Activation of human STING by a molecular glue-like compound.

Stimulator of interferon genes (STING) is a dimeric transmembrane adapter protein that plays a key role in the human innate immune response to infection and has been therapeutically exploited for its antitumor activity. The activation of STING requires its high-order oligomerization, which could be induced by binding of the endogenous ligand, cGAMP, to the cytosolic ligand-binding domain. Here we report the discovery through functional screens of a class of compounds, named NVS-STGs, that activate human STING. Our cryo-EM structures show that NVS-STG2 induces the high-order oligomerization of human STING by binding to a pocket between the transmembrane domains of the neighboring STING dimers, effectively acting as a molecular glue. Our functional assays showed that NVS-STG2 could elicit potent STING-mediated immune responses in cells and antitumor activities in animal models.

Comparing the efficacy of 308-nm light-emitting diode and 308-nm excimer lamp for treating vitiligo: A randomized controlled trial.

BACKGROUND: In previous studies, the 308-nm light-emitting diode (LED) has been proven safe and effective for treating vitiligo. However, direct comparisons between the 308-nm LED and 308-nm excimer lamp (308-nm MEL) for the treatment of vitiligo are lacking. OBJECTIVE: To compare the efficacy of the 308-nm LED and 308-nm MEL for treating nonsegmental stable vitiligo. PATIENTS AND METHODS: This randomized controlled trial was conducted between January 2018 and August 2023. Enrolled patients were randomly assigned to either the 308-nm LED or the 308-nm MEL groups, both receiving 16 treatment sessions. Adverse events that occurred during the treatment were documented. RESULTS: In total, 269 stable vitiligo patches from 174 patients completed the study. A total of 131 lesions were included in the 308-nm LED group, and 138 lesions were included in the 308-nm MEL group. After 16 treatment sessions, 38.17% of the vitiligo patches in the 308-nm LED group achieved repigmentation of at least 50% versus 38.41% in the 308-nm MEL group. The two devices exhibited similar results in terms of efficacy for a repigmentation of at least 50% (p = .968). The incidence of adverse effects with the two phototherapy devices was comparable (p = .522). CONCLUSIONS: Treatment of vitiligo with the 308-nm LED had a similar efficacy rate to the 308-nm MEL, and the incidence of adverse effects was comparable between the two devices.

Roles of negative emotions and personality traits in psoriasis vulgaris: A mendelian randomization study.

BACKGROUND: Many studies have indicated that negative emotions and personality traits are related to psoriasis, though few have provided causal evidence. METHODS: Our analysis utilized 15 genome-wide association study datasets to identify instrumental variables associated with negative emotions, personality traits and psoriasis vulgaris. Two-sample Mendelian randomization was conducted to identify the causal associations of negative emotions and personality traits with psoriasis vulgaris. To mitigate bias from multiple tests, we adjusted p-values using the Benjamini-Hochberg method. RESULTS: Our study revealed causal links between negative emotions and psoriasis vulgaris, including depressed affect, worry too long, feeling hurt, guilty feelings, mood swings, unenthusiasm, miserableness, fed-up feelings. However, there was no significant evidence of a causal relationship between feeling lonely and psoriasis vulgaris. Additionally, personality traits including neuroticism and openness to experience were found to have causal effects on psoriasis vulgaris. However, no significant evidence supported a causal relationship between agreeableness, conscientiousness, and extraversion with psoriasis vulgaris. CONCLUSION: Our findings suggest that experiencing negative emotions including depressed affect, worrying excessively, feeling hurt, guilty feelings, mood swings, lack of enthusiasm, miserableness and fed-up feelings may pose risks for psoriasis vulgaris. Additionally, neuroticism is associated with a risk of psoriasis vulgaris. Conversely, the openness trait may serve a protective role against psoriasis vulgaris.

The prophylaxis functions of Lactobacillus fermentum GLF-217 and Lactobacillus plantarum FLP-215 on ulcerative colitis via modulating gut microbiota of mice.

BACKGROUND: The strong connection between gut microbes and human health has been confirmed by an increasing number of studies. Although probiotics have been found to relieve ulcerative colitis, the mechanism varies by the species involved. In this study, the physiological, immune and pathological factors of mice were measured and shotgun metagenomic sequencing was conducted to investigate the potential mechanisms in preventing ulcerative colitis. RESULTS: The results demonstrated that ingestion of Lactobacillus fermentum GLF-217 and Lactobacillus plantarum FLP-215 significantly alleviated ulcerative colitis induced by dextran sulfate sodium (DSS), as evidenced by the increase in body weight, food intake, water intake and colon length as well as the decrease in disease activity index, histopathological score and inflammatory factor. Both strains not only improved intestinal mucosa by increasing mucin-2 and zonula occludens-1, but also improved the immune system response by elevating interleukin-10 levels and decreasing the levels of interleukin-1ß, interleukin-6, tumor necrosis factor-α and interferon-γ. Moreover, L. fermentum GLF-217 and L. plantarum FLP-215 play a role in preventing DSS-induced colitis by regulating the structure of gut microbiota and promoting the formation of short-chain fatty acids. CONCLUSIONS: This study may provide a reference for the prevention strategy of ulcerative colitis. © 2024 Society of Chemical Industry.

Comprehensive analysis of lncRNA-mRNAs co-expression network identifies potential lncRNA biomarkers in cutaneous squamous cell carcinoma.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the second most common type of skin cancer, the prognosis for patients with metastatic cSCC remains relatively poor. Thus, there is an urgent need to identify new diagnostic, prognostic, and therapeutic targets and pathways in cSCC. RESULTS: It detected a total of 37,507 lncRNA probes and 32,825 mRNA probes and found 3593 differentially expressed lncRNAs and 3236 differentially expressed mRNAs. It has been found that mRNAs ACY3, NR1D1, MZB1 has co-expression relationship with six lncRNAs, GXYLT1P3, LINC00348, LOC101928131, A-33-p3340852, A-21-p0003442 and LOC644838. CONCLUSIONS: The aim of this study is to identify cSCC-specific lncRNAs and indicated that six unstudied lncRNAs may serve an important role in endoplasmic reticulum stress apoptosis, autophagy and the progression of cSCC by modulating ACY3, NR1D1 and MZB1.

The reliability, validity and screening effect of the happiness index scale among inpatients in a general hospital.

BACKGROUND: The Happiness Index Scale (HIS) is a newly developed scale by our group to screen for common psychological illnesses among general hospital inpatients. This study aimed to analyze the reliability, validity and screening effect of the HIS and to explore its clinical application. METHODS: From April 1, 2021, to December 31, 2021, a total of 8405 continuous inpatients were enrolled from different departments of a large tertiary general hospital with 1385 inpatient beds in Guangzhou, Guangdong Province, China. Using a cross-sectional survey design, each participant was assessed with the Patient Health Questionnaire 9(PHQ-9), Generalized Anxiety Disorder 7 items(GAD-7), Athens Insomnia Scale (AIS), Columbia Suicide Severity Rating Scale (C-SSRS) and HIS within 24 h of admission. McDonald's ω coefficient, the Guttman split-half coefficient and the test-retest reliability coefficient were used to evaluate the reliability of the HIS and the construct validity and criterion validity of the validity tests. Scores on the PHQ-9, GAD-7, AIS, and C-SSRS were used as the gold standard tools to analyze the screening effect of the HIS. RESULTS: The HIS exhibited very good reliability, with a McDonald's ω coefficient of 0.825, a Guttman split-half coefficient of 0.920 and a test-retest reliability coefficient of 0.745 (P < 0.05). Confirmatory factor analysis showed a satisfactory model fitting index with a χ2/df = 2.602, a root mean squared error of approximation (RMSEA) of 0.014, a standardized root mean square residual (SRMR) of 0.010, a comparative fit index (CFI) of 0.992, and a Tucker-Lewis index (TLI) of 0.983. The correlation coefficient between the total score of each dimension of the scale and the corresponding criterion was 0.854 ~ 0.949 (P < 0.001). The HIS showed a very good distinguishing effect. The average HIS score of inpatients who screened positive for psychological problems was significantly higher than that of inpatients who screened negative for psychological problems (t = 3790.619, P < 0.001). The effect size was very large (Cohens d = 2.695, 95% CI = 2.630 ~ 2.761). Approximately 90.2% of the positive and negative screening results of the HIS were matched with the gold standard tools, with a kappa value of 0.747 (P < 0.001). The screening effect test showed a sensitivity (true positive rate) of 92.9% and a specificity (true negative rate) of 89.5%. CONCLUSION: The HIS exhibited satisfactory reliability and validity and a clinically meaningful screening effect with a much shorter version compared to the commonly used screening scales. Thus, it could potentially be useful as the first screening step to rule out psychological conditions for inpatients in general hospitals or to remind medical teams of further psychological concerns.

PAQR3 regulates phosphorylation of FoxO1 in insulin-resistant HepG2 cells via NF-κB signaling pathway.

Insulin resistance is a significant feature of type 2 diabetes mellitus and glucose and lipid metabolism disorders. Activation of NF-κB signaling pathway plays an important role in the formation of insulin resistance. FoxO1 plays a major role in regulating glucose and lipid metabolism, as well as insulin signaling pathway. Previous studies have shown that Progestin and AdipoQ Receptor 3 (PAQR3) suppresses the activity of PI3K/Akt, which is an upstream pathway of FoxO1, and additionally promotes the pathological process of diabetic renal inflammatory fibrosis via activating NF-κB pathway. On this basis, it has caused us great concern whether NF-κB is involved in PAQR3 regulation of FoxO1 under insulin resistance. In this study, we aimed to investigate whether PAQR3 regulates phosphorylation of FoxO1 via NF-κB pathway in palmitic acid (PA)-induced insulin-resistant HepG2 cells, thereby causing glucose and lipid metabolism disorders. We found that PA stimulation and PAQR3 overexpression decreased the phosphorylation of FoxO1 and the expressions of glucokinase (GCK) and low density lipoprotein receptor (LDLR), in addition, promoted the nuclear accumulation of NF-κB. Inhibition of NF-κB pathway increased the phosphorylation of FoxO1 and the expressions of GCK and LDLR which were downregulated by PA stimulation and PAQR3 overexpression. Taken together, in PA-induced insulin-resistant HepG2 cells, PAQR3 might regulate the phosphorylation of FoxO1 and the expressions of GCK and LDLR through NF-κB pathway, thereby regulating the glucose and lipid metabolism disorders induced by insulin resistance.

Determining the cleavage site for the mature antimicrobial peptide of Nile tilapia ß-defensin using 2D electrophoresis, western blot, and mass spectrometry analysis.

Several proteomic techniques were used to determine the cleavage site of the mature antimicrobial peptide of Nile tilapia ß-defensin. The computer-predicted Nile tilapia ß-defensin (25ASFPWSCLSLSGVCRKVCLPTELFFGPLGCGKGSLCCVSHFL66) composed of 42 amino acids was chemically synthesized and prepared to produce an antibody for Western blotting. Total proteins from the skin of the Nile tilapia were separated on two-dimensional electrophoresis, and the spot of Nile tilapia ß-defensin was recognized using Western blot analysis. It was then excised and extracted from the gel. The precise molecular mass of this spot was determined by LC-MS/MS spectrometry. Four major peptides were discovered, with molecular weights of 4293.2 Da, 4306.5 Da, 4678.9 Da, and 4715.0 Da. The calculated mass of the 40-amino-acid sequence (27FPWSCLSLSGVCRKVCLPTELFFGPLGCGKGSLCCVSHFL66) of Nile tilapia ß-defensin starting from Phe27 and ending with Leu66 was 4293.18 Da, which completely matched the 4293.2 Da peptide that was obtained from the mass spectrometry analysis. This result confirmed that the cleavage site for the mature C-terminal Nile tilapia ß-defensin is at residue Ser26-Phe27, not at Ala24-25 as predicted by computer analysis. This study provides a simple but reliable model to determine the cleavage site for a mature antimicrobial peptide.

Comparative proteomic analysis of Litopenaeus vannamei gills after vaccination with two WSSV structural proteins.

White spot syndrome virus (WSSV) is one of the most devastating viral pathogens of cultured shrimp worldwide. Recently published papers show the ability of WSSV structural protein VP28 to vaccinate shrimp and raise protection against the virus. This study attempted to identify the joining proteins of the aforementioned shrimp quasi-immune response by proteomic analysis. The other envelope protein, VP36B, was used as the non-protective subunit vaccine control. Shrimp were intramuscularly injected with rVPs or PBS on day 1 and day 4 and then on day 7 their gill tissues were sampled. The two-dimensional electrophoresis (2-DE) patterns of gill proteins between vaccinated and PBS groups were compared and 20 differentially expressed proteins identified by mass spectrometry, some of which were validated in gill and hemocyte tissues using real-time quantitative RT-PCR. Many of identified proteins and their expression levels also linked with the shrimp response during WSSV infection. The list of up-regulated protein spots found exclusively in rVP28-vaccinated shrimp include calreticulin and heat shock protein 70 with chaperone properties, ubiquitin, and others. The two serine proteases, chymotrypsin and trypsin, were significantly increased in shrimp of both vaccinated groups compared to PBS controls. The information presented here should be useful for gaining insight into invertebrate immunity.

Dipeptidyl peptidase-4 inhibition improves left ventricular function in chronic kidney disease.

PURPOSE: Heart failure with preserved ejection fraction (HFpEF) is a common comorbidity in people with chronic kidney disease (CKD) for which no evidence-based treatment currently exists. Recently, a group of anti-hyperglycemic agents used in the treatment of Type 2 diabetes, termed incretin-based therapies, have come under scrutiny for their putative glucose-independent effects on cardiac function. In the present study, the actions of the dipeptidyl peptidase-4 (DPP-4) inhibitor class of incretin-based therapy in preventing HFpEF induced by chronic renal impairment were investigated. METHODS: Sham-operated and subtotally-nephrectomized rats were randomized to receive the DPP-4 inhibitors, linagliptin or sitagliptin for seven weeks before assessment of cardiac and renal structure and function. RESULTS: Analysis of pressure-volume loops revealed that both linagliptin and sitagliptin prevented the development of cardiac diastolic dysfunction, with cardiac collagen I synthesis also being reduced by DPP-4 inhibition. These attenuating cardiac effects occurred without change in renal function or structure where, in the doses administered, neither linagliptin nor sitagliptin affected GFR decline, proteinuria, renal fibrosis or the increased urinary excretion of biomarkers of renal toxicity. CONCLUSION: The beneficial cardiac effects of DPP-4 inhibition, in the absence of a concurrent improvement in renal dysfunction, raise the possibility that these agents may confer cardiovascular advantages in the CKD population.

Upregulated miR-374a-5p drives psoriasis pathogenesis through WIF1 downregulation and Wnt5a/NF-κB activation.

BACKGROUND: Psoriasis is a chronic, inflammatory skin disease. MicroRNAs (miRNAs) are an abundant class of non-coding RNA molecules. Recent studies have shown that multiple miRNAs are abnormally expressed in patients with psoriasis. The upregulation of miR-374a-5p has been associated with psoriasis severity. However, the specific role of miR-374a-5p in the pathogenesis of psoriasis remain unclear. METHODS: qRT-PCR was employed to validate the expression of miR-374a-5p in psoriatic lesions and in a psoriasis-like cell model constructed using a mixture of M5 (IL-17A, IL-22, OSM, IL-1α, and TNF-α). HaCaT cells were transfected with miR-374a-5p mimic/inhibitor, and assays including EdU, CCK-8, and flow cytometry were conducted to evaluate the effect of miR-374a-5p on cell proliferation. The expression of inflammatory cytokines IL-1ß, IL-6, IL-8, and TNF-α was verified by qRT-PCR. Bioinformatics analysis and dual-luciferase reporter gene assay were performed to detect the downstream target genes and upstream transcription factors of miR-374a-5p, followed by validation of their expression through qRT-PCR and Western blotting. A psoriasis-like mouse model was established using imiquimod cream topical application. The psoriasis area and severity index scoring, hematoxylin-eosin histology staining, and Ki67 immunohistochemistry were employed to validate the effect of miR-374a-5p on the psoriatic inflammation phenotype after intradermal injection of miR-374a-5p agomir/NC. Additionally, the expression of pathway-related molecules and inflammatory factors such as IL-1ß, IL-17a, and TNF-α was verified by immunohistochemistry. RESULTS: Upregulation of miR-374a-5p was observed in psoriatic lesions and the psoriasis-like cell model. In vitro experiments demonstrated that miR-374a-5p not only promoted the proliferation of HaCaT cells but also upregulated the expression of inflammatory cytokines, including IL-1ß, IL-6, IL-8, and TNF-α. Furthermore, miR-374a-5p promoted skin inflammation and epidermal thickening in the Imiquimod-induced psoriasis-like mouse model. Mechanistic studies revealed that miR-374a-5p led to downregulation of WIF1, thereby activating the Wnt5a/NF-κB signaling pathway. The transcription factor p65 encoded by RELA, as a subunit of NF-κB, further upregulated the expression of miR-374a-5p upon activation. This positive feedback loop promoted keratinocyte proliferation and abnormal inflammation, thereby facilitating the development of psoriasis. CONCLUSION: Our findings elucidate the role of miR-374a-5p upregulation in the pathogenesis of psoriasis through inhibition of WIF1 and activation of the Wnt5a/NF-κB pathway, providing new potential therapeutic targets for psoriasis.

Hepatic steatosis predicts metachronous liver metastasis in colorectal cancer patients: a nested case-control study and systematic review.

Nearly twenty-five percent of colorectal cancer (CRC) patients develop metachronous colorectal liver metastasis (CRLM) after curative surgery. Hepatosteatosis is the most prevalent liver condition worldwide, but its impact on the incidence of metachronous CRLM is understudied. In the present study, we aimed to investigate the predictive value of hepatic steatosis on the development of metachronous CRLM. First, a nested case-control study was conducted, enrolling stage I to III CRC patients in the National Colorectal Cancer Cohort (NCRCC) database. Metachronous CRLM patients and recurrence-free patients were matched via propensity-score matching. Fatty liver was identified based on treatment-naïve CT scans and the degree of hepatic fibrosis was scored. Multivariable analysis was conducted to investigate the association between fatty liver and metachronous CRLM. In our database, a total of 414 patients were included. Metachronous CRLM patients had considerably higher rates of hepatic steatosis (30.9% versus 15.9%, P<0.001) and highly fibrotic liver (11.6% versus 2.9%, P=0.001) compared to recurrence-free patients. Multivariable analysis showed that fatty liver (odds ratios [OR]=1.99, 95% confidence interval [CI] 1.19-3.30, P=0.008) and fibrotic liver (OR=4.27, 95% CI 1.54-11.81, P=0.005) were associated with high risk of metachronous CRLM. Further, a systematic literature review was performed to assess available evidence on the association between hepatosteatosis and development of metachronous CRLM. In the systematic review, 1815 patients were pooled from eligible studies, and hepatic steatosis remained a significant risk factor for metachronous CRLM (OR=1.90, 95% CI 1.35-2.66, P<0.001, I2=25.3%). In conclusion, our data suggest that patients with a steatotic liver and a high fibrosis score at CRC diagnosis have elevated risk of developing metachronous CRLM.

Ciprofol ameliorates ECS-induced learning and memory impairment by modulating aerobic glycolysis in the hippocampus of depressive-like rats.

Electroconvulsive shock (ECS) is utilized to treat depression but may cause learning/memory impairments, which may be ameliorated by anesthetics through the modulation of hippocampal synaptic plasticity. Given that synaptic plasticity is governed by aerobic glycolysis, it remains unclear whether anesthetics modulate aerobic glycolysis to enhance learning and memory function. Depression-like behavior in rats was induced by chronic mild unpredictable stress (CUMS), with anhedonia assessed via sucrose preference test (SPT). Depressive-like behaviors and spatial learning/memory were assessed with forced swim test (FST), open field test (OFT), and Morris water maze (MWM) test. Changes in aerobic glycolysis and synaptic plasticity in the hippocampal region of depressive-like rats post-ECS were documented using immunofluorescence analysis, Western blot, Lactate Assay Kit and transmission electron microscopy. Both the OFT and FST indicated that ECS was effective in alleviating depressive-like behaviors. The MWM test demonstrated that anesthetics were capable of attenuating ECS-induced learning and memory deficits. Immunofluorescence analysis, Western blot, Lactate Assay Kit and transmission electron microscopy revealed that the decline in learning and memory abilities in ECS-induced depressive-like rats was correlated with decreased aerobic glycolysis, and that the additional use of ciprofol or propofol ameliorated these alterations. Adding the glycolysis inhibitor 2-DG diminished the ameliorative effects of the anesthetic. No significant difference was observed between ciprofol and propofol in enhancing aerobic glycolysis in astrocytes and synaptic plasticity after ECS. These findings may contribute to understanding the mechanisms by which anesthetic drugs modulate learning and memory impairment after ECS in depressive-like behavior rats.

METTL14 affects UVB-induced human dermal fibroblasts photoaging via miR-100-3p biogenesis in an m6A-dependent manner.

Exposure to ultraviolet radiation can lead to skin photoaging, which increases the risk of skin tumors. This study aims to investigate how microRNA m6A modification contributes to skin photoaging. This study found that skin fibroblasts exposed to a single UVB dose of 30 mJ/cm2 exhibited characteristics of photoaging. The m6A level of total RNA decreased in photoaged cells with a down-regulated level of METTL14, and overexpression of METTL14 displayed a photoprotective function. Moreover, miR-100-3p was a downstream target of METTL14. And METTL14 could affect pri-miR-100 processing to mature miR-100-3p in an m6A-dependent manner via DGCR8. Furthermore, miR-100-3p targeted at 3' end untranslated region of ERRFI1 mRNA with an inhibitory effect on translation. Additionally, photoprotective effects of overexpression of METTL14 were reversed by miR-100-3p inhibitor or overexpression of ERRFI1. In UVB-induced photoaging of human skin fibroblasts, METTL14-dependent m6A can regulate miR-100-3p maturation via DGCR8 and affect skin fibroblasts photoaging through miR-100-3p/ERRFI1 axis.

Laparoscopic ileocecal-sparing vs traditional right hemicolectomy for cancer of the hepatic flexure or proximal transverse colon: a dual-center propensity score-matched study.

Background: Traditional right hemicolectomy (TRH) is the standard treatment for patients with nonmetastatic right colon cancer. However, the ileocecum, a vital organ with mechanical and immune functions, is removed in these patients regardless of the tumor location. This study aimed to evaluate the technical and oncological safety of laparoscopic ileocecal-sparing right hemicolectomy (LISH). Method: Patients who underwent LISH at two tertiary medical centers were matched 1:2 with patients who underwent TRH by propensity score matching based on sex, age, body mass index, tumor location, and disease stage. Data on surgical and perioperative outcomes were collected. Oncological safety was evaluated in a specimen-oriented manner. Lymph nodes (LNs) near the ileocolic artery (ICA) were examined independently in the LISH group. Disease outcomes were recorded for patients who completed one year of follow-up. Results: In all, 34 patients in the LISH group and 68 patients in the TRH group were matched. LISH added 8 minutes to the dissection of LNs around the ileocolic vessels (groups 201/201d, 202, and 203 LNs), without affecting the total operation time, blood loss, or perioperative adverse event rate. Compared with TRH, LISH had a comparable lymphadenectomy quality, specimen quality, and safety margin while preserving a more functional bowel. The LISH group had no cases of LN metastasis near the ICA. No difference was detected in the recurrence rate at the 1-year follow-up time point between the two groups. Conclusion: In this dual-center study, LISH presented comparable surgical and oncological safety for patients with hepatic flexure or proximal transverse colon cancer.

Roles of prokineticin 2 in electroconvulsive shock-induced memory impairment via regulation of phenotype polarization in astrocytes.

Electroconvulsive shock (ECT) is the most effective treatment for depression but can impair learning and memory. ECT is increasingly being shown to activate astrocytes and induce neuroinflammation, resulting in cognitive decline. Activated astrocytes can differentiate into two subtypes, A1-type astrocytes and A2-type astrocytes. Regarding cognitive function, neurotoxic A1 astrocytes and neuroprotective A2 astrocytes may exhibit opposite effects. Specifically, prokineticin 2 (PK2) functions as an essential mediator of inflammation and induces a selective A2-protective phenotype in astrocytes. This study aimed to clarify how PK2 promotes improved learning memory following electroconvulsive shock (ECS). As part of the study, rats were modeled using chronic unpredictable mild stress. Behavioral experiments were conducted to assess their cognitive abilities and depression-like behaviors. Western blot was used to determine the expression of PK2. Immunohistochemical and electron microscopy analyses of the hippocampal CA1 region were conducted to study the activation of astrocyte subtypes and synaptic ultrastructure, respectively. In this study, rats' spatial learning and memory impairment began to improve as activated A1-subtype astrocytes gradually decreased, and PK2 and A2 phenotype activation peaked on the third day after ECS. PKRA7 (PK2 antagonist) inhibits A2-type astrocyte activation partially and suppresses spatial learning and memory improvement. Collectively, our findings support that PK2 may induce a selective modulation of astrocytic polarization to a protective phenotype to promote learning and memory improvement after ECS.

Crosstalk between cholesterol metabolism and psoriatic inflammation.

Psoriasis is a chronic autoinflammatory skin disease associated with multiple comorbidities, with a prevalence ranging from 2 to 3% in the general population. Decades of preclinical and clinical studies have revealed that alterations in cholesterol and lipid metabolism are strongly associated with psoriasis. Cytokines (tumor necrosis factor-α (TNF-α), interleukin (IL)-17), which are important in the pathogenesis of psoriasis, have been shown to affect cholesterol and lipid metabolism. Cholesterol metabolites and metabolic enzymes, on the other hand, influence not only the biofunction of keratinocytes (a primary type of cell in the epidermis) in psoriasis, but also the immune response and inflammation. However, the relationship between cholesterol metabolism and psoriasis has not been thoroughly reviewed. This review mainly focuses on cholesterol metabolism disturbances in psoriasis and their crosstalk with psoriatic inflammation.

Vitamin C inhibits the growth of colorectal cancer cell HCT116 and reverses the glucose-induced oncogenic effect by downregulating the Warburg effect.

Malnutrition caused by insufficient nutritional supply may significantly hinder the quality of life among cancer patients. Sugar provides energy and nutritional support, but it also promotes cancer growth. Warburg effect is the reprogrammed glucose metabolic mode of cancer cells that meets the intensified ATP demand and biosynthesis. Vitamin C (VC) has anti-tumor effect. However, the relationship between cytotoxicity of VC on cancer cells and Warburg effect remains elusive, the effect of VC on glucose-induced oncogenic effect is also unclear. Based on colorectal cancer cell HCT116, our finding revealed that the discrepant oncogenic effect of different sugar is closely related to the intensification of Warburg effect, with glucose being the potent oncogenic component. Notably, as a potential Warburg effect inhibitor, VC suppressed cancer growth in a concentration-dependent manner and further reversed the glucose-induced oncogenic effect. Furthermore, VC protected tumor-bearing mice from insulin sensitivity impairment and inflammatory imbalance. These findings imply that VC might be a useful adjuvant treatment for cancer patients seeking to optimize nutritional support.

Lactobacillus gasseri CKCC1913 mediated modulation of the gut-liver axis alleviated insulin resistance and liver damage induced by type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by dysregulation of lipid metabolism, insulin resistance, and gut microbiota disorder. Compared to drug interventions, probiotic interventions may have a more enduring effect without producing any side effects. Thus, the potential of probiotics as a therapeutic approach for diabetes and other metabolic disorders has gained increasing attention in recent years. In this study, we evaluated the therapeutic efficacy of Lactobacillus gasseri CKCC1913, a potential probiotic strain, in high-fat diet-induced insulin-resistant diabetes using the C57BL/6J mouse animal model. From the results, L. gasseri CKCC1913 has been shown to increase glucose tolerance, reduce fasting blood glucose levels in diabetic mice, and reduce the expression of pro-inflammatory cytokines, such as TNF-α and IL-6. Besides, L. gasseri CKCC1913 intervention effectively alleviated oxidative stress damage by increasing SOD activity, decreasing MDA levels, reducing insulin resistance, and improving dyslipidemia caused by diabetes. The potential mechanism of L. gasseri CKCC1913 in improving metabolic health and alleviating diabetes involves an increased abundance of beneficial bacteria, such as Parabacteroides merdae, which directly produce short-chain fatty acids that help regulate immune cells and reduce inflammation. SCFAs also enter the bloodstream and promote antioxidant enzyme activity in the liver, protecting against oxidative damage. Additionally, L. gasseri CKCC1913 influences local bacterial metabolism pathways, such as the superpathway of unsaturated fatty acid biosynthesis, leading to an increase in unsaturated fatty acids, increasing high-density lipoprotein cholesterol (HDL-C) levels and improving lipid metabolism and glucose control in diabetic mice. In summary, in this study, L. gasseri CKCC1913 and its potential impact on metabolic health highlight the promising potential of probiotics as a therapeutic approach for diabetes. Future research should focus on identifying the optimal dose and duration, investigating the long-term effects and mechanisms of action, and exploring the potential use of probiotics as an adjunct to other therapies or in preventing metabolic disorders.