Search Results (1,244)

Neuroinflammation plays a central role in the pathogenesis of Alzheimer’s disease (AD), with amyloid-β (Aβ) deposition and neurofibrillary tangles driving both central and peripheral inflammatory responses. This study investigated the neuroprotective and anti-inflammatory effects of Vitex trifolia (VT), Plantago major (PM), Apocyni Veneti Folium (AVF), and Eucommiae folium (EF) using network pharmacology and a co-culture model of PC12 neuronal and Caco-2 intestinal epithelial cells. Bioactive compounds were identified via high-performance liquid chromatography (HPLC) and screened with network pharmacology analysis, yielding 27 for VT, 10 for PM, 6 for AVF, and 3 for EF. Molecular docking confirmed strong binding affinities between the key bioactive compounds and AD-related targets. A co-culture system of PC12 neuronal and Caco-2 intestinal epithelial cells was established to evaluate the effects of VT, PM, AVF, and EF extracts (at concentrations of 10 µg/mL, 20 µg/mL, and 50 µg/mL) and donepezil hydrochloride (positive-control) on Aβ_25–35-induced neurotoxicity and lipopolysaccharide (LPS)-induced intestinal inflammation, to assess cell viability, and effects on oxidative stress, mitochondrial function, and inflammatory markers. The VT, PM, AVF, and EF extracts activated phosphoinositide 3-kinase (PI3K)-Akt-glycogen synthase kinase-3β (GSK-3β) signaling, enhanced phosphorylation of AMP kinase, suggesting inhibition of Aβ accumulation and tau hyperphosphorylation (p < 0.05). However, donepezil hydrochloride only enhanced AMPK phosphorylation. The extracts reduced lipid peroxidation and acetylcholinesterase by about 5-fold. JC-1 staining confirmed preserved mitochondrial membrane potential, while hematoxylin and eosin staining indicated improved intestinal barrier integrity (p < 0.05). PM and AVF reduced the number of mast cells (p < 0.05). In conclusion, these findings highlight the multi-target potential of VT, PM, AVF, and EF in mitigating both neuronal and intestinal inflammation. Their dual regulatory effects on the gut–brain axis suggest promising therapeutic applications in AD through the modulation of central and peripheral immune responses. Full article

Mammalian sperm has a high metabolic activity and primarily relies on glycolysis and mitochondrial oxidative phosphorylation for energy supply. It has been reported that imiquimod (R837), a specific ligand of TLR7 protein, reduces the motility of sperm. However, the specific molecular mechanism by which TLR7 modulates boar sperm is unclear. In this study, the effect of R837, a Toll-like receptor 7 (TLR7) agonist, on boar sperm motility was investigated. Sperm samples were incubated with varying concentrations of R837 (0 to 0.8 µM) at different time points (30, 60, and 90 min). Findings reveal for the first time that TLR7 protein, a key component of the immune system’s Toll-like receptors, is predominantly localized in the middle section of the boar sperm tail, with a smaller concentration observed in the neck. Also, immunofluorescence (IF) revealed that approximately half of the boar sperm sample expressed TLR7. Furthermore, the TLR7 agonist influenced glycolytic hexokinase activity and mitochondrial function via the PI3K-GSK3β signaling pathway. It also selectively inhibited motility in the lower-layer sperm, while motility in the upper-layer sperm remained unaffected. Additionally, this study determined that incubation conditions for boar sperm with 0.2 μM R837 at 37 °C for 60 min yielded the most pronounced inhibition of forward motility in the lower layer of sperm, without compromising the integrity of the acrosome or plasma membrane. The present study reveals the crucial role of R837 in boar sperm motility and highlights TLR7 as an important protein that regulates boar sperm energy metabolism. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic lipid accumulation and insulin resistance, yet effective therapies remain limited. This study evaluated the hepatoprotective effects of Desmodium caudatum (Thunb.) DC. Extract (DCE) in vitro and in vivo. In 600 μM oleic acid (OA)-challenged HepG2 cells, DCE (25, 50, and 100 μg/mL) reduced lipid accumulation, oxidative stress, and glycogen depletion by modulating lipogenic and oxidative pathways. In a MASLD mouse model induced by high-fat diet (HFD)/streptozotocin (HFD/STZ), oral administration of DCE (100 or 200 mg/kg) for six weeks improved fasting glucose, serum lipids, and hepatic injury markers. Histology confirmed reduced steatosis, while Western blotting showed downregulation of SREBP-1, HMGCR, and ACC, and upregulation of CPT-1, PPARα, and phosphorylated AMPK. Additionally, DCE enhanced insulin signaling and restored hepatic glycogen synthesis through IRS-1, AKT, and GSK3β activation. These findings suggest that DCE ameliorates MASLD by regulating lipid and glucose metabolism, supporting its potential as a plant-based therapeutic strategy. Full article

Crohn’s disease is a chronic, idiopathic inflammatory bowel disease characterized by patchy, transmural inflammation that is influenced by genetic, environmental, and microbial factors. The NOD2 pathway mediates NFκB activation and pro-inflammatory cytokine production. In the SHIP–/– murine model of Crohn’s disease-like ileitis, macrophage-derived IL-1β production drives intestinal inflammation. SHIP reduces NOD2 signaling by preventing downstream interaction between RIPK2 and XIAP, leading us to hypothesize that blocking RIPK2 in SHIP–/– mice would ameliorate intestinal inflammation. We examined the effects of RIPK2 inhibition on pro-inflammatory cytokine production in SHIP+/+ and SHIP–/– macrophages and in mice, using the RIPK2 inhibitor, GSK2983559. We found that GSK2983559 blocked RIPK2 activation in SHIP+/+ and SHIP–/– bone marrow-derived macrophages (BMDMs), and reduced Il1b transcription and IL-1β production in (MDP+LPS)-stimulated SHIP–/– BMDMs. Despite the reduction of IL-1β production in BMDMs, in vivo treatment with GSK2983559 worsened intestinal inflammation and increased IL-1β concentrations in the ileal tissues of SHIP–/– mice. GSK2983559 only modestly reduced IL-1β in (MDP+LPS)-stimulated SHIP–/– peritoneal macrophages, and did not suppress pro-inflammatory cytokine production in response to TLR ligands in peritoneal macrophages from either SHIP+/+ or SHIP–/– mice. Taken together, our data suggest that although RIPK2 inhibition can block IL-1β production by (MDP+LPS)-stimulated macrophages in vitro, it is not an effective anti-inflammatory strategy in vivo, highlighting the limitations of targeting RIPK2 to treat intestinal inflammation in the context of SHIP deficiency. Full article

Noni juice polysaccharides demonstrate promising hypoglycemic activity, but their high molecular weight restricts bioavailability. This study established a controlled degradation approach to optimize the functional properties of Noni juice polysaccharides. Molecular characterization demonstrated that the degraded Noni juice polysaccharides (DNJPs, Mw 191.8 kDa) retained the core monosaccharide composition, while exhibiting enhanced solubility. In vitro experiments with insulin-resistant HepG2 cells showed that DNJPs (0.5–2 mg/mL) significantly enhanced glucose consumption (p < 0.01) and mitigated oxidative stress by upregulating antioxidant enzymes (SOD, CAT, and GSH-Px) and decreasing malondialdehyde (MDA) levels. DNJPs activated the PI3K/AKT-Nrf2-GSK3β signaling axis through a multifaceted mechanism involving the following: upregulating the phosphorylation levels of PI3K and AKT; enhancing Nrf2 nuclear translocation, which in turn promotes the expression of downstream targets such as HO-1 and NQO1; inhibiting GSK3β activity; and suppressing FOXO1-mediated gluconeogenesis. These findings underscore DNJPs as promising functional food ingredients that modulate two key pathways to improve glucose metabolism. Full article

Focal adhesion kinase (FAK) is a crucial protein component of focal adhesions (FAs) and belongs to the cytoplasmic non-receptor protein tyrosine kinase family. FAK primarily regulates adhesion signaling and cell migration and is highly expressed in various tumors, including lung, liver, gastric, and colorectal cancers, as well as in conditions such as acute lung injury (ALI) and pulmonary fibrosis (PF). Recent research on FAK and its small-molecule inhibitors has revealed that targeting FAK provides a novel approach for treating various lung diseases. FAK inhibitors can obstruct signaling pathways, demonstrating anti-tumor, anti-inflammatory, and anti-fibrotic effects. In lung cancer, FAK inhibitors suppress tumor growth and metastasis; in ALI, they exert protective effects by alleviating inflammatory responses and oxidative stress; and in pulmonary fibrosis, FAK inhibitors reduce fibroblast activation and inhibit collagen deposition. The findings demonstrate promising efficacy and an acceptable safety profile in preclinical models. However, these early-stage results require further validation through clinical studies. Additionally, the underlying mechanisms, as well as the toxic effects and side effects, necessitate further in-depth investigation. Some have progressed to clinical trials (Defactinib (Phase II), PF-562271 (Phase I), CEP-37440 (Phase I), PND-1186 (Phase I), GSK-2256098 (Phase II), BI-853520 (Phase I)), offering potential therapeutic targets for lung diseases. Collectively, these findings establish a foundational basis for the advancement of FAK inhibitor discovery. Emerging methodologies, such as PROTAC degraders and combination regimens, demonstrate significant potential for future research. Based on a comprehensive analysis of the relevant literature from 2015 to the present, this review briefly introduces the structure and function of FAK and discusses recent research advancements regarding FAK and its inhibitors in the context of pulmonary diseases. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, with current therapies offering only limited symptomatic relief and lacking disease-modifying efficacy. Addressing this critical therapeutic gap, natural multi-target compounds like mulberroside A (MsA)—a bioactive glycoside from Morus alba L.—present promising alternatives. This study investigated MsA’s neuroprotective potential using scopolamine-induced AD-like mice and N2a/APP695swe cells. In vivo, MsA significantly ameliorated cognitive deficits and neuronal loss, concurrently enhancing cholinergic neurotransmission through increased acetylcholine levels and inhibited acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) activities. MsA also upregulated neurotrophic factors (BDNF, CREB) in critical brain regions. In vitro, MsA restored cholinergic function, mitigated oxidative stress, and crucially reduced amyloid-β (Aβ) production by dual regulation of APP processing: promoting the non-amyloidogenic pathway via ADAM10 upregulation and inhibiting the amyloidogenic pathway via suppression of BACE1 and γ-secretase components. Mechanistically, these multi-target benefits were mediated by MsA’s activation of the PI3K/AKT pathway, which triggered downstream inhibitory phosphorylation of GSK3β—directly reduced tau hyperphosphorylation—and activation of CREB/BDNF signaling. Collectively, our findings demonstrate that MsA confers comprehensive neuroprotection against AD pathology by simultaneously targeting cholinergic dysfunction, oxidative stress, Aβ accumulation, tau phosphorylation, and impaired neurotrophic signaling, highlighting its strong therapeutic candidacy. Full article

Background: Alzheimer’s disease is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. Gamma (γ) oscillations are closely linked to learning and memory, and recent interest has grown around Gamma ENtrainment Using Sensory stimulation (GENUS) as a non-invasive neuromodulation strategy. However, the therapeutic impact of vibrotactile gamma stimulation under varying physical parameters such as acceleration remains underexplored. Methods: Differentiated SH-SY5Y cells were treated with amyloid-β (Aβ) and exposed to vibrotactile stimulation at 2.2 or 4.0 m/s². In vivo, male C57BL/6N mice (7 weeks old, 35 g) were administered scopolamine to induce neurotoxicity and randomly assigned to sham, scopolamine, donepezil, or vibrotactile stimulation groups (n = 10 each). Behavioral tests, biochemical assays, Western blotting, and immunohistochemistry were performed to evaluate cognitive function, oxidative stress, cholinergic activity, synaptic plasticity, and neuroinflammation. Results: In vitro, SH-SY5Y cells exposed to amyloid-beta (Aβ) were treated with vibrotactile stimulation, resulting in enhanced neuronal marker expression at 2.2 m/s². In vivo, mice receiving stimulation at 2.2 m/s² showed improved cognitive performance, reduced oxidative stress, restored cholinergic function, suppressed neuroinflammation, and enhanced synaptic plasticity. Mechanistically, these effects were associated with activation of the AKT/GSK3β/β-catenin pathway. Conclusions: Our findings demonstrate that vibrotactile gamma stimulation at 2.2 m/s² exerts greater therapeutic efficacy than higher acceleration, highlighting the importance of optimizing stimulation parameters. This work supports the potential of acceleration-tuned, non-invasive GENUS-based therapies as effective strategies for cognitive recovery in neurodegenerative conditions. Full article

The capability to generate induced pluripotent stem cells (iPSCs) from adult somatic cells, enabling them to differentiate into any cell type, has been demonstrated in several studies. In humans and mice, iPSCs have been shown to differentiate into primordial germ cells (PGCs), spermatozoa, and oocytes. However, research on iPSCs in deer is novel. Despite the necessity for establishing germplasm banks from endangered cervid species, the collection and cryopreservation of gametes and embryos have proven complex for this group. Therefore, the focus of this study was to establish protocols for deriving stable iPSC lines from Blastocerus dichotomus (Marsh deer) using primary cells derived from antler, adipose tissue, or skin, with the ultimate goal of producing viable gametes in the future. To achieve this, two main reprogramming approaches were tested: (1) transfection using PiggyBac transposons (plasmid PB-TET-MKOS) delivered via electroporation and (2) lentiviral transduction using the STEMCCA system with either human (hOSKM) or murine (mOSKM) reprogramming factors. Both systems utilized murine embryonic fibroblasts (MEFs) as feeder cells. The PiggyBac system was further supplemented with a culture medium containing small molecules to aid reprogramming, including a GSK inhibitor, MEK inhibitor, ALK/TGF inhibitor, and thiazovivin. Initial colony formation was observed; however, these colonies failed to expand post-selection. Despite these challenges, important insights were gained that will inform and guide future studies toward the successful generation of iPSCs in deer. Full article

This study investigated the regulatory role of the long non-coding RNA maternally expressed gene 3 (MEG3) in tau hyperphosphorylation and insulin signaling (PI3K/AKT1/GSK3β) under high-glucose (HG)-induced neurotoxic conditions mimicking Alzheimer’s disease pathology. To explore the function of MEG3 within a hyperglycemic (Hyp) model, MEG3 was silenced using small interfering RNA (siRNA) assay, followed by Western blot analysis, qRT-PCR, and network analyses. The siMEG3 + Hyp group had lower levels of AKT1 (0.48-fold) and PI3K (0.52-fold) than did the Hyp group. In the siMEG3 + Hyp group, GSK3β (2.51-fold) and TNFα (2.38-fold) expressions were higher than were those in the Hyp group, while in the siMEG3 group, GSK3β (4.59-fold), microtubule-associated protein TAU (MAPT, TAU) (6.37-fold), interleukin (IL)1β (5.67-fold), IL6 (3.29-fold), and tumor necrosis factor-α (TNFα) (3.06-fold) were all significantly upregulated in comparison to the control group. A higher level of p-tau protein was seen in the siMEG3 group in comparison to the control group, as well as in the siMEG3 + Hyp group in comparison to the Hyp group. Gene ontology analysis following MEG3 administration showed that genes downstream of the PI3K pathway were suppressed, whereas genes regulating the neuroinflammatory response were upregulated. The results suggest that the lncRNA MEG3 may be a promising therapeutic target in HG-induced neurodegenerative AD. Full article

Background: GSK3β is an intracellular regulatory kinase that is dysregulated in multiple tissues in Type 1 myotonic dystrophy (DM-1). Tideglusib inhibits GSK3β activity in preclinical models of DM-1 and promotes cellular maturation, normalising aberrant molecular and behavioural phenotypes. It is currently in clinical development for the treatment of paediatric and adult patients affected by congenital and juvenile-onset DM-1. Here, we summarise the development of a population pharmacokinetic model and subsequent characterisation of influential demographic and clinical factors on the systemic exposure to tideglusib. The availability of a population PK model will allow further evaluation of age-and weight-related changes in drug disposition, supporting the dose rationale and implementation of a paediatric extrapolation plan. Methods: Given the sparse pharmacokinetic sampling scheme in patients receiving tideglusib, model development was implemented in two steps. First, data from Phase I studies in healthy elderly subjects (i.e., 1832 plasma samples, n = 54) were used to describe the population pharmacokinetics of tideglusib in adults. Then, pharmacokinetic model parameter estimates obtained from healthy subjects were used as priors for the evaluation of the disposition of tideglusib in adolescent and adult DM-1 patients (51 plasma samples, n = 16), taking into account demographic and clinical baseline characteristics, as well as food intake. Secondary pharmacokinetic parameters (AUC, C_max and T_max) were derived and summarised by descriptive statistics. Results: Tideglusib pharmacokinetics was described by a two-compartment model with first-order elimination and dose-dependent bioavailability. There were no significant differences in disposition parameters between healthy subjects and DM-1 patients. Body weight was a significant covariate on clearance and volume of distribution. Median AUC_(0–12) and C_max were 1218.1 vs. 3145.7 ng/mL∙h and 513.5 vs. 1170.9 ng/mL, following once daily doses of 400 and 1000 mg tideglusib, respectively. In addition, the time of food intake post-dose or the type of meal appeared to affect the overall exposure to tideglusib. No accumulation, metabolic inhibition, or induction was observed during the treatment period. Conclusions: Even though clearance was constant over the dose range between 400 and 1000 mg, a less than proportional increase in systemic exposure appears to be caused by the dose-dependent bioavailability, which reflects the solubility properties of tideglusib. Despite large interindividual variability in the tideglusib concentration vs. time profiles, body weight was the only explanatory covariate for the observed differences. This finding suggests that the use of weight-banded or weight-normalised doses should be considered to ensure comparable exposure across the paediatric population, regardless of age or body weight. Full article

Background/Objectives: Hair loss, driven by disrupted hair cycles, age-related hormonal imbalances, and oxidative stress, poses significant psychological challenges, necessitating the development of safe and effective therapies. This research investigates the trichogenic potential and underlying mechanisms of a standardized Ageratum conyzoides extract (ACE) using human follicle dermal papilla cells (HFDPCs) and C57BL/6 mice as models. Methods: HFDPCs were treated with ACE to assess its effects on 5α-reductase activity, estrogen receptor (ERα/ERβ) signaling, and activation of Wnt/β-catenin and MAPK pathways. Reactive oxygen species (ROS) levels and antioxidant enzyme expression were also evaluated. In vivo, C57BL/6 mice were administered ACE orally, and hair regrowth, follicle number and depth, and histological changes were measured. Results: In HFDPCs, ACE inhibited 5α-reductase activity, modulated ERα and ERβ signaling, and activated Wnt/β-catenin and MAPK pathways. ACE treatment at 100 μg/mL significantly increased β-catenin, p-GSK3β, and vascular endothelial growth factor (VEGF) expression (p < 0.01) and decreased Dickkopf-related protein-1 (DKK-)1 expression (p < 0.05). It also upregulated VEGF and other hair-growth-related factors and exhibited substantial antioxidant properties by reducing reactive oxygen species (ROS) and elevating the expression of antioxidant enzymes, notably SOD2 at 100 μg/mL. In C57BL/6 mice, oral administration of ACE significantly increased hair regrowth, with the 50 mg/kg group showing the most prominent effects, including increased hair follicle number and depth compared to the negative control group (p < 0.05). These effects were observed to be dose-dependent and comparable to those of minoxidil. Histological analysis confirmed enhanced anagen-phase follicle development. Conclusions: These findings highlight ACE’s multifaceted biological activity in promoting hair growth through hormonal modulation, pathway activation, and antioxidant protection, positioning it as a promising natural supplement for hair growth and health, although further clinical studies are required to confirm its efficacy in humans. Full article

Melanin overproduction contributes to hyperpigmentation disorders such as melasma and solar lentigines, leading to increasing demand for safe and effective skin-lightening agents. D-cycloserine (DCS), a known antimicrobial agent, has not been previously evaluated for dermatological applications. This study aimed to explore the potential of DCS as a novel anti-melanogenic compound and to elucidate its underlying molecular mechanisms in melanogenesis inhibition. The cytotoxicity and anti-melanogenic effects of DCS were assessed in B16F10 melanoma cells stimulated with α-MSH. Cell viability was determined via MTT assays, while melanin content, tyrosinase activity, and the expression levels of MITF, TYR, TRP-1, TRP-2, and major signaling proteins (e.g., CREB, MAPKs, GSK-3β/β-catenin) were evaluated using colorimetric assays and Western blotting. A 3D human skin model was also used to confirm in vitro findings, and a primary skin irritation test was conducted to assess dermal safety. DCS significantly reduced α-MSH-induced melanin content and tyrosinase activity without cytotoxicity at concentrations ≤100 µM. It downregulated MITF and melanogenic enzyme expression and modulated signaling pathways by enhancing ERK activation while inhibiting CREB, JNK, and p38 phosphorylation. Additionally, DCS suppressed β-catenin stabilization via GSK-3β activation. These effects were confirmed in a 3D human skin model, and a clinical skin irritation study revealed no adverse reactions in human volunteers. DCS exerts its anti-melanogenic effect by targeting multiple pathways, including CREB/MITF, MAPK, and GSK-3β/β-catenin signaling. Its efficacy and safety profiles support its potential as a novel cosmeceutical agent for the treatment of hyperpigmentation. Further clinical studies are warranted to confirm its therapeutic utility in human skin pigmentation disorders. Full article

Tau protein is essential for the structural stability of neurons, particularly through its role in microtubule assembly and axonal transport. However, when abnormally hyperphosphorylated or cleaved, Tau can aggregate into insoluble forms that disrupt neuronal function, contributing to the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD). Emerging evidence suggests that similar Tau-related alterations may occur in individuals with chronic exposure to psychoactive substances. This review compiles experimental, clinical, and postmortem findings that collectively indicate a substance-specific influence on Tau dynamics. Alcohol and opioids, for instance, promote Tau hyperphosphorylation and fragmentation through the activation of kinases such as GSK-3β and CDK5, as well as proteases like caspase-3, leading to neuroinflammation and microglial activation. Stimulants and dissociatives disrupt insulin signaling, increase oxidative stress, and impair endosomal trafficking, all of which can exacerbate Tau pathology. In contrast, cannabinoids and psychedelics may exert protective effects by modulating kinase activity, reducing inflammation, or enhancing neuroplasticity. Psychedelic compounds such as psilocybin and harmine have been demonstrated to decrease Tau phosphorylation and facilitate cognitive restoration in animal models. Although the molecular mechanisms differ across substances, Tau consistently emerges as a convergent target altered in substance-related cognitive disorders. Understanding these pathways may provide not only mechanistic insights into drug-induced neurotoxicity but also identify Tau as a valuable biomarker and potential therapeutic target for the prevention or treatment of cognitive decline associated with substance use. Full article