of cathepsin S (CTSS) and major histocompatibility complex class II (MHC-II). Consequently, activated DCs promote CD4+ T cell proliferation and cytokine secretion, including interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-9 (IL-9), and tumour necrosis factor-alpha (TNF-α), thereby contributing to the development of IBS. Importantly, the downregulation of PDIA3 and the administration of punicalagin (Pun), a crucial active compound found in pomegranate peel, alleviate IBS symptoms in rats, such as increased visceral hypersensitivity and abnormal stool characteristics. Collectively, these findings highlight the involvement of the PDIA3-STAT3 protein complex in IBS, providing a novel perspective on the modulation of immune and inflammatory responses. Additionally, this research advances our understanding of the role and mechanisms of PDIA3 inhibitors, presenting new therapeutic possibilities for managing IBS.

The aim of this study was to investigate NAD+/NADH redox regulation in astrocytes by Ginsenoside Rb1 subjected to oxygen–glucose deprivation/reoxygenation (OGD/R) and to reveal the neuroprotective mechanism of ginseng. Neonatal mouse brain was used to culture primary astrocytes. The third generation of the primary astrocytes was used for the experiments. OGD/R was introduced by culturing the cells in a glucose-free media under nitrogen for 6 h followed by a regular culture for 24 h. Ginsenoside Rb1 attenuated OGD/R-induced astrocyte injury in a dose-dependent manner. It improved the mitochondrial function of OGD/R astrocytes indicated by improving mitochondrial distribution, increasing mitochondrial membrane potential, and enhancing mitochondrial DNA copies and ATP production. Ginsenoside Rb1 significantly lifted intracellular NAD+/NADH, NADPH/NADP+, and GSH/GSSG in OGD/R astrocytes. It inhibited the protein expression of both PARP1 and CD38, while attenuating the SIRT1 drop in OGD/R cells. In line with its effects on PARP1, Ginsenoside Rb1 significantly reduced the expression of poly-ADP-ribosylation (PARylation) proteins in OGD/R cells. Ginsenoside Rb1 also significantly increased the expression of NAMPT and NMNAT2, both of which are key players in NAD/NADH synthesis. The results suggest that the regulation of NAD+/NADH redox involves the protective effects of ginsenoside Rb1 against OGD/R-induced astrocyte injury.

To examine the effects of clomiphene citrate (CC) on follicular fluid metabolites and related metabolic pathways in rats with polycystic ovary syndrome (PCOS) using non-targeted metabolomics and determine how CC treats ovulation disorder in PCOS. The Sprague Dawley rats were randomly divided into control, model, and CC groups. A PCOS model was established with letrozole. Body weight, ovarian weight, estrus cycles, serum hormone levels, and ovary histopathology of the rats were collected for further evaluation. Moreover, through ultra-performance liquid chromatography-mass spectrometry, the study of follicular fluid metabolites revealed the mechanism of action of CC. CC reduced ovarian weight and regulated estrous cycles and serum hormone levels in PCOS rats but did not affect their body weight. Moreover, the metabolomic results showed that CC adjusted 153 metabolites, among which 16 cross metabolites like testosterone, androstenedione, 17α-hydroxyprogesterone, and cholic acid were considered as potential biomarkers for CC to improve ovulation disorders in PCOS rats. Kyoto Encyclopedia of Genes and Genomes pathway enrichment also showed that the CC group mainly engaged in tryptophan metabolism and steroid hormone biosynthesis. CC can improve ovulation disorders in rats, and its mechanism is related to the regulation of the secretion of serum hormone and follicular fluid metabolites and the amelioration of multi-metabolic pathways.

OBJECTIVES:The nuclear factor-κB (NF-κB) signaling pathway plays an important role in regulating tubular epithelial-mesenchymal transition (EMT), an indispensable cellular programme for driving organ fibrosis and tumor progression. Liuwei Dihuang Decoction (LWD) is an effective Chinese formula for treating chronic renal failure.METHODS:First, by using morphological examination, immunofluorescence staining assay, RTqPCR, and Western blot analysis, in vitro experiments were designed to analyze NF-κB and EMT markers (including Snail, α-SMA, and E-cadherin) in transforming growth factor-β1 (TGF-β1) induced renal tubular epithelial cells (HK-2) and to detect the expression levels of LWD-CS cotreatment. Then, the recombinant lentiviral vector was overexpressed and knocked down by NF- κB and transfected into HK-2 cells. Cells were treated with TGF-β1 (10 ng/ml) with blank serum or LWD-containing serum, respectively, and the expression of these molecules in the NF-κB/Snail signaling pathway was further evaluated.RESULTS:Our results confirmed that TGF-β1 could induce EMT, nuclear translocation of NF-κB p65, and activate the NF-κB/Snail signaling pathway in HK-2 cells. Furthermore, NF-κB knocked-down dramatically increases the TGF-β1-induced mRNA and protein expression level of E-cadherin and reduces the level of Snail and α-SMA; this is reversed by NF-κB overexpression. LWD can decrease the EMT levels through the NF-κB/Snail signaling activation in TGF-β1-induced EMT of HK-2 cells.CONCLUSION:The present study provides evidence suggesting a novel mechanism that LWD exerts anti-fibrosis effects through inhibiting activation of the NF-κB/Snail signaling pathway and consequently downregulating the TGF-β1-induced EMT in renal tubular epithelial cells.

Observation studies have postulated that atopic eczema is associated with a risk of inflammatory bowel disease in the East Asian population; however, this association does not obviate the biases resulting from confounding effects and reverse causation. This study aimed to determine whether this association is causal in the East Asian population using a bidirectional two-sample Mendelian randomization design. Independent genetic variants obtained from public genome-wide association studies for atopic eczema (4296 cases, 163 807 controls) were extracted to estimate the causal effects on inflammatory bowel disease (2824 cases, 3719 controls) and its two main conditions: Crohn's disease (1690 cases, 3719 controls) and ulcerative colitis (1134 cases, 3719 controls). Atopic eczema was found to be strongly associated with inflammatory bowel disease (odds ratio [95% confidence interval]: 1.520 [1.179, 1.959]; p = 0.001), but not vice versa. Subtype analyses revealed that atopic eczema is significantly associated with Crohn's disease (1.650 [1.293, 2.106]; p = 0.000) but not with ulcerative colitis. Both Crohn's disease and ulcerative colitis were found to be causally related to atopic eczema; Crohn's disease could reduce the risk of atopic eczema (0.866 [0.807, 0.930]; p = 0.000) while ulcerative colitis could increase the risk of atopic eczema (1.112 [1.021, 1.212]; p = 0.015). In conclusion, this study revealed that statistically causal relationships are present between atopic eczema and inflammatory bowel disease in the East Asian population. These findings are significant for guiding the treatment of atopic eczema and inflammatory bowel disease in clinical practice.

Abstract Background Spinal cord injury (SCI) is a life-threatening traumatic disorder. Paeonol has been confirmed to be involved in a variety of diseases. The purpose of this study is to investigate the role of paeonol on SCI progression. Methods Sprague Dawley (SD) rat was used for the establishment of SCI model to explore the anti-inflammation, anti-oxidation, and neuroprotective effects of paeonol (60 mg/kg) on SCI in vivo. For in vitro study, mouse primary microglial cells (BV-2) were induced by lipopolysaccharide (LPS)/adenosine triphosphate (ATP) treatment. The effect of paeonol on the polarization of LPS/ATP-induced BV-2 cells was determined by detection the expression inducible nitric oxide synthase (iNOS), tumour necrosis factor alpha (TNF-α), arginase-1 (Arg-1), and interleukin (IL)-10 using qRT-PCR. ELISA was used to assess the levels of IL-1β, IL-18, TNF-α, malondialdehyde (MDA), and glutathione (GSH). Western blotting was conducted to determine the levels of NLRP3 inflammasomes and TLR4/MyD88/NF-κB (p65) pathway proteins. Results Paeonol promoted the recovery of locomotion function and spinal cord structure, and decreased spinal cord water content in rats following SCI. Meanwhile, paeonol reduced the levels of apoptosis-associated speck-like protein (ASC), NLRP3, active caspase 1 and N-gasdermin D (N-GSDMD), repressed the contents of IL-1β, IL-18, TNF-α and MDA, and elevated GSH level. In vitro, paeonol exerted similarly inhibiting effects on pyroptosis and inflammation. Meanwhile, paeonol promoted BV-2 cells M2 polarization. In addition, paeonol also inactivated the expression of TLR4/MyD88/NF-κB (p65) pathway. Conclusion Paeonol may regulate NLRP3 inflammasomes and pyroptosis to alleviate SCI, pointing out the potential for treating SCI in clinic.

Abstract Background Accumulating evidence from observational studies has shown that circulating C-reactive protein (CRP) levels are correlated with Type 1 diabetes (T1D) appearing a potential predictive marker of intervention, yet are of unknown causality. To clarify, we introduce a bidirectional two-sample Mendelian randomization (MR) framework to investigate the causality between circulating CRP levels and T1D. Methods Based on aggregated statistics from large-scale genome-wide association studies (GWAS), we evaluated the pooled impact of CRP on the risk of developing T1D. We obtained 6 single nucleotide polymorphisms (SNPs) for CRP selected as instrumental variables from a recent GWAS (n = 204,402). The T1D related SNPs were from a large-scale T1D GWAS (n = 6,808 T1D cases; n = 12,173 controls). Subsequent inverse-variance weighted (IVW) method, simple median method, weighted median method were conducted to acquire the genetic correlation between CRP levels and T1D. In sensitivity analyses, MR-Egger, MR-PRESSO, and leave-one-out analysis were applied to exclude the potentially pleiotropic variants in this study. Results The results of IVW provided no causal evidence that genetically predicted circulating CRP levels on the risk of T1D, with OR of 0.922 (95% CI: 0.662–1.285, P = 0.631). Furthermore, we denoted 14 T1D-related SNPs as an instrumental variable in MR analyses and yielded no significant associations of T1D on CRP levels according to the IVW result (OR: 1.000, 95% CI: 0.990–1.010, P = 0.930). MR-Egger, MR-PRESSO, and leave-one-out analysis indicated no indication for potential directional pleiotropy effects. Conclusion Our findings failed to provide evidence to support the causal relationship between CRP levels and T1D.

Background: This study investigated the therapeutic targets of aortic aneurysm (AA) and provided insights into the pathogenesis and molecular mechanisms of AA. Methods: The messenger RNA (mRNA) datasets, GSE9106 (blood samples) and GSE7084 (tissue samples), and the microRNA (miRNA) datasets, GSE92427 (blood samples) and GSE110527 (tissue samples), were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) and differentially expressed miRNAs (DE-miRNAs) were analyzed by limma. Based on the co-DEGs and co-DE-miRNAs between the AA blood and tissue datasets, the miRNA-mRNA regulatory pairs were predicted. Functional enrichment analyses and gene set enrichment analysis (GSEA) were performed and the protein-protein interaction (PPI) network was generated to further analyze the related genes and their functions. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and tyramide signal amplification (TSA)-in situ hybridization (ISH) assays were performed to detect the expression of co-DE-miRNAs in AA clinical tissue samples and normal aorta samples. Results: There were 19 upregulated and 5 downregulated co-differential mRNAs. MiR-4306 was the upregulated co-differential miRNA, and miR-3198 was the downregulated co-differential miRNA by blood-tissue co-analysis. Based on the co-DEGs and co-DE-miRNAs, 4 miRNA-mRNA regulatory pairs were predicted. PPI networks were constructed of co-DEGs with 6 relationship pairs. RT-qPCR and TSA-ISH assays showed the upregulation of miR-4306 and the downregulation of miR-3198 in AA tissue samples. Conclusions: This study provided evidence regarding the differential regulatory miRNA-mRNA networks in AA blood and tissue samples and identified key genes and signaling pathways related to AA, which provided insights into potential targets and mechanisms of AA pathogenesis and progression.

Background: Telomere shortening is a hallmark of cellular senescence. However, telomere length (TL)-related cellular senescence has varying effects in different cancers, resulting in a paradoxical relationship between senescence and cancer. Therefore, we used observational epidemiological studies to investigate the association between TL and skin cancer and aging, and to explore whether such a paradoxical relationship exists in skin tissue.Methods: This study employed two-sample Mendelian randomization (MR) to analyze the causal relationship between TL and skin cancer [melanoma and non-melanoma skin cancers (NMSCs)] and aging. We studied single nucleotide polymorphisms (SNPs) obtained from pooled data belonging to genome-wide association studies (GWAS) in the literature and biobanks. Quality control was performed using pleiotropy, heterogeneity, and sensitivity analyses.Results: We used five algorithms to analyze the causal relationship between TL and skin aging, melanoma, and NMSCs, and obtained consistent results. TL shortening reduced NMSC and melanoma susceptibility risk with specific odds ratios (ORs) of 1.0344 [95% confidence interval (CI): 1.0168–1.0524, p = 0.01] and 1.0127 (95% CI: 1.0046–1.0209, p = 6.36E-07), respectively. Conversely, TL shortening was validated to increase the odds of skin aging (OR = 0.96, 95% CI: 0.9332–0.9956, p = 0.03). Moreover, the MR-Egger, maximum likelihood, and inverse variance weighted (IVW) methods found significant heterogeneity among instrumental variable (IV) estimates (identified as MR-Egger skin aging Q = 76.72, p = 1.36E-04; melanoma Q = 97.10, p = 1.62E-07; NMSCsQ = 82.02, p = 1.90E-05). The leave-one-out analysis also showed that the SNP sensitivity was robust to each result.Conclusion: This study found that TL shortening may promote skin aging development and reduce the risk of cutaneous melanoma and NMSCs. The results provide a reference for future research on the causal relationship between skin aging and cancer in clinical practice.

Objective: To evaluate whether ginsenoside Rb1 (Rb1) can attenuate lipopolysaccharide (LPS)-induced chronic neuroinflammation in mice and to explore its relationship with glial cell polarization. Methods: Intraperitoneal injection with an escalating dose of LPS was used to establish a chronic neuroinflammation model in mice. Once LPS was initiated, 10 or 20 mg/kg Rb1, or sterile saline, was administered for 14 consecutive days. Open field test and beam walking test were used to monitor the changes in behavior. The concentration of cytokines in the serum and brain were used to monitor the systemic inflammation and neuroinflammation, respectively. Molecules specific to each glial cell phenotype were used to investigate glial cell polarization. Results: Mice in the LPS group had reduced spontaneous activities and impaired beam walking performance. Rb1 obviously eased LPS-induced behavior disturbances. Regarding the levels of serum cytokines, both tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were significantly increased, while interleukin-10 (IL-10) and transforming growth factor β (TGF-β) remarkably decreased after LPS treatment (all P < .001). Rb1 treatment significantly attenuated LPS-induced serum cytokine changes (all P < .05). The results of quantitative polymerase chain reaction and western blotting showed that the mRNA and protein expression levels of TNF-α and complement component 3 (C3) in the brain were significantly increased after LPS treatment (all P < .01). Rb1 treatment significantly inhibited LPS-induced inflammation in the brain (all P < .05). Glial cell polarization analysis showed that M1 and M2 microglia, and A1 astrocytes increased following LPS treatment, while A2 astrocytes decreased. Rb1 treatment reduced M1 and M2 microglia, and A1 astrocytes, and significantly increased A2 astrocytes. Conclusion: Rb1 can attenuate chronic neuroinflammation induced by LPS in mice, which may be partially attributable to its fine tuning of microglia and astrocyte polarization. Rb1 has potential value for treating neurodegenerative diseases.

BACKGROUND:Sepsis is a major medical challenge. Magnolol is an active constituent of Houpu that improves tissue function and exerts strong anti-endotoxin and anti-inflammatory effects, but the mechanism by which it reduces intestinal inflammation in sepsis is yet unclear.AIM:To assess the protective effect of magnolol on intestinal mucosal epithelial cells in sepsis and elucidate the underlying mechanisms.METHODS:Enzyme-linked immunosorbent assay was used to measure tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and regulated on activation, normal T-cell expressed and secreted (RANTES) levels in serum and ileal tissue in animal studies. The histopathological changes of the ileal mucosa in different groups were observed under a microscope. Cell Counting Kit-8 and cell permeability assays were used to determine the concentration of drug-containing serum that did not affect the activity of Caco2 cells but inhibited lipopolysaccharide (LPS)-induced decrease in permeability. Immunofluorescence and Western blot assays were used to detect the levels of RANTES, inhibitor of nuclear factor kappa-B kinase β (IKKβ), phosphorylated IKKβ (p-IKKβ), inhibitor of nuclear factor kappa-B kinase α (IκBα), p65, and p-p65 proteins in different groups in vitro.RESULTS:In rats treated with LPS by intravenous tail injection in the presence or absence of magnolol, magnolol inhibited the expression of proinflammatory cytokines, IL-1β, IL-6, and TNF-α in a dose-dependent manner. In addition, magnolol suppressed the production of RANTES in LPS-stimulated sepsis rats. Moreover, in vitro studies suggested that magnolol inhibited the increase of p65 nucleation, thereby markedly downregulating the production of the phosphorylated form of IKKβ in LPS-treated Caco2 cells. Specifically, magnolol inhibited the translocation of the transcription factor nuclear factor-kappa B (NF-κB) from the cytosol into the nucleus and down-regulated the expression level of the chemokine RANTES in LPS-stimulated Caco2 cells.CONCLUSION:Magnolol down-regulates RANTES levels by inhibiting the LPS/NF-κB signaling pathways, thereby suppressing IL-1β, IL-6, and TNF-α expression to alleviate the mucosal barrier dysfunction in sepsis.