Search Results (642)

Metabolic associated fatty liver disease (MAFLD), redefined from non-alcoholic fatty liver disease (NAFLD), is a global health concern driving the search for dietary interventions based on natural compounds. Phloroglucinaldehyde (PGA), a primary phenolic metabolite of the widely consumed anthocyanin cyanidin-3-glucoside (C3G) found in berries and other fruits, has emerged as a promising candidate due to its potential higher bioavailability than its parent compound. This study investigates the protective effects of PGA against high-fat diet (HFD)-induced MAFLD. Using both in vitro (LO2 cells) and in vivo (C57BL/6J mice) models, we found that PGA administration significantly attenuated body weight gain and hepatic steatosis, while reducing serum levels of TG, TC, liver transaminases (AST & ALT), and insulin resistance (p < 0.05). Further liver lipidomic profiling revealed that PGA supplementation specifically down-regulated 46 lipid species (p < 0.05), predominantly triglycerides characterized by long-chain and very-long-chain saturated fatty acids. Mechanistically, PGA enhanced the hepatic antioxidant capacity by increasing superoxide dismutase (SOD) activity (p < 0.05) and decreasing malondialdehyde (MDA) (p < 0.05) and exerted anti-inflammatory effects by reducing pro-inflammatory cytokines (IL-6, TNF, MCP-1) (p < 0.05) and endotoxin levels (p < 0.05). Correlation analyses further linked the down-regulated lipids to improvements in oxidative stress and inflammation. Our findings underscore that PGA, a key bioactive metabolite derived from dietary anthocyanins, alleviates MAFLD through its potent antioxidant and anti-inflammatory properties, highlighting its potential as a functional food ingredient or nutraceutical for metabolic health. Full article

Background: Hashimoto’s thyroiditis (HT) is the result of a complex interplay between genetic, environmental, and epigenetic factors. The role of cellular and humoral immunity in the pathogenesis of the disease is well-established. Inflammatory infiltration of T and B lymphocytes is a key feature identified on ultrasound examination. The lack of data on the effect of L-thyroxine (LT-4) doses on the level of anti-TPO and anti-TG antibodies in Hashimoto’s thyroiditis and the relationship with anthropometric measurements resulted in the desire to fill this niche. Methods: A total of 70 Caucasian patients diagnosed with Hashimoto’s thyroiditis within the past two years were examined. The participants were divided into three groups based on their L-thyroxine dosage (≤50, 50–100, >100 μg). Results: The results revealed no correlation between the dosage of L-thyroxine and anthropometric measurements (age, height, body weight, and body fat content). No correlation was identified between the levels of anti-TPO and anti-TG and the dose of L-thyroxine in patients with Hashimoto’s thyroiditis. Conclusions: The mechanism regulating the levels of anti-TPO and anti-TG appears to be associated with a more advanced thyroid inflammation and disease process. Long-term observation of patients would be advisable. We present evidence of no effect of hormone dose on antibody levels in Hashimoto’s thyroiditis. Regardless of disease severity, immune regulation remains outside the scope of hormonal regulation. Full article

Celiac disease (CeD) is a chronic immune-mediated enteropathy triggered by dietary gluten in genetically predisposed individuals which also entails intestinal dysbiosis. This hallmark microbial imbalance provides a rationale for exploring interventions that could modulate the gut ecosystem. Cocoa is a bioactive food rich in polyphenols, theobromine, and fiber, compounds known to have an influence on both immune function and gut microbiota composition. Here, we investigated the effects of cocoa supplementation on the gut microbial profile and predicted functionality in DQ8-D^d-villin-IL-15tg mice, genetically predisposed to CeD. Animals were assigned to a reference group receiving a gluten-free diet (GFD), a gluten-containing diet group (GLI), or the latter supplemented with defatted cocoa (GLI + COCOA) for 25 days. The cecal microbiota was analyzed via 16S rRNA sequencing, and functional pathways were inferred using PICRUSt2. Goblet cell counts and CeD-relevant autoantibodies were measured and correlated with microbial taxa. Cocoa supplementation partially attenuated gluten-induced dysbiosis, preserving beneficial taxa such as Akkermansia muciniphila and Lactobacillus species while reducing opportunistic and pro-inflammatory bacteria. Functional predictions suggested differences in the predicted microbial metabolic potential related to amino acid, vitamin, and phenolic compound metabolism. Cocoa also mitigated goblet cell loss and was inversely associated with anti-gliadin IgA levels. These findings suggest that cocoa, as an adjuvant to a GFD, could be of help in maintaining microbial homeostasis and intestinal health in CeD, supporting further studies to assess its translational potential. Full article

Vascular function is a direct factor affecting blood pressure, and it is a primary strategy for clinically controlling hypertension by regulating the constriction/relaxation of blood vessels. This study evaluates the vasodilatory and anti-hypertensive effects of norisoboldine (NOR), an isoquinoline alkaloid in Ayurvedic medicine. The rat thoracic aorta was isolated to investigate the vasodilatory effect, and L-NAME-induced hypertensive rats were established, respectively. In the isolated vascular ring, removal of the endothelium resulted in a significant decrease in the vasodilatory effect. Pretreatment with L-NAME, ODQ, KT5823, WT, Tri, Dilt, calcium-free solution, TG, Gd³⁺, 2-APB, Indo, 4-AP, Gli, and BaCl₂ inhibited the vasodilatory effect of NOR. In vascular endothelial cells, NOR promoted eNOS phosphorylation and inhibited TNF-α-induced expression of ICAM-1 and VCAM-1. SBP and DBP were significantly decreased after administration of different doses of NOR in the femoral vein of rats. In addition, NOR significantly reduced the blood pressure of L-NAME-induced hypertensive rats, up-regulated the serum levels of NO, cGMP, and CAT, and down-regulated MDA, IL-6, and TNF-α in hypertensive rats. NOR administration improved pathological changes in the thoracic aorta by regulating the arrangement of thoracic aortic smooth muscle cells, decreasing the thickness of the thoracic aortic wall, and reducing the degree of collagen deposition and fibrosis. In conclusion, the vasodilatory mechanisms of NOR were related to the Ca²⁺-eNOS signaling pathway, including the PGI₂ and various K⁺/Ca²⁺ channels, the inositol triphosphate receptor (IP₃R) calcium release, and the α-adrenergic receptor pathway. The anti-hypertensive mechanism of NOR may be related to increased NO and cGMP bioavailability, inhibition of oxidative stress and inflammatory responses, and improved vascular remodeling. Full article

Down Syndrome (DS) is the most common chromosomal abnormality characterized by neurodevelopmental impairment. Apart from maternal age, its risk factors remain poorly understood. This prospective case-control study aimed to evaluate the role of maternal anti-zona pellucida (ZP) antibodies (Ab) and anti-thyroid-Ab in predicting DS. Correlations of anti-ZP-Ab and anti-thyroid-Ab with maternal age were also assessed. Anti-ZP-Ab were measured after childbirth using ELISA. Anti-thyroid peroxidase (aTPO) and anti-thyroglobulin (aTgII) antibodies were also analysed with the Allelica IM platform. Statistical analyses included receiver operating characteristic curve assessment, expressed as area under the curve (AUC) and linear regression modeling. Between September 2020 and October 2022, 58 women were enrolled. Anti-ZP-Ab levels were significantly higher in women with DS pregnancy with an odds ratio adjusted for maternal age of 71.52 (95% CI: 7.05–725.18) and an excellent predictive performance (AUC = 0.94; 95% CI: 0.88–1.00). For optical density levels > 1, the accuracy was 89.7% (95% CI: 78.2–100.0). No statistically significant differences were observed for aTPO and aTgII. Neither Anti-ZP-Ab nor anti-thyroid antibodies increased with age. These findings suggest that Anti-ZP-Ab are strongly associated with DS risk, suggesting a potential age-independent autoimmune contribution to trisomy 21. Their evaluation may support preconception counseling, especially for women aged > 35 years. Future studies could clarify causality and define the role of maternal autoimmunity in DS etiology. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality. It usually arises in cirrhotic liver, where chronic inflammation and fibrosis create a tumor-permissive microenvironment. Dysregulation of microRNAs (miRNAs), particularly upregulation of the oncomiR miR-221 and loss of the tumor suppressor miR-199a-3p represent key drivers of liver carcinogenesis. The TG221 transgenic mouse, designed to overexpress miR-221 in hepatocytes, provides a relevant in vivo platform for mechanistic studies and for testing preventive and therapeutic approaches. The TG221 model recapitulates miR-221-driven tumorigenesis, including suppression of p27, p57 and Bmf. It is characterized by steatohepatitic injury and accelerated tumor formation after genotoxic challenge. In the cirrhotic CCl₄-induced background, TG221 mice develop fibrosis and cirrhosis followed by dysplastic and malignant lesions, mirroring the natural history of human HCC. Metformin administered during early fibrosis prevented macroscopic tumor formation and suppressed PI3K/AKT/mTOR signaling. Anti-miR-221 and miR-199a-3p mimics reduced tumor burden, restored tumor-suppressive pathways and improved liver integrity, thus indicating feasible chemopreventive strategies. From a therapeutic point of view, miR-199a-3p replacement synergized with palbociclib and overcame sorafenib resistance. A miR-199a-3p-responsive oncolytic adenovirus achieved tumor-selective replication with minimal toxicity. This review highlights the importance of the TG221 transgenic mouse as a powerful model for studying miRNA-driven hepatocarcinogenesis and enables preclinical evaluation of RNA-based chemopreventive and therapeutic approaches. Metformin, miRNA inhibition, miRNA replacement and miRNA-guided viral therapies emerge as promising approaches for advancing precision prevention and treatment strategies in HCC. Full article

Obesity is closely linked to dyslipidemia, hepatic injury, and chronic inflammation through disturbances in the gut–liver axis. Here, we evaluated the anti-obesity effects of L. rhamnosus (Lacticaseibacillus rhamnosus) CU262 in a high-fat diet (HFD) mouse model and elucidated mechanisms using an integrated multi-omics strategy. Male C57BL/6 mice received CU262 during 12 weeks of HFD feeding. Phenotypes, serum/liver biochemistry, gut microbiota (16S rRNA sequencing), fecal short-chain fatty acids (SCFAs), and hepatic transcriptomes (RNA-seq) were assessed. CU262 significantly attenuated weight gain and adiposity; improved serum TC, TG, LDL-C and HDL-C; lowered ALT/AST and FFA; and mitigated oxidative stress and inflammatory imbalance (↓ IL-6/TNF-α, ↑ IL-10). CU262 restored alpha diversity, reduced the Firmicutes/Bacteroidetes ratio, enriched beneficial taxa (e.g., Akkermansia), and increased acetate and butyrate. Liver transcriptomics showed CU262 reversed HFD-induced activation of cholesterol/steroid biosynthesis and endoplasmic reticulum stress, with downregulation of key genes (Mvk, Mvd, Fdps, Nsdhl, and Dhcr7) and Pcsk9, yielding negative enrichment of steroid and terpenoid backbone pathways and enhancement of oxidative phosphorylation and glutathione metabolism. Correlation analyses linked Akkermansia and SCFAs with improved lipid/inflammatory indices and repression of cholesterol-synthetic and stress-response genes. These findings demonstrate that CU262 alleviates HFD-induced metabolic derangements via microbiota-SCFA-hepatic gene network reprogramming along the gut–liver axis, supporting its potential as a functional probiotic for obesity management. Full article

Background/Objectives: Essential oils (EOs) from plants of the genus Cinnamomum have been widely used based on their antimicrobial, antioxidant, and anti-inflammatory properties. However, their elevated volatility and limited aqueous solubility restrict their use in pharmaceutical and food formulations. Cyclodextrins (CDs) have emerged as a promising strategy to overcome these limitations through the formation of inclusion complexes. Methods: In this study, inclusion complexes of essential oil from C. camphora L. (EOCNM) with β-cyclodextrin (β-CD) were developed using physical mixing (PM), ultrasonic treatment (US), and freeze-drying (FD). The inclusion complexes were physicochemically characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TG/DTG), X-ray diffraction (XRD), and scanning electron microscopy (SEM) to evaluate their physicochemical interactions and complexation efficiency. Results: Our results demonstrated successful complex formation, with the FD and US methods showing greater amorphization and stronger inclusion characteristics compared to the PM method. Thermal analysis confirmed improved physicochemical stability of the essential oil when complexed with β-CD. Furthermore, the cytotoxicity assay of the complexes was assessed using the MTT assay and J774 macrophage cells. The complexes exhibited low cytotoxicity, indicating their potential biocompatibility for biomedical and food applications. Conclusions: Overall, β-CD encapsulation effectively enhanced the physicochemical stability and safety profile of C. camphora essential oil, providing a promising strategy for its controlled delivery and protection against degradation. Full article

Alpha-1 antitrypsin (AAT) is a serine protease inhibitor with potent anti-inflammatory and immunomodulatory properties, but its role in cancer is context-dependent across tumor types. We integrated transcriptomic analyses of human melanoma cohorts, in vivo studies using AAT-transgenic (hAAT-TG) mice, and in vitro assays in murine and human melanoma cells to define the biological functions of AAT in melanoma. SERPINA1 expression increased progressively from normal skin to nevi and metastatic melanoma, yet higher intratumoral levels correlated with improved overall survival in metastatic disease. In hAAT-TG mice, melanoma growth was markedly inhibited compared with wild-type controls, and the inhibitory effect required CD8⁺ T cells and was enhanced by CD4⁺ T-cell depletion, demonstrating that AAT promotes cytotoxic T-cell activity while attenuating regulatory T-cell suppression. Histologic analysis showed heavily pigmented tumors in hAAT-TG mice. In vitro, hAAT upregulated melanocytic differentiation markers (MITF, TYR, PMEL, MART-1) and increased melanin production in murine and human melanoma lines, suggesting enhanced tumor immunogenicity. In conclusion, hAAT exerts antitumor effects in melanoma indirectly by reprogramming the tumor microenvironment toward differentiation and immune activation. These findings highlight a previously unrecognized role for AAT as a dual immunoregulatory and differentiation-promoting factor and support AAT as a potential immunoregulatory adjuvant in melanoma. Full article

Atherosclerosis seriously endangers human health. Quercetin has drawn attention for its potential anti-atherosclerotic pharmacological effects. This study aimed to comprehensively assess quercetin’s effect and potential mechanism in treating atherosclerosis through a systematic review and meta-analysis. Preclinical studies published before 20 January 2025 were searched for in databases including PubMed, Embase, Web of Science, CNKI, Wanfang, and VIP. The CAMARADES list was used to assess the quality of the included studies. Stata 12 was applied for overall effect, sensitivity, subgroup, and publication bias analyses. Time–dose interval analyses were conducted to explore how quercetin dose and dosing cycle affect intervention effects. Finally, trial sequential analyses were performed using TSA 0.9 software. A total of 22 studies involving 421 animals were included, with a mean methodological quality score of 7.73/10. Meta-analysis showed that relative to the control group, quercetin reduced aortic plaque area, adjusted lipids (lowered TC, TG, and LDL-C and raised HDL-C), downregulated adhesion factors (e.g., VCAM-1) and pro-inflammatory factors (e.g., IL-1β and IL-6), upregulated anti-inflammatory factor IL-10 and antioxidant enzymes (SOD, CAT) while decreasing MDA content, and regulated atherosclerosis-related targets (e.g., LXRα, SIRT1, and mTOR). Subgroup analyses found model establishment time and quercetin administration time affected aortic lesion areas, TC, and TG. Time–dose analysis indicated quercetin had better ameliorative effects on atherosclerosis at 25–100 mg/kg with an 8–10-week intervention. Quercetin significantly improves atherosclerosis and inhibits its occurrence and progression through multiple pathways, such as regulating lipid metabolism, anti-inflammatory effects, and counteracting oxidative stress. Based on current evidence, quercetin is a potential therapeutic agent for treating atherosclerosis. Full article

Background and clinical significance: Idiopathic hypertrophic pachymeningitis (IHPM) is a rare inflammatory disorder characterized by diffuse or focal dural thickening and heterogeneous presentations. We report a corticosteroid-responsive IHPM with elevated anti-thyroglobulin (anti-Tg) antibodies despite oncologic control after thyroidectomy. This case suggests that systematic assessment for autoimmunity should be a standard component of the IHPM work-up. Case presentation: A 77-year-old woman presented with recurrent vertigo, imbalance, and headaches. Brain MRI showed diffuse pachymeningeal thickening with mild heterogeneous enhancement, radiologically stable over >2 years. Extensive evaluation excluded infectious, neoplastic (including paraneoplastic), cerebrospinal fluid hypotension and systemic autoimmune causes; findings did not support IgG4-related disease. Thyroid work-up revealed hypothyroidism with multinodular goiter; total thyroidectomy was performed, and there was no indication for adjuvant radioiodine therapy. Despite oncologic control, anti-Tg antibodies remained markedly elevated, while anti-thyroid peroxidase antibodies (anti-TPO) declined. Symptoms repeatedly improved with oral methylprednisolone and recurred on taper; adverse effects were mild and manageable. The patient remains under clinical and oncologic surveillance with symptom-guided steroid re-challenge. Conclusions: IHPM may exhibit a dissociation between clinical response and radiologic course. Persistently elevated anti-Tg after thyroidectomy can coexist with IHPM and may signal ongoing autoimmunity rather than active cancer. Full article

Objective: Acteoside (ACT) has different pharmacological properties such as antioxidant, hepatoprotective and anti-inflammatory effects. Impaired mitophagy has been recognized as an important pathogenic factor in metabolic dysfunction-associated steatotic liver disease (MASLD). Nevertheless, the possible therapeutic role of ACT in MASLD and the exact effect of ACT on mitophagy regulation are not explored. This study aims to elucidate the therapeutic efficacy of ACT in a high-fat and high-sugar (HFHS) diet-induced mouse model of MASLD and to determine whether its effects are related to the activation of PINK1/Parkin-related mitophagy markers. Methods: C57BL/6J mice were randomly allocated to control, model, rosuvastatin (RSF, 3 mg/kg), and ACT (30, 60, and 120 mg/kg) groups. Following a 14-week continuous intervention, biochemical parameters, liver histology, and mitophagy-related markers were assessed. Results: ACT administration significantly improved serum lipid profiles, liver function and insulin resistance, marked by reduced levels of MDA, IL-6, TNF-α, IL-1β, LDL-C, TC, TG, AST, ALT, HOMA-IR (p < 0.05), while increasing HDL-C and enhancing hepatic GSH-Px and SOD activities (p < 0.05). Histological examination revealed a notable attenuation of hepatic steatosis and lipid accumulation. At the molecular level, ACT promoted mitophagy activation, as indicated by upregulated PINK1, LC3II/I, and Parkin expression and downregulated P62 and p-P62. Electron microscopy further validated the restoration of mitochondrial morphology and reduction in lipid droplets. Conclusions: These results demonstrate that ACT ameliorates MASLD progression by improving metabolic homeostasis, reducing inflammation and oxidative stress, and alleviating PINK1/Parkin-related mitophagy impairment to restore mitophagy homeostasis. Our study highlights the potential of ACT as a new therapeutic agent for MASLD. Full article

Background/Objectives: Wound healing requires simultaneous pain control, inflammation management, infection prevention, and tissue regeneration. This study aimed to develop and evaluate in vitro a non-contact thermosensitive spray hydrogel combining lidocaine for rapid analgesia and allantoin for tissue repair. Methods: The effects of chitosan and Poloxamer 407 on viscosity, spray diameter, and bioadhesion ability of hydrogels were optimized using response surface methodology. Lead formulations (S1 and S2) were selected via a desirability function within the software. The pH, gelation temperature (T_G), rheological behavior, sprayability, bioadhesion, and lidocaine release using the dialysis bag method were assessed. The in vitro cytotoxicity, anti-inflammatory activity (TNF-α), and cell migration (scratch assay) of the formulations were investigated. Results: The viscosity values (42.7–58.7 mPa·s) indicated suitability for spraying at room temperature. T_G was 28.7 ± 0.6 °C (S1) and 29.3 ± 0.3 °C (S2), enabling rapid sol–gel transition at skin temperature. The lidocaine release reached 95–100% within 120 min. S2 exhibited lower viscosity and wider spray diameter, improving applicability on larger wound areas. In vitro cytotoxicity, scratch assay, and inflammatory marker analyses demonstrated that the optimized sprayable hydrogels exhibited a biocompatible and cell-healing profile. Conclusions: The developed thermosensitive spray hydrogel enables the combined delivery of lidocaine and allantoin, rapid gelation at body temperature, and touch-free administration. Its suitable viscosity and sprayability, and fast lidocaine release profile indicate high patient compliance and a significant advantage over conventional cream/ointment formulations, particularly regarding painless application, reduced contamination risk, enhanced therapeutic potential, and confirmed in vitro biocompatibility with supportive effects on keratinocyte behavior. Full article

Colorectal cancer (CRC) incidence is a significant cancer globally, and radiotherapy resistance is a serious problem. Cucurbitacin D (CBD), extracted from many plants such as the tubers of Trichosanthes kirilowii and the fruits of Ecballium elaterium (squirting cucumber), has various therapeutic effects, such as anti-cancer, -inflammation, -diabetes, and -viral infection effects. Since reports have indicated that CBD exhibits effective anti-cancer activity across various cancer types, our hypothesis is that CBD will overcome radioresistance in CRC radiotherapy. In the present study, we identified that CBD, a triterpenoid compound isolated from Trichosanthes kirilowii and Ecballium elaterium, has an anti-cancer and anti-inflammatory effect in vivo and in vitro. In LPS-induced murine models, CBD suppresses LPS-mediated cytokines, including TNFα, IL-6, IL-1β, and COX-2. In CRC xenograft mouse models, CBD treatment results in significantly smaller tumor volumes than the control. In HCT116 and HT29 cells, CBD treatment suppresses cell viability and increases LDH cytotoxicity and caspase-3 activity and cleavage. However, combined treatment of CBD and Z-VAD-FMK inhibits caspase-dependent apoptosis and cell death. Since CBD induces intracellular calcium (Ca²⁺) and reactive oxygen species (ROS) generation, it mediates ER stress-induced apoptotic cell death through the PERK-ATF4-CHOP axis. Moreover, ER stress inducer thapsigargin (TG) mediates synergistic apoptotic cell death in CBD-treated HCT116 and HT29 cells. However, PERK or CHOP knockdown suppresses ER stress-mediated apoptosis in CBD-treated HCT116 and HT29 cells. CBD treatment induces oxidative stress through the NADPH Oxidase 4 (NOX4) and also increases ROS generation. However, NOX4 knockdown and ROS inhibitor NAC or DPI block ER stress-induced apoptotic cell death by inhibiting the suppression of cell viability and the elevation of caspase-3 activity, LDH cytotoxicity, and intracellular ROS activity in CBD-mediated HCT116 and HT29 cells. We established radioresistant CRC models (HCT116R and HT29R); subsequently, radiation (2 Gy) in combination with CBD treatment overcame radioresistance via the modulation of the epithelial–mesenchymal transition (EMT) phenomenon, including the increase in N-cadherin and vimentin and the reduction in E-cadherin. Thus, these results show that CBD may be a new powerful therapeutic approach for CRC radiotherapy. Full article

Cervical cancer (CC) can be prevented through continuous screening and the timely detection of cervical intraepithelial neoplasia (CIN) using immunohistochemistry techniques to identify biomarker expressions. In a previous study, we proposed nuclear REST loss as a biomarker in precancerous lesions and CC; however, no validated antibodies are available for detecting REST in cytology or cervical tissues. Although we have developed an IgM-type anti-REST monoclonal antibody capable of detecting REST in liquid-based cytology cells, it was not useful for the detection of REST in cervical tissues by immunohistochemistry. The main objective of this study is to generate single-chain variable fragments (scFvs) for the clinical evaluation of REST in cervical tissues from women with CIN and CC. Using RNA from an IgM-producing hybridoma anti-REST, we conducted RT-PCR and PCR to obtain the coding sequences for the variable regions of the heavy and light chains. These sequences were joined with a linker to create a single-chain antibody. The scFv was then cloned into the pSyn1 vector, expressed in E. coli TG1, and purified through chromatography. Subsequently, it was characterized using immunological methods to assess its biological activity and employed to evaluate REST expression in cytological samples and cervical tissues. The anti-REST scFv represents an innovative detection tool that retains the antigen recognition of the parental IgM while overcoming its size limitation, enabling tissue penetration and detection of REST in cervical samples. Its application facilitates the identification of REST in cervical samples, reinforcing REST’s potential as a diagnostic biomarker for CC and CIN. Full article