Search Results (3,005)

The plugging of fractured gas reservoirs with severe lost circulation during oil and gas drilling and production has long been challenged by technical issues such as low plugging strength and short effective duration. This paper reports the preparation of a high-strength supramolecular gel plugging agent via micellar copolymerization based on the synergistic effects of hydrophobic association and hydrogen bonding. Systematic optimization determined the optimal synthesis formula: acrylamide (AM) 12%, 2-acrylamido-2-methylpropanesulfonic acid (AMPS) 2%, stearyl methacrylate (SMA) 0.4%, sodium dodecyl sulfate (SDS) 1.5%, and potassium persulfate 0.3%, with a reaction temperature of 60 °C. Performance evaluations revealed that the gel possesses a controllable gelation time (120 min) and excellent viscoelastic recovery properties. At a compressive strain of 87%, the compressive stress reached 1.43 MPa while maintaining structural integrity. Swelling behavior analysis indicated that the gel follows a non-Fickian diffusion mechanism, with its swelling process governed by the synergistic interplay of water molecule diffusion and polymer network relaxation. Core plugging experiments demonstrated that the gel achieved plugging efficiencies exceeding 95% for cores with permeabilities ranging from 0.18 to 0.90 μm², with a maximum breakthrough pressure gradient of up to 11.48 MPa/m. These results highlight the gel’s efficient and broad-spectrum plugging capability for fractured lost circulation zones. This preliminary study provides experimental foundations for the material design and performance optimization of supramolecular gel-based long-lasting plugging agents for severe lost circulation gas reservoirs, and further field-scale validation is required for engineering application. Full article

Pertussis toxin (PTx) is a major virulence factor of Bordetella pertussis and an AB5-type exotoxin that disrupts host signaling. Its enzymatic A subunit ADP-ribosylates the α-subunit of inhibitory G proteins (Gα_i), preventing them from mediating receptor-induced inhibition of adenylyl cyclase (AC). This leads to unrestrained cAMP accumulation in host cells, a canonical mechanism underlying many pertussis disease manifestations. PTx works in concert with the bacterium’s adenylate cyclase toxin (ACT) to subvert immune defenses and establish infection. Interestingly, PTx exerts both cAMP-dependent and cAMP-independent effects. In addition to the well-known cAMP-mediated pathway, PTx’s B oligomer can engage host cell surface receptors to trigger signaling cascades independent of the A subunit’s catalytic activity. Such B oligomer-mediated pathways modulate cellular responses in the absence of ADP-ribosylation. This review provides a comprehensive analysis of PTx’s dual functionality, distinguishing its G_i protein-dependent elevation of cAMP from the noncanonical activities of the B oligomer. It also highlights how disruption of constitutive G_i signaling and the interplay between PTx and ACT shape host–pathogen interaction in pertussis pathogenesis. Full article

The second messenger cyclic AMP (cAMP) is very likely involved in phototactic as well as gravitactic behavior of the unicellular flagellate Euglena gracilis. A slight but significant increase in cAMP was observed when cells encountered sub-threshold acceleration (0.16 × g) force after microgravity [µg]. No differences in cAMP levels were found between cells on a clinostat and 1x-controls. This observation is consistent with the ones of earlier studies. Illumination of cells resulted in a significant increase in cellular cAMP levels. After RNAi-mediated knockdown or CRISPR-Cas9 knockout of the photoactivated adenylyl cyclases PACα and/or PACβ in the photoreceptor, light-induced changes in cAMP levels were no longer observed. In parallel, phototactic behavior was abolished, supporting the essential role of photoactivated adenylyl cyclases in phototaxis. Cells spin around their length axis during locomotion (1–2 Hz). In order to generate a signal in the light direction, the cells should be capable of synthesizing and degrading cAMP within 0.5–1 s. The rapid fixation of cells upon transition from dark to light or light to dark revealed that detectable changes in cAMP-levels (increase or decrease) occur within a 100–200 ms time window, which is sufficiently fast to account for the proposed theoretical kinetics of cAMP oscillations. Full article

The appearance of antibiotic-resistant strains of Helicobacter pylori (H. pylori) is leading to a decreased eradication rate of H. pylori infection. There is an urgent need to find new agents with antimicrobial mechanisms different from those of antibiotics, with therapeutic potential to clear colonization of H. pylori in the stomach. Some antimicrobial peptides (AMPs) possess bactericidal activity by enhancing the permeability of the outer membrane and damaging the integrity of the cell membrane. Bacteria are not susceptible to drug resistance through this antimicrobial mechanism. In this study, 28 short peptides containing 12 amino acid residues were designed based on nine amino acid fragments (KRIVQRIKD) from human cathelicidin LL-37, which is stable in gastric juice, and 3 amino acids were added at the C-terminus of the peptide. These designed peptides were not digested and degraded by pepsin at low pH values. The peptides were predicted using the online tool platform. Then, the strongest antimicrobial peptide, named SAMP-12aa (KRIVQRIKDVIR), was screened from 28 short peptides. Further studies found that SAMP-12aa retained anti-H. pylori activity after incubation in simulated gastric juice. The MIC and MBC of SAMP-12aa were 8 μg/mL and 32 μg/mL, respectively. SAMP-12aa showed good bactericidal kinetics. SAMP-12aa was found to have cell selectivity, penetrating and damaging bacterial cell membranes and exhibiting almost no toxicity to human cells at a relatively high concentration (128 μg/mL). Regulatory T (Treg) cells express CD25^High with immunosuppressive activity that induces immune tolerance in response to H. pylori. Molecular docking prediction revealed that SAMP-12aa could target the active center of Foxp3. Flow cytometry analysis revealed that SAMP-12aa can inhibit Foxp3 activity and downregulate CD25 protein expression on CD4⁺ T cells, thereby reducing the development and differentiation of CD4⁺Foxp3⁺CD25^High Treg cells with immunosuppressive effects. Further research revealed that the levels of the cytokine interferon-γ (IFN-γ), which activates CD8⁺ T-cell activity, were significantly elevated, and the levels of transforming growth factor-β (TGF-β), which inhibits CD8⁺ T-cell activity, were significantly reduced. The results of this study reveal that SAMP-12aa not only possesses antibacterial activity but also has immunomodulatory effects. Full article

Melanoma is a highly malignant neoplasm of the skin with early metastatic spread and increasing incidence worldwide. Although there are significant therapeutic advances in immunotherapy, especially with the checkpoint inhibitors targeting PD-1 and CTLA-4, challenges such as treatment-related toxicities, a heterogeneous response to therapy, and drug resistance continue to exist. There are unmet needs for novel therapeutic strategies and/or approaches to complement the existing treatment options. Potential targets for future melanoma treatment are the gap junction proteins, connexins, which show an altered pattern of regulation during melanoma progression. In this review, we highlight the regulation of gap junctions during melanoma progression and the characterization of gap junctions as tumor suppressors during early-stage tumor development and then the reversion to enhancers of tumor metastasis during late-stage melanoma progression. We provide a comprehensive overview of gap junctions in the skin and how the connexin proteins, which comprise gap junctions, are alternatively regulated in melanoma progression. Connexins are protein channels in the human body that consist of 21 isoforms. These isoforms form gap junctions that provide important intercellular signaling and permeability channels. Each connexin protein consists of four transmembrane domains and a C-terminal tail, which is an important part of its function and regulation. Permeants of gap junctions include signaling molecules such as cyclic AMP and inositol triphosphate which are linked to key cellular behaviors such as proliferation and migration, making them essential for several tumor-related processes. At least ten connexin isoforms are found in normal skin. Connexin 43 (Cx43) is classified as the most prevalent isoform while Connexin 26 (Cx26) has been reported to be more specialized with restricted expression patterns. Cx43 and Cx26 regulate the growth, differentiation, and repair of the epidermis after injury. Evidence suggests that connexins have a stage-related function in melanoma. Loss of connexin expression and gap junctional intercellular communication is linked to tumor suppression and loss of differentiation in early-stage melanoma, while re-expression or overexpression of specific connexins, notably Cx43, may promote metastasis through enhanced tumor–stromal interactions and increased motility in late-stage melanoma. Such opposing actions of connexins support their candidacy as biomarkers and therapeutic targets. Understanding the dual-stage related functions of connexins in melanoma development and progression may lead to less cytotoxic and more efficient future therapeutic approaches. Full article

Background/Objectives: Psychological stress triggers excessive melanin deposition via neuroendocrine pathways, yet targeted interventions for stress-induced hyperpigmentation remain limited. Salidroside (SAL) exhibits established depigmenting effects in UV-induced models and possesses neuroprotective properties. This study investigated SAL’s efficacy in psychological stress-induced hyperpigmentation and elucidated its underlying mechanisms. Methods: B16F10 melanocytes, C57BL/6J mice, zebrafish, and human foreskin organ cultures were subjected to stress factor (Substance P/cortisol) or α-MSH/IBMX stimulation to model psychological stress-induced and canonical cAMP-driven hyperpigmentation, respectively. Melanin content, tyrosinase activity, melanosome maturation (transmission electron microscopy/HMB45 staining), and melanogenic protein/mRNA expression were assessed. Drug Affinity Responsive Target Stability (DARTS) assays, molecular docking, and SEC23A siRNA knockdown were employed to identify and validate SAL’s molecular target and downstream signaling pathways. Results: SAL dose-dependently reduced melanin content, tyrosinase activity, and TYR/TRP-1/DCT expression in SP/Cort-stimulated melanocytes, exhibiting greater potency (200 μM) than in IBMX-induced models (400 μM). SAL reversed SP/Cort-induced hyperpigmentation in human skin explants, zebrafish, and C57BL/6J mice, and normalized melanosome number/maturation. DARTS and molecular docking identified SEC23A as a direct SAL-binding target. SP/Cort specifically upregulated SEC23A, which SAL suppressed. SAL concurrently activated the SEC23A-p-ERK-MITF axis and inhibited the NK1R-p38-MITF axis in the stress model. SEC23A knockdown potentiated SAL’s anti-melanogenic effects specifically in SP/Cort-stimulated cells. Conversely, in IBMX-induced models, SEC23A remained unchanged, and SAL acted via PKA/CREB, PI3K/AKT, and Wnt/β-catenin pathways. Conclusions: SEC23A is a novel core target in psychological stress-induced hyperpigmentation. SAL selectively binds SEC23A to inhibit stress-induced melanogenesis via dual ERK and p38 MAPK signaling axes, demonstrating etiological specificity distinct from canonical cAMP pathway inhibition. Full article

Obesity is characterized by abnormal adipose tissue expansion and energy metabolism imbalance. Browning of white adipose tissue (WAT), wherein white adipocytes acquire thermogenic properties similar to brown adipose tissue, represents a key mechanism for increasing energy expenditure. Although ginseng (Panax ginseng C.A. Meyer) is widely recognized as a health-promoting botanical, its role in WAT browning has not been fully elucidated. This review summarizes evidence that ginseng and its bioactive components regulate major thermogenic pathways, including β-adrenergic/cyclic adenosine monophosphate-protein kinase (cAMP-PKA) signaling, AMP-activated protein kinase (AMPK), and the peroxisome proliferator-activated receptor γ (PPARγ)/coactivator 1α (PGC-1α) axis, thereby upregulating key markers such as uncoupling protein 1 (UCP1), PR domain containing 16 (PRDM16) and type II iodothyronine deiodinase (DIO2). These effects promote mitochondrial function and fatty acid oxidation, reduce lipogenesis, alleviate inflammation, and improve insulin sensitivity, collectively fostering a microenvironment conducive to browning. Furthermore, fermentation has been found to enhance the bioactivity and thermogenic efficacy of ginseng. Recent evidence indicates that gut microbiota and their metabolites—such as short-chain fatty acids, unsaturated fatty acids, and bile acids—play a notable role in ginseng-induced thermogenesis via receptors including G-protein-coupled receptor 41/43 (GPR41/43), takeda G-protein-coupled receptor 5 (TGR5), and farnesoid X receptor (FXR). These multi-organ interaction networks involving the gut–fat, gut–liver, and gut–brain axes reflect the role of ginseng in integrating systemic metabolism. In summary, this review discusses the multi-level regulatory network through which ginseng promotes WAT browning, providing a mechanistic basis for its potential application in body weight and metabolic health management. Full article

Background: Aging-related cognitive decline is closely associated with microglial senescence and the resulting chronic neuroinflammation. Emerging evidence identifies the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway as a pivotal innate immune signaling pathway linking DNA damage to cellular senescence and the senescence-associated secretory phenotype (SASP), particularly in microglia. Targeting the formation or selective clearance of senescent cells thus emerges as a promising therapeutic approach to ameliorate cognitive dysfunction. Resveratrol has shown promise in modulating immune response and exerting anti-aging effects. However, the therapeutic potential and underlying mechanisms of resveratrol in mitigating age-associated microglial senescence and cognitive decline are not fully understood. Methods: In the present study, we employed a well-established murine model of accelerated aging induced by chronic intraperitoneal injection of D-galactose (D-gal) to elicit pronounced senescence-associated phenotypes and neuroinflammation. Resveratrol was administered via oral gavage daily for three weeks following D-gal injections. Behavioral assays were conducted to assess cognitive performance. Immunohistochemistry, quantitative PCR, and Western blot analyses were used to evaluate markers of cellular senescence, microglial activation and pro-inflammatory cytokine expression. In addition, in vitro assays in cultured microglia coupled with RNA sequencing were used to investigate the downstream signaling events following resveratrol treatment. Results: Chronic D-gal treatment induced significant cognitive impairment, enhanced microglial activation, elevated pro-inflammatory cytokine levels, and increased markers of cellular senescence in the brain. Resveratrol administration remarkably attenuated these effects, as evidenced by improved memory performance, reduced microglial senescence markers, and suppressed expression of Cxcl-10, Il-1β, and other SASP factors. Mechanistically, unbiased transcriptomic analysis revealed that the cGAS-STING signaling and neuroinflammation pathways were prominently dysregulated with double-stranded DNA-induced cellular senescence, which was effectively normalized by resveratrol in cultured microglia. Interestingly, resveratrol inhibited the translocation of STING from the endoplasmic reticulum to the Golgi apparatus and suppressed phosphorylation of TBK1, thereby blocking downstream STING signaling. Conclusions: These findings demonstrate that resveratrol mitigates microglial senescence and neuroinflammation and preserves cognitive function in D-gal-induced aging mice, at least partly through modulation of the cGAS-STING signaling. Therefore, targeting this pathway may represent a promising therapeutic strategy for age-related neuroinflammatory and cognitive disorders. Full article

Background: During aging, skeletal muscle mass constantly diminishes and myogenic potential declines. At the cellular level, a decline in mitochondrial function is a hallmark of the aging process and the deficiency of the mitochondrial network contributes to a progressive reduction in muscle mass. Autophagic clearance of mitochondria through the process of mitophagy is required to remove impaired or damaged mitochondria, while mitophagy is a key regulator of muscle maintenance. Dysfunctional degradation of mitochondria is increasingly associated with aging (mitophaging), while mechanical stimuli have been shown to ameliorate the aging-induced impaired muscle mass and function; however, less is known about the potential effects of mechanical loading on mitophaging. The aim of the present study was to investigate the effect of mechanical stretching on mitophagy in aged myoblasts, in vitro. Methods: Cell senescence was replicated using a multiple cell division model of C2C12 myoblasts. The control and aged cells were cultured on elastic membranes and underwent passive stretching using a mechanical loading protocol of 15% elongation for 12 h at a frequency of 1 Hz. Cell signaling and gene expression responses of mitophagy-associated and myogenic regulatory factors (MRFs) were assessed through immunoblotting and qRT-PCR of the cell lysates derived from stretched and non-stretched control and aged myoblasts. Results: Mitophagy factor AMP-activated protein kinase (AMPK), mitochondrial biogenesis stimulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a), and mitophagy/mitochondrial biogenesis factor Parkin were downregulated in control stretched myoblasts compared to non-stretched cells, while the specific mechanical loading protocol used also reduced the phosphorylation of unc-51-like autophagy-activating kinase 1 (p-ULK1) (p < 0.05), as well as the expression of myogenic factor 5 (Myf5) and myogenic factor 4 (myogenin) (p < 0.001). Interestingly, this mechanical loading resulted in increased PGC-1a and Parkin expression (p < 0.05) and induced the previously undetected BCL2 interacting protein 3-like (BNIP3L/NIX) and AMPK expression and p-ULK1 activation in the aged myoblasts. In addition, mechanical stretching differentially affected the expression of MRFs in aged cells, upregulating the early differentiation factor, Myf5 (p < 0.01), while downregulating the late differentiation factor myogenin (p < 0.001). Conclusions: These findings suggest the beneficial effects of mechanical loading on the impaired mitophagy and early differentiation in aged myoblasts, as indicated by the mitophagy initiation and the promotion of mitochondrial biogenesis in these cells. The mechanical loading-induced downregulation of mitophagy and myogenesis in the control myoblasts might indicate their loading-specific differential responses compared to the aged cells. Full article

The field of immunometabolism highlights the intricate interplay between immunity and metabolism. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a central component of innate immunity that detects double-stranded DNA (dsDNA) from a range of sources, including pathogenic and host-derived DNA. It is now recognized that the cGAS-STING pathway has broad implications in a variety of human conditions including cancer, age-related diseases, and autoimmune disorders. Given the abundance and diversity of lipids across cellular compartments serving as structural components and signaling molecules, it is unsurprising that lipid metabolism influences the regulation of cGAS-STING signaling. Lipids can directly alter signaling protein dynamics through interactions within membrane compartments, while alterations in lipid metabolism can remodel multiple cell-intrinsic signaling cascades. Here, we summarize emerging concepts and recent discoveries that have advanced our understanding of how lipid metabolism and lipids regulate the cGAS-STING pathway. Full article

Background/Objectives: Humans have at least 26 bitter taste receptors (T2Rs), and among these, bitter taste receptor 14 (T2R14) is highly expressed in both oral and extraoral tissues. Over 100 bitter ligands can activate T2R14, including hormones, vitamins, plant compounds, and peptides. Previous studies suggest that bitter tastants such as quinine and caffeine can inhibit G protein-coupled receptor kinases (GRKs) and delay T2R signal termination. Our earlier research showed that peptides from alcalase and chymotrypsin hydrolysates of beef proteins inhibited quinine-dependent calcium release through T2R4, with AGDDAPRAVF and ETSARHL showing the greatest effectiveness. However, the effect of these antagonistic peptides on other T2Rs, such as T2R14 signaling, remains unknown. This study aimed to evaluate the ability of these beef protein-derived peptides to activate or inhibit T2R14 signaling and the involvement of GRK2 in signal termination. Methods and Results: Our results indicate that the above two antagonist peptides significantly inhibit T2R14 activity. Furthermore, GRK2 knockout in HEK cells stably expressing T2R14 decreases intracellular calcium release, as measured by the area under the curve (AUC), and also delays the fall time (indication of desensitization) of the calcium response when exposed to the T2R14 agonist diphenhydramine (DPH) or beef protein-derived agonist peptide TMTL. Next, we measured the effects of these ligands on cAMP accumulation, and our results suggest no significant change in cAMP levels upon treatment with beef protein-derived peptides. Conclusions: Thus, this study showed that beef protein-derived peptides can function as both T2R inhibitors and mediate T2R14 desensitization through GRK2 signaling. These antagonistic food protein-derived peptides inform strategies to enhance nutrition, such as promoting healthier food choices by reducing bitterness and thereby improving the palatability of health-promoting bitter foods, such as fruit and vegetable extracts, as well as bitter medications. Full article

Background: Fibrotic remodelling of the lamina cribrosa (LC) is a defining pathological feature of glaucomatous optic neuropathy and contributes to progressive optic nerve head deformation and axonal vulnerability. LC cells from glaucomatous donors exhibit a myofibroblast-like phenotype characterised by excessive extracellular matrix (ECM) production, a process associated with chronic cellular stress. cAMP responsive element-binding protein 3-like 1 (CREB3L1) is an endoplasmic reticulum–resident transcription factor implicated in stress-responsive regulation of collagen synthesis and matrix homeostasis. The role of CREB3L1 in glaucomatous LC cells, however, remains poorly defined. Methods: Primary human LC cells derived from donors with confirmed glaucoma (GLC; n = 3) and age-matched non-glaucomatous controls (NLC; n = 3) were examined. CREB3L1 expression was assessed at the mRNA and protein levels using quantitative RT-PCR and Western immunoblotting. The functional effects of CREB3L1 suppression were evaluated using siRNA-mediated knockdown in GLC cells, followed by analysis of ECM gene transcription (α-smooth muscle actin, collagen type I alpha 1, fibronectin) and cellular metabolic activity using an MTS assay. Results: CREB3L1 mRNA and protein expression were significantly elevated in GLC cells compared with NLC cells. siRNA-mediated knockdown of CREB3L1 effectively reduced its expression in GLC cells and was associated with significant suppression of profibrotic ECM gene transcription. In addition, CREB3L1 knockdown resulted in a marked reduction in cellular metabolic activity in glaucomatous LC cells. Conclusions: These findings identify CREB3L1 as a regulator of ECM-associated gene expression and cellular behaviour in glaucomatous lamina cribrosa cells. While preliminary, the data suggest that CREB3L1 may contribute to pathological fibrotic remodelling at the optic nerve head. Further mechanistic and in vivo studies will be required to determine whether modulation of CREB3L1-mediated pathways represents a viable therapeutic strategy in glaucoma. Full article

Background: Raw-meat-based diets (RMBDs) for companion animals have gained popularity but may serve as vehicles for antimicrobial-resistant (AMR) bacteria, posing risks to animal and public health. This study investigated the occurrence and risk factors of AMR in indicator bacteria (Escherichia coli, Enterococcus faecalis, Enterococcus faecium) and Campylobacter spp. from commercial RMBD products. Methods: In 2023, 50 RMBD samples were collected in Belgium, representing 21 brands from five countries. After both selective and non-selective isolation and MALDI-TOF identification, antimicrobial susceptibility testing of the isolates was performed using broth microdilution. Results: From non-selective media, E. coli was found in 45 samples (90.0%), E. faecalis in 31 samples (62.0%), E. faecium in 23 samples (46.0%), and Campylobacter spp. in 3 samples (6.0%). Among these, one E. faecalis strain with acquired resistance to vancomycin and daptomycin was isolated. Multidrug resistance (MDR) was identified in 17 isolates from 15 samples (30.0%), including 14 MDR E. coli, 1 MDR E. faecalis, and 2 MDR E. faecium. From selective media, presumptive ESBL/AmpC-producing E. coli were detected in 17 samples (34.0%), and 5 E. faecium from linezolid-supplemented media were confirmed by the broth microdilution method. Samples from Belgian origin showed significantly higher E. faecium prevalence (76.5%) compared to Dutch samples (21.4%) (OR = 11.9, p < 0.001). Minor livestock sources were associated with increased MDR risk (OR = 5.52, p = 0.016). Conclusions: Commercial RMBDs in Belgium exhibit widespread bacterial contamination with concerning AMR patterns. These findings highlight the need for improved production standards in the RMBD industry and the need to raise awareness in pet owners. Full article

Background: Abnormal activation of the NRF2-cGAS-STING-NF-κB pathway can trigger an inflammatory cascade in rheumatoid arthritis (RA). Curcumin (CUR), a polyphenolic compound extracted from turmeric, possesses anti-inflammatory activity, but whether it can modulate this pathway to ameliorate RA remains unclear. This study aims to elucidate whether CUR inhibits the inflammatory response in synovial fibroblasts (MH7A) by suppressing the NRF2-cGAS-STING-NF-κB signaling cascade. Methods: An RA inflammatory model was constructed by stimulating MH7A cells with 20 ng/mL tumor necrosis factor (TNF). Groups included a control group, a model group, a methotrexate positive control group [MTX(methotrexate), 10 μmol/L], and curcumin treatment groups at varying concentrations (10–100 μmol/L). Cell viability was assessed using the CCK-8(Cell Counting Kit-8) assay. Cell migration and invasion capabilities were evaluated via scratch wound healing and Transwell assays, respectively. Apoptosis was detected by flow cytometry. mRNA and protein expression levels of NRF2(Nuclear factor erythroid 2-related factor 2), cGAS(cyclic GMP-AMP synthase), STING(stimulator of interferon genes), and NF-κB(nuclear factor kappa-light-chain-enhancer of activated B cells) were measured using qRT-PCR and Western blot, respectively. Protein localization was determined by immunofluorescence. Results: Compared to the model group (TNF-induced), the cell migration rate in the curcumin (CUR) groups was significantly decreased (p < 0.001), with a particularly marked reduction observed at a concentration of 50 μmol/L. Furthermore, as the concentration of curcumin increased, cell invasion capacity showed a significant dose-dependent decline. The apoptosis rate also significantly decreased with increasing curcumin concentrations, demonstrating a clear concentration-dependent effect. Mechanistically, curcumin treatment significantly upregulated the expression of NRF2 and inhibited the activation of its downstream cGAS-STING-NF-κB signaling pathway. Specifically, both mRNA and protein expression levels of NRF2 were markedly elevated (p < 0.001), while the mRNA and protein levels of cGAS, STING, and NF-κB were all significantly reduced (p < 0.001). Conclusions: Curcumin (CUR) can effectively inhibit the inflammatory response of synovial fibroblasts by activating the expression of NRF2 and subsequently suppressing the cGAS-STING-NF-κB signaling pathway. This study provides a new molecular mechanism target for curcumin in the treatment of RA and offers a theoretical basis for the intervention of autoimmune diseases with natural products. Full article

Mild cognitive impairment (MCI) represents an intermediate stage between normal aging and Alzheimer’s disease. This study investigated the neuroprotective effects of a combined extract of Mentha piperita (MP) and Cornus officinalis (CO) (MC) using in vitro and in vivo models. In SK-N-SH cells, pretreatment with MC (50–150 μg/mL) significantly attenuated H₂O₂-induced cellular injury, as evidenced by a reduction in Annexin V-positive cells and an increase in brain-derived neurotrophic factor (BDNF) mRNA expression. Rosmarinic acid and loganin, the marker compounds of MP and CO, alone or combined at a 6:4 ratio, mitigated H₂O₂-induced decreases in cell viability and BDNF mRNA. In the in vivo study, male Sprague–Dawley rats were orally administered MC (50, 100, or 200 mg/kg/day) for 28 days, with phosphatidylserine (50 mg/kg/day) serving as a positive control. MC administration significantly improved cognitive performance in rats with scopolamine-induced memory impairment, as demonstrated by increased step-through latency in the passive avoidance test and reduced escape latency in the Morris water maze. Furthermore, in the probe trial, MC-treated rats spent significantly more time in the target quadrant, indicating enhanced spatial memory retention. Mechanistically, MC restored hippocampal acetylcholine levels and reversed the scopolamine-induced decrease in BDNF and its downstream signaling. Specifically, MC upregulated hippocampal BDNF expression and enhanced the phosphorylation of extracellular signal-regulated kinase (ERK), protein kinase B (AKT), and cAMP response element-binding protein (CREB). In conclusion, these results demonstrate that the MC extract possesses potent neuroprotective and learning- and memory-enhancing effects, highlighting its potential as a therapeutic candidate for managing age-related cognitive decline and MCI. Full article