Background: Nonalcoholic steatohepatitis (NASH) is a liver disease characterized by inflammation and fibrosis. Oridonin (Ori) exhibits anti-inflammatory and anti-fibrotic properties, but its role in NASH remains unclear. The study aimed to investigate whether Ori alleviates NASH injury by regulating pyroptosis through the nuclear factor-kappa B (NF-kappa B)/nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) axis. Methods: An in vitro NASH model was established in HepG2 cells using free fatty acids (FFA), and an in vivo model was induced in mice using a methionine-choline-deficient (MCD) diet. Biochemical assays, staining, flow cytometry, Western blot, and immunofluorescence assessed lipid accumulation, oxidative stress, inflammation, pyroptosis, and fibrosis. Results: Ori treatment (2.5-10 & micro;M) dose-dependently reduced FFA-induced cell injury, lipid accumulation, reactive oxygen species (ROS) production, and release of interleukin (IL)-1 beta and IL-18, while decreasing PI and Caspase-1-positive cells and expression of N-GSDMD (p < 0.05). Ori also suppressed the expression of fibrosis markers alpha smooth muscle actin (alpha-SMA), Collagen III, and fibronectin (p < 0.05). In MCD-fed mice, Ori significantly attenuated hepatic steatosis, oxidative stress, inflammation, pyroptosis, and fibrosis, and alleviated liver enzyme levels and stiffness (p < 0.05). Mechanistically, Ori inhibited NF-kappa B activation (p-p65 and p-I kappa B alpha) and NLRP3 inflammasome assembly, as confirmed by lipopolysaccharide (LPS)/adenosine triphosphate (ATP) experiments. Conclusion: Ori can delay NASH progression via suppressing the NF-kappa B/NLRP3 pathway, reducing liver cell damage, lipid deposition, inflammation, pyroptosis, and fibrosis.
Despite the advancements achieved in chemotherapy, cancer continues to remain a formidable and lethal global threat, ranking as the second leading cause of death worldwide. The development of chemoresistance poses a significant hurdle in cancer treatment. Nonetheless, a therapeutic strategy known as chemosensitization has emerged to counteract cancer cell resistance, wherein the efficacy of one drug is augmented by another. Accumulating evidence suggests that natural products have attracted considerable attention in the cancer therapeutic realm due to their ability to combat multidrug resistance with minimal side effects. Ginsenosides, triterpene saponins extracted from Panax ginseng, have demonstrated significant anticancer activity while exhibiting relatively low toxicity and reduced adverse effects. Co-administration of ginsenosides with chemotherapeutic drugs has been shown to trigger apoptosis, as evidenced by an increased Bcl-2-associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2) ratio, inhibit angiogenesis through suppression of vascular endothelial growth factor (VEGF); and hinder replicative immortality by downregulating stemness-associated markers such as octamer-binding transcription factor 4 (Oct4), Nanog, and sex determining region Y-box 2 (SOX2) in various cancers. Additionally, ginsenosides modulate key chemoresistance pathways, including nuclear factor-kappa B (NF-κB), signal transducers and activators of transcription (STAT), and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), as well as their downstream targets, thereby rendering cancer cells more susceptible to chemotherapy. Notably, ginsenosides have been shown to modulate the tumor microenvironment and mitigate the side effects associated with chemotherapeutic drugs. This review aims to consolidate findings from preclinical and clinical studies to elucidate the role of ginsenosides as effective chemosensitizing agents.
Diabetes, inflammation, and neurodegeneration, particularly Alzheimer’s disease (AD), are deeply interconnected (brain diabetes). Type 2 diabetes mellitus (T2DM) acts as a significant risk factor for neurodegenerative diseases like Alzheimer’s (AD) and Parkinson’s (PD) by inducing chronic inflammation, oxidative stress, and metabolic dysfunction. Hyperglycemia drives neuroinflammation and damages the blood-brain barrier (BBB), exacerbating cognitive decline and neuronal loss. Chronic inflammation acts as a central bridge, linking high blood sugar, insulin resistance, and metabolic dysfunction in the brain to the buildup of amyloid plaques, tau tangles, and neuronal damage due to shared insulin signaling issues in the brain. Diabetes accelerate AD risk through inflammation-driven mitochondrial damage and impaired insulin pathways, which hinder amyloid clearance and disrupt normal brain function. Insulin resistance and impaired glucose metabolism accelerate brain aging and neurodegeneration. This narrative review aims to summarize the underlying molecular and cellular mechanisms in the pathophysiology of hyperglycemia-associated neurodegeneration with a focus on Alzheimer’s disease as a manifestation of type 3 diabetes mellitus (type 2 diabetes in the brain).
Objectives: Neuroinflammation, largely mediated by microglial activation, plays a central role in the pathogenesis of neurodegenerative diseases. In this study, we aimed to evaluate olive leaf extracts (OLEs) from three Croatian cultivars (Bu & zcaron;a, Oblica, and Leccino) in the context of lipopolysaccharide (LPS)-induced activation of BV-2 microglia. Methods: Extracts were prepared by aqueous maceration and ethanol extraction under conditions compatible with downstream cell-culture use. Total phenolic and flavonoid contents were determined for both extract types, alongside targeted liquid chromatography-mass spectrometry (LC-MS/MS) quantification of major phenolic compounds. Based on compositional analysis, ethanolic extracts were selected for further evaluation, including antioxidant capacity assays [2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2 '-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS)] and assessment of BV-2 microglial responses to LPS, i.e., measurements of cell viability, activation markers (CD86, CD206, iNOS), and selected markers of inflammatory (phospho-p65, Sirt1) and cytoprotective pathways (Nrf2, HSP70). Results: Ethanolic extracts exhibited higher total phenolic and flavonoid contents than aqueous macerates, supported by LC-MS/MS analysis showing increased levels of key constituents such as oleuropein and other flavonoids. Antioxidant activity varied depending on the assay: DPPH activity was comparable across cultivars (p = 0.858), whereas ABTS activity was highest for the Oblica extract (p = 0.0002). Ethanolic extracts were noncytotoxic at 10 & micro;g/mL, while higher concentrations induced dose-dependent cytotoxicity (p = 0.0001). In BV-2 cells, LPS (1 & micro;g/mL, 3 h) increased CD86 (p = 0.017) and CD206 expression (p < 0.0001), with no change in iNOS levels (p = 0.0697). Short-term, non-cytotoxic pretreatment with ethanolic extracts (10 & micro;g/mL, 3 h) did not significantly alter microglial activation markers or the examined inflammatory and cytoprotective pathways. Conclusion: These findings define the experimental limits under the applied conditions and indicate that compositional richness alone does not necessarily translate into measurable biological effects, supporting further studies with extended exposure and refined dosing.
The tuberculosis (TB) epidemic continues to be one of the largest public health challenges affecting people globally, especially due to late diagnosis, disease monitoring, and prognosis. Currently used diagnostic tools have variable sensitivity and accessibility, and many have limited ability to differentiate between latent and active TB. In case of TB, exosomes from cells infected with Mycobacterium tuberculosis (M. tuberculosis) have disease-specific antigens, microRNAs, and other molecular components, which make them potential diagnostic and prognostic biomarkers. This review focuses on previously published literature regarding the role of exosomes and exosomal antigens in TB screening and prognostication. It highlights their potential as non-conventional biomarkers due to their stability in biological fluids, specificity, and the availability of less invasive sampling techniques. Moreover, it covers recent developments in techniques for isolating and characterizing exosomes and also ways in which the gaps between exosome-based biomarkers have been challenged in real-world clinical settings. In the future, research needs to prioritize large validation studies, achievement-in-exosome-based assays, and incorporation of multi-omics techniques to improve their clinical relevance. The use of exosome-based biomarkers shows promise for improving diagnostic processes for tuberculosis and may support a worldwide campaign for tuberculosis control.
