Search Results (34)

Patients with sepsis often receive mechanical ventilation (MV). Continued use of MV may increase overdistention in the lungs, inflammatory mediator production, and inflammatory cell recruitment, eventually causing ventilator-induced lung injury (VILI). Endoplasmic reticulum (ER) stress caused by MV, oxidative stress, and sepsis results in dissociation of GRP78 from transmembrane proteins (PERK, IRE1α, and ATF6) and generates abundant incorrect protein structures. Phosphoinositide 3-kinase-γ (PI3K-γ) has been demonstrated to modulate ER stress associated with sepsis and acute lung injury (ALI). However, the regulatory mechanisms by which ER stress is involved in VILI remain unclear. In this study, MV was hypothesized to augment lung injury and induce ER stress through the PI3K-γ pathway, regardless of endotoxemia. Wild-type or PI3K-γ-deficient C57BL/6 mice were exposed to 30 mL/kg tidal volume of MV with or without endotoxemia for 5 h. The control group comprised nonventilated mice. MV with endotoxemia increased microvascular permeability, lung edema, interleukin-6 and metalloproteinase-9 production, oxidative loads, ER stress biomarkers (GRP78, IRE-1α, PERK), morphological rearrangement, PI3K-γ expression, and bronchial epithelial apoptosis in rodent lungs. The increase in lung injury was substantially reduced in PI3K-γ-deficient mice and in mice administered 4-phenylbutyric acid. In conclusion, MV-augmented ALI after endotoxemia partially depends on the PI3K-γ pathway. Full article

Oregano essential oil (OEO) has gained attention for its broad pharmacological activities, such as anti-inflammatory, antimicrobial, and anticancer properties. This study aimed to analyze the phytochemical composition and biological activity of OEO obtained from wild-growing Origanum vulgare L. in Romania. Gas chromatography–mass spectrometry (GC–MS) analysis identified p-cymene (43.98%), γ-terpinene (22.16%), and thymol (11.46%) as major constituents, with notable differences from previously reported chemotypes. Antioxidant activity was assessed using the DPPH, ABTS radical scavenging assay, and TPC. OEO has a moderate antioxidant activity, with IC₅₀ values of 134.67 ± 1.32 µg/mL (DPPH) and 88.15 ± 0.045 Inh% (ABTS) and a TPC of 159.63 mg GAE/g extract. The cytotoxicity of the simple water dispersion of OEO, OEO solubilized with polyethylene glycol 400 (OEO-PEG), and that solubilized with Tween 20 (OEO-Tw) was evaluated on human melanoma (A375) and human colorectal adenocarcinoma (HT-29) cancer cell lines, as well as on the normal human immortalized keratinocytes (HaCaT) cell line. The results demonstrated a significant inhibition of cancer cell viability with no recorded cytotoxic effect on normal cells. The highest inhibition of cell viability was recorded for OEO-PEG 200 µg/mL (7.22% ± 6.51 in A375 cell line and 22.25% ± 10.08 in HT-29 cell line). In cancer cells, OEO and its formulations significantly reduced malondialdehyde (MDA) levels (up to 41.24% in A375 cells and up to 48.58% in HT-29 cells), suggesting potent antioxidant activity. Moreover, treatment with OEO increased caspase 3/7 activation two-fold in treated A375 cells, while high-resolution respirometry studies revealed that OEO induces mitochondrial dysfunction by acting as a potential uncoupling agent. Molecular docking analysis suggested that β-caryophyllene oxide (CPO), a minor constituent of OEO, may act as a potential inhibitor of 3-phosphoinositide-dependent protein kinase-1 (PDPK1), indicating a possible mechanism of anticancer activity. Our findings highlight the potential of OEO as a natural anticancer agent, emphasizing the need for further investigations to elucidate its exact molecular mechanisms and therapeutic applicability. Full article

Phosphoinositide 3-kinases (PI3Ks), members of the lipid kinase family, play a significant role in modulating immune cell functions, including activation, proliferation, and differentiation. Recent studies have identified the PI3K signaling pathway as a key regulator in tumor biology and the immune microenvironment. This pathway enhances the activity of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), contributing to an immunosuppressive tumor microenvironment that impairs the effectiveness of cancer vaccines and immunotherapies. The present study explores PI3K isoforms, particularly p110γ and p110δ, and their associated signaling pathways. The therapeutic potential of selective PI3K inhibitors and their capacity to act synergistically with immunization strategies are analyzed. Targeting the PI3K signaling pathway represents a promising approach to counteract tumor-induced immune suppression and improve the efficacy of immune checkpoint inhibitors and vaccines, ultimately leading to better clinical outcomes. Full article

Mechanical ventilation (MV), used in patients with acute lung injury (ALI), induces diaphragmatic myofiber atrophy and contractile inactivity, termed ventilator-induced diaphragm dysfunction. Phosphoinositide 3-kinase-γ (PI3K-γ) is crucial in modulating fibrogenesis during the reparative phase of ALI; however, the mechanisms regulating the interactions among MV, myofiber fibrosis, and PI3K-γ remain unclear. We hypothesized that MV with or without bleomycin treatment would increase diaphragm muscle fibrosis through the PI3K-γ pathway. Five days after receiving a single bolus of 0.075 units of bleomycin intratracheally, C57BL/6 mice were exposed to 6 or 10 mL/kg of MV for 8 h after receiving 5 mg/kg of AS605240 intraperitoneally. In wild-type mice, bleomycin exposure followed by MV 10 mL/kg prompted significant increases in disruptions of diaphragmatic myofibrillar organization, transforming growth factor-β1, oxidative loads, Masson’s trichrome staining, extracellular collagen levels, positive staining of α-smooth muscle actin, PI3K-γ expression, and myonuclear apoptosis (p < 0.05). Decreased diaphragm contractility and peroxisome proliferator-activated receptor-γ coactivator-1α levels were also observed (p < 0.05). MV-augmented bleomycin-induced diaphragm fibrosis and myonuclear apoptosis were attenuated in PI3K-γ-deficient mice and through AS605240-induced inhibition of PI3K-γ activity (p < 0.05). MV-augmented diaphragm fibrosis after bleomycin-induced ALI is partially mediated by PI3K-γ. Therapy targeting PI3K-γ may ameliorate MV-associated diaphragm fibrosis. Full article

Neuroinflammation is the major cause of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. Currently available drugs present relatively low efficacy and are not capable of modifying the course of the disease or delaying its progression. Identifying well-tolerated and brain-penetrant agents of plant origin could fulfil the pressing need for novel treatment techniques for neuroinflammation. Attention has been drawn to a large family of flavonoids in citrus fruits, which may function as strong nutraceuticals in slowing down the development and progression of neuroinflammation. This review is aimed at elucidating and summarizing the effects of the flavonoid tangeretin (TAN) in the management of neuroinflammation-mediated neurodegenerative disorders. A literature survey was performed using various resources, including ScienceDirect, PubMed, Google Scholar, Springer, and Web of Science. The data revealed that TAN exhibited immense neuroprotective effects in addition to its anti-oxidant, anti-diabetic, and peroxisome proliferator-activated receptor-γ agonistic effects. The effects of TAN are mainly mediated through the inhibition of oxidative and inflammatory pathways via regulating multiple signaling pathways, including c-Jun N-terminal kinase, phosphoinositide 3-kinase, mitogen-activated protein kinase, nuclear factor erythroid-2-related factor 2, extracellular-signal-regulated kinase, and CRE-dependent transcription. In conclusion, the citrus flavonoid TAN has the potential to prevent neuronal death mediated by neuroinflammatory pathways and can be developed as an auxiliary therapeutic agent in the management of neurodegenerative disorders. Full article

Selenium (Se) is a trace mineral found in plants with a distinct sulfuric odor that is cardioprotective and reported to have low toxicity. West Java, Indonesia, has a variety of plants with a distinct odor that are consumed raw, such as jengkol (Archidendron pauciflorum). This study is conducted to determine the Se content of jengkol using the fluorometric method, where the jengkol extract is separated, and the Se content is detected using high-pressure liquid chromatography (HPLC), combined with fluorometry. Two fractions with the highest Se concentration (A and B) are found and characterized using liquid chromatography mass spectrometry to predict the organic Se content by comparing the results with those in the external literature. The Se content of fraction (A) is found to be selenomethionine (m/z 198), gamma glutamyl-methyl-selenocysteine-(GluMetSeCys; m/z 313), and the Se-sulfur (S) conjugate of cysteine-selenoglutathione (m/z 475). Furthermore, these compounds are docked on receptors involved in cardioprotection. The receptors are peroxisome proliferator-activated receptor-γ (PPAR-γ), nuclear factor kappa-B (NF-κB), and phosphoinositide 3-kinase (PI3K/AKT). The interaction of receptor and ligan that has the lowest binding energy of the docking simulation is measured with molecular dynamic simulation. MD is performed to observe bond stability and conformation based on root mean square deviation, root mean square fluctuation, radius gyration, and MM-PBSA parameters. The results of the MD simulation show that the stability of the complex organic Se compounds tested with the receptors is lower than that of the native ligand, while the binding energy is lower than that of the native ligand based on the MM-PSBA parameter. This indicates that the predicted organic Se in jengkol, i.e., gamma-GluMetSeCys to PPAR-γ, gamma-GluMetSeCys AKT/PI3K, and Se-S conjugate of cysteine-selenoglutathione to NF-κB, has the best interaction results and provides a cardioprotection effect, compared to the molecular interaction of the test ligands with the receptors. Full article

Mechanical ventilation (MV) used in patients with acute lung injury (ALI) induces lung inflammation and causes fibroblast proliferation and excessive collagen deposition—a process termed epithelial–mesenchymal transition (EMT). Phosphoinositide 3-kinase-γ (PI3K-γ) is crucial in modulating EMT during the reparative phase of ALI; however, the mechanisms regulating the interactions among MV, EMT, and PI3K-γ remain unclear. We hypothesized that MV with or without bleomycin treatment would increase EMT through the PI3K-γ pathway. C57BL/6 mice, either wild-type or PI3K-γ-deficient, were exposed to 6 or 30 mL/kg MV for 5 h after receiving 5 mg/kg AS605240 intraperitoneally 5 days after bleomycin administration. We found that, after bleomycin exposure in wild-type mice, high-tidal-volume MV induced substantial increases in inflammatory cytokine production, oxidative loads, Masson’s trichrome staining level, positive staining of α-smooth muscle actin, PI3K-γ expression, and bronchial epithelial apoptosis (p < 0.05). Decreased respiratory function, antioxidants, and staining of the epithelial marker Zonula occludens-1 were also observed (p < 0.05). MV-augmented bleomycin-induced pulmonary fibrogenesis and epithelial apoptosis were attenuated in PI3K-γ-deficient mice, and we found pharmacological inhibition of PI3K-γ activity through AS605240 (p < 0.05). Our data suggest that MV augmented EMT after bleomycin-induced ALI, partially through the PI3K-γ pathway. Therapy targeting PI3K-γ may ameliorate MV-associated EMT. Full article

The genus Moricandia (Brassicaceae) comprises about eight species that were used in traditional medicine. Moricandia sinaica is used to alleviate certain disorders such as syphilis and exhibits analgesic, anti-inflammatory, antipyretic, antioxidant, and antigenotoxic properties. Throughout this study, we aimed to figure out the chemical composition of lipophilic extract and essential oil obtained from M. sinaica aerial parts using GC/MS analysis, as well as their cytotoxic and antioxidant activities correlated with the major detected compounds’ molecular docking. The results revealed that both the lipophilic extract and the oil were found to be rich in aliphatic hydrocarbons, accounting for 72.00% and 79.85%, respectively. Furthermore, the lipophilic extract’s major constituents are octacosanol, γ-sitosterol, α-amyrin, β-amyrin acetate, and α-tocopherol. Contrarily, monoterpenes and sesquiterpenes accounted for the majority of the essential oil. The essential oil and the lipophilic extract of M. sinaica showed cytotoxic properties towards human liver cancer cells (HepG2) with IC₅₀ values of 126.65 and 220.21 µg/mL, respectively. The lipophilic extract revealed antioxidant activity in the DPPH assay with an IC₅₀ value of 2679 ± 128.13 µg/mL and in the FRAP assay, moderate antioxidant potential was expressed as 44.30 ± 3.73 µM Trolox equivalent/mg sample. The molecular docking studies revealed that ꞵ-amyrin acetate, α -tocopherol, γ-sitosterol, and n-pentacosaneachieved the best docking scores for NADPH oxidase, phosphoinositide-3 kinase, and protein kinase B. Consequently, M. sinaica essential oil and lipophilic extract can be employed as a viable management strategy for oxidative stress conditions and the formulation of improved cytotoxic treatment regimens. Full article

Chimeric antigen receptor (CAR)-expressing macrophages (CAR-M) have a great potential to improve cancer therapy, as shown from several recent preclinical studies. However, unlike CAR-T cell therapy, which has been widely studied, the efficacy and limitations of CAR-M cells remain to be established. To address this issue, in the present study, we compared three intracellular signaling domains (derived from common γ subunit of Fc receptors (FcRγ), multiple EGF-like-domains protein 10 (Megf10), and the CD19 cytoplasmic domain that recruits the p85 subunit of phosphoinositide-3 kinase (PI3K), respectively) for their ability to promote primary CAR-M functions, and investigated the potential synergistic effect between CAR-M and CAR-T cells in their ability to kill tumor cells. We found that CAR-M^FcRγ exerted more potent phagocytic and tumor-killing capacity than CAR-M^Megf10 and CAR-M^PI3K. CAR-M and CAR-T demonstrated synergistic cytotoxicity against tumor cells in vitro. Mechanistically, the inflammatory factors secreted by CAR-T increased the expression of costimulatory ligands (CD86 and CD80) on CAR-M and augmented the cytotoxicity of CAR-M by inducing macrophage M1 polarization. The upregulated costimulatory ligands may promote the fitness and activation of CAR-T cells in turn, achieving significantly enhanced cytotoxicity. Taken together, our study demonstrated for the first time that CAR-M could synergize with CAR-T cells to kill tumor cells, which provides proof-of-concept for a novel combinational immunotherapy. Full article

Platelets are crucial for hemostasis and arterial thrombosis, which may lead to severe cardiovascular diseases (CVDs). Thus, therapeutic agents must be developed to prevent pathological platelet activation. Glabridin, a major bioalkaloid extracted from licorice root, improves metabolic abnormalities (i.e., obesity and diabetes) and protects against CVDs and neuronal disorders. To the best of our knowledge, no studies have focused on glabridin’s effects on platelet activation. Therefore, we investigated these effects in humans and mice. Glabridin exhibited the highest inhibitory effects on collagen-stimulated platelet aggregation and moderate effects on arachidonic-acid-stimulated activation; however, no effects were observed for any other agonists (e.g., thrombin or U46619). Glabridin evidently reduced P-selectin expression, ATP release, and intracellular Ca²⁺ ([Ca²⁺]i) mobilization and thromboxane A₂ formation; it further reduced the activation of phospholipase C (PLC)γ2/protein kinase C (PKC), phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK3β), mitogen-activated protein kinase (MAPK), and NF-κB. In mice, glabridin reduced the mortality rate caused by acute pulmonary thromboembolism without altering bleeding time. Thus, glabridin effectively inhibits the PLCγ2/PKC cascade and prevents the activation of the PI3K/Akt/GSK3β and MAPK pathways; this leads to a reduction in [Ca²⁺]i mobilization, which eventually inhibits platelet aggregation. Therefore, glabridin may be a promising therapeutic agent for thromboembolic disorders. Full article

Phosphoinositide 3-kinase (PI3K) is the family of lipid kinases participating in vital cellular processes such as cell proliferation, growth, migration, or cytokines production. Due to the high expression of these proteins in many human cells and their involvement in metabolism regulation, normal embryogenesis, or maintaining glucose homeostasis, the inhibition of PI3K (especially the first class which contains four subunits: α, β, γ, δ) is considered to be a promising therapeutic strategy for the treatment of inflammatory and autoimmune diseases such as systemic lupus erythematosus (SLE) or multiple sclerosis. In this work, we synthesized a library of benzimidazole derivatives of pyrazolo[1,5-a]pyrimidine representing a collection of new, potent, active, and selective inhibitors of PI3Kδ, displaying IC₅₀ values ranging from 1.892 to 0.018 μM. Among all compounds obtained, CPL302415 (6) showed the highest activity (IC₅₀ value of 18 nM for PI3Kδ), good selectivity (for PI3Kδ relative to other PI3K isoforms: PI3Kα/δ = 79; PI3Kβ/δ = 1415; PI3Kγ/δ = 939), and promising physicochemical properties. As a lead compound synthesized on a relatively large scale, this structure is considered a potential future candidate for clinical trials in SLE treatment. Full article

Metformin is widely used as first-line medication for type 2 diabetes (T2D), the main disease comorbid with kidney disease, cardiovascular diseases (CVDs), and retinopathy. Platelets are crucial in platelet-dependent arterial thrombosis, which causes CVDs and cerebrovascular diseases. Research indicates that metformin may improve these diseases; metformin reportedly reduced platelet activation in rats. However, no reports have included human platelets. We investigated the mechanisms underlying metformin’s effects on platelet activation by using human platelets and evaluated its in vivo effectiveness in experimental mice. Metformin inhibited platelet aggregation stimulated by collagen but not by arachidonic acid, U46619, or thrombin. Metformin suppressed ATP release, [Ca²⁺]i mobilization, and P-selectin expression, as well as phospholipase C (PLC)γ2/protein kinase C (PKC), p38 mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK3β) phosphorylation. Metformin did not affect vasodilator-stimulated phosphoprotein (VASP) phosphorylation. In the animal studies, metformin reduced acute pulmonary thromboembolism mortality without increasing bleeding times. These results provide insights into the role and mechanisms of metformin in human platelet activation. Metformin decreased platelet activation by interfering with the PLCγ2/PKC, PI3K/Akt/GSK3β, and p38 MAPK pathways through a VASP-independent mechanism. Metformin demonstrates promise as a new class of antiplatelet agent that can inhibit platelet activation. Full article

High myopia is a major cause of irreversible visual impairment globally. In the present study, we investigated the microRNA (miRNA) profile in the vitreous of macular hole (MH) and high myopic MH. We performed miRNA analysis using TaqMan^® Low Density Arrays (Thermo Fisher Scientific, Waltham, MA, USA) to investigate the circulating vitreous miRNA profile from patients with MH (axial length < 26.5 mm, n = 11) and high myopic MH (axial length ≥ 26.5 mm, n = 11) who underwent pars plana vitrectomy. The vitreous inflammatory cytokine signature was examined in high myopic MH eyes using a multiplex assay. A miRNA-Array analysis revealed that let-7c was significantly up-regulated and miR-200a was significantly down-regulated in high myopic MH eyes compared to those in MH eyes. The bioinformatics analysis for up-regulated miRNA targeted gene identified 23 pathways including mitogen-activated protein kinase (MAPK) and several inflammatory signaling pathways, whereas the bioinformatics analysis for down-regulated miRNA targeted genes showed 32 enriched pathways including phosphoinositide 3-kinase/protein kinase B (PI3K/AKT). The levels of inflammatory cytokines including IP-10, IFN-γ, and MCP-1 were significantly higher in the vitreous of high myopic MH eyes. These results suggest that specific miRNAs expressed in the vitreous may be associated with the pathological condition of high myopic MH and the above mentioned miRNAs may contribute to the development of inflammatory status in the vitreous of high myopic eyes. Full article

Phosphoinositide 3-kinases (PI3Ks) signaling regulates key cellular processes, such as growth, survival and apoptosis. Among the three classes of PI3K, class I is the most important for the development, differentiation and activation of B and T cells. Four isoforms are distinguished within class I (PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ). PI3Kδ expression is limited mainly to the B cells and their precursors, and blocking PI3K has been found to promote apoptosis of chronic lymphocytic leukemia (CLL) cells. Idelalisib, a selective PI3Kδ inhibitor, was the first-in-class PI3Ki introduced into CLL treatment. It showed efficacy in patients with del(17p)/TP53 mutation, unmutated IGHV status and refractory/relapsed disease. However, its side effects, such as autoimmune-mediated pneumonitis and colitis, infections and skin changes, limited its widespread use. The dual PI3Kδ/γ inhibitor duvelisib is approved for use in CLL patients but with similar toxicities to idelalisib. Umbralisib, a highly selective inhibitor of PI3Kδ and casein kinase-1ε (CK1ε), was found to be efficient and safe in monotherapy and in combination regimens in phase 3 trials in patients with CLL. Novel PI3Kis are under evaluation in early phase clinical trials. In this paper we present the mechanism of action, efficacy and toxicities of PI3Ki approved in the treatment of CLL and developed in clinical trials. Full article

Inflammatory cells contribute to the pathogenesis of renal ischemia-reperfusion injury (IRI). However, the signaling mechanisms underlying the infiltration of inflammatory cells into the kidney are not well understood. In this study, we examined the effects of phosphoinositide 3 kinase γ (PI3Kγ) on inflammatory cells infiltration into the kidney in response to ischemia-reperfusion injury. Compared with wild-type mice, PI3Kγ knockout mice displayed less IRI in the kidney with fewer tubular apoptotic cell. Furthermore, PI3Kγ deficiency decreased the number of infiltrated neutrophils, macrophages, and T cells in the kidney, which was accompanied by a decrease in the expression of pro-inflammatory cytokines in the kidney. Moreover, wild-type mice treated with AS-605240, a selective PI3Kγ inhibitor, displayed less tubular damage, accumulated fewer inflammatory cells, and expressed less proinflammatory molecules in the kidney following IRI. These results demonstrate that PI3Kγ has a critical role in the pathogenesis of kidney damage in IRI, indicating that PI3Kγ inhibition may serve as a potential therapeutic strategy for the prevention of ischemia-reperfusion-induced kidney injury. Full article