Phosphatidylinositol 3-kinase Research Articles

Schwann Cell-Specific Ablation of Beclin 1 Impairs Myelination and Leads to Motor and Sensory Neuropathy in Mice.

The core component of the class III phosphatidylinositol 3-kinase complex, Beclin 1, takes part in different protein networks, thus switching its role from inducing autophagy to regulating autophagosomal maturation and endosomal trafficking. While assessed in neurons, astrocytes, and microglia, its role is far less investigated in myelinating glia, including Schwann cells (SCs), responsible for peripheral nerve myelination. Remarkably, the dysregulation in endosomal trafficking is emerging as a pathophysiological mechanism underlying peripheral neuropathies, such as demyelinating Charcot-Marie-Tooth (CMT) diseases. By knocking out Beclin 1 in SCs here a novel mouse model (Becn1 cKO) is generated, developing a severe and progressive neuropathy, accompanied by involuntary tremors, body weight loss, and premature death. Ultrastructural analysis revealed abated myelination and SCs displaying enlarged cytoplasm with progressive accumulation of intracellular vesicles. Transcriptomic and histological analysis from sciatic nerves of 10-day and 2-month-old mice revealed pro-mitotic gene deregulation and increased SCs proliferation at both stages with axonal loss and increased immune infiltration in adults, well reflecting the progressive motor and sensory functional impairment that characterizes Becn1 cKO mice, compared to controls. The study establishes a further step in understanding key mechanisms in SC development and points to Beclin 1 and its regulated pathways as targets for demyelinating CMT forms.

Replace part of regenerative rice silage feed with whole cottonseed enhances growth performance and nutrient digestibility via regulating gH/IGF axis in beef cattle

This work was designed to assess the impacts of whole cottonseed (WCs) on growth performance, nutrient digestion, GH /IGF-1 axis, and meat quality in beef cattle. Twenty-four healthy male simmental cattle (18 months old and 370.5 ± 12.5 kg) were arbitrarily classified into two groups (n=12 per group): Control group (without WCs) and WCs replaced group (part of regenerative rice silage was replaced with WCs). The dry matter intake (DMI) was declined(P < 0.01), while the average daily gain (ADG) was increased(P < 0.05), therefore the feed conversion ratio (FCR) was lower (P < 0.05) in WCs replaced group. Beef cattle consuming WCs had a higher digestibility of total gastrointestinal nutrients (P < 0.01 or P < 0.05). The growth hormone receptor (GHR), insulin-like growth factor 1 (IGF-1), and insulin-like growth factor 1 receptor (IGF-1R) mRNA amounts were all enhanced (P < 0.05) in liver, longissimus dorsi muscle, and semitendinosus muscle of beef cattle after feeding WCs relative to control group. The mRNA amounts of phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), and ribosomal protein S6 kinase beta-1 (S6K1) and the protein phosphorylation levels of Akt、mTOR, and S6K1 were all markedly enhanced (P < 0.05 or P < 0.01) in liver, longissimus dorsi muscle, and semitendinosus muscle for WCs replacement. The shear force and cooking loss values having somewhat raised(P < 0.05) for WCs replacement. Altogether, WCs improves the growth performance and nutrient digestibility via regulating GH/IGF axis in beef cattle, and has negative effects on meat quality.

Combined bisoprolol and trimetazidine ameliorate arsenic trioxide -induced acute myocardial injury in rats: targeting PI3K/GSK-3β/Nrf2/HO-1 and NF-κB/iNOS signaling pathways, inflammatory mediators and apoptosis

Background Arsenic-trioxide (ATO) is an effective therapy for acute promyelocytic leukemia. Unfortunately, its utility is hindered by the risk of myocardial injury. Both bisoprolol (BIS) and trimetazidine (TMZ) have various pharmacological features, including anti-oxidant, anti-inflammatory, and anti-apoptotic properties. Aim The cardioprotective effects of BIS and TMZ were studied, and their mechanistic role in ameliorating ATO-induced myocardial injury. Materials and Methods Forty male Wistar rats were randomly allotted into five groups as follows: normal control group (received normal saline, orally), ATO group (7.5 mg/kg, orally), BIS (8 mg/kg, orally), TMZ (60 mg/kg, orally), and finally combination group (BIS+TMZ+ATO). Following 21 days, samples of serum and cardiac tissues were obtained to perform biochemical, molecular, and histopathological investigations. Results The present study showed that ATO caused myocardial injury evidenced by changes in serum biomarkers (Aspatate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, creatine kinase-MB, and cardiac troponin-1), electrolyte imbalance, and lipid profiles alongside histopathologic changes. In addition, ATO administration significantly elevated malondialdehyde, nicotinamide adenine dinucleotide phosphate hydrogen oxidase, myloperoxidase, total nitrite, inducible nitric oxide synthase, tumor necrosis factor-alpha, interleukin-1β, interleukin-6, 8-Hydroxy-2’-deoxyguanosine, nuclear factor NF-kappa-B p65 subunit, glycogen synthase kinase-3 beta, and caspase-3 expression contemporaneously with down-regulation of reduced glutathione, glutathione peroxidase, superoxide dismutase, catalase, heme oxygenase 1, nuclear factor erythroid 2–related factor 2, phosphatidylinositol-3 kinase, p-PI3K, and Bcl-2 expression. Interestingly, pretreatment with BIS and TMZ significantly reversed the detrimental effects of ATO-induced myocardial injury at both cellular and molecular levels. Otherwise, combining the two drugs displayed more enhancement than each drug alone. Conclusion The present research depicted that BIS and TMZ have the potential to protect the heart and provide therapeutic benefits by preventing acute heart injury induced by ATO. This is achieved by reversing the redox-sensitive pathway, reducing inflammation, and inhibiting apoptosis.

2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione mediates the effect of ROS-enhanced PI3K/Akt/mTOR pathway on autophagy in breast cancer.

Several studies have suggested a potential antitumor effect of 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD). To further understand the mechanism of action of this compound, we investigated its effect on the phosphatidylinositol-3-kinase (PI3K)/serine-threonine kinase (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. We show that DMDD application significantly inhibited the proliferation of breast cancer cell lines MDA-MB-231 and ER-α positive MCF-7. Furthermore, DMDD application resulted in increased intracellular reactive oxygen species (ROS) levels, apoptosis and autophagy, whereas it downregulated the expression of PI3K, Akt and mTOR mRNA and proteins, and increased the expression of LC3II/I and p62 proteins. In a mouse breast cancer xenograft model, DMDD inhibited tumor growth. Expression analyses suggest that ROS levels were higher in DMDD treated tumor tissues, whereas immunohistochemical analyses suggest that apoptotic cells were more prevalent in the DMDD treated group compared to the control group. Taken together, our results suggest that the molecular mechanism of action of DMDD may involve the enhancement of breast cancer autophagy through the PI3K/Akt/mTOR signaling pathway by mediating ROS expression.

MicroRNAs Dependent G-ELNs Based Intervention Improves Glucose and Fatty Acid Metabolism While Protecting Pancreatic β-Cells in Type 2 Diabetic Mice.

Metabolic disorders such as Type 2 diabetes mellitus (T2DM) imposes a significant global health burden. Plant-derived exosome like nanoparticles (P-ELNs) have emerged as a promising therapeutic alternate for various diseases. Present data demonstrates that treatment with Ginger-derived exosome like nanoparticles (G-ELNs) enhance insulin dependent glucose uptake, downregulate gluconeogenesis and oxidative stress in insulin resistant HepG2 cells. Furthermore, oral administration of G-ELNs in T2DM mice decreases fasting blood glucose levels and improves glucose tolerance as effectively as metformin. These improvements are attributed to the enhanced phosphorylation of Protein kinase B (Akt-2), the phosphatidylinositol 3-kinase at serine 474 which consequently leads to increase in hepatic insulin sensitivity, improvement in glucose homeostasis and decrease in ectopic fat deposition. Oral administration of G-ELNs also exerts protective effect on Streptozotocin (STZ)-induced pancreatic β-cells damage, contributing to systemic amelioration of T2DM. Further, as per computational tools, miRNAs present in G-ELNs modulate the phosphatidylinositol 3-kinase (PI3K)/Akt-2pathway and exhibit strong interactions with various target mRNAs responsible for hepatic gluconeogenesis, ectopic fat deposition and oxidative stress. Furthermore, synthetic mimic of G-ELNs miRNA effectively downregulates its target mRNA in insulin resistant HepG2 cells. Overall, the results indicate that the miRNAs present in G-ELNs target hepatic metabolism thus, exerting therapeutic effects in T2DM.

Delta opioid receptor agonists activate PI3K-mTORC1 signaling in parvalbumin-positive interneurons in mouse infralimbic prefrontal cortex to exert acute antidepressant-lie effects.

The delta opioid receptor (DOP) is a promising target for novel antidepressants due to its potential for rapid action with minimal adverse effects; however, the functional mechanism underlying acute antidepressant actions remains elusive. We report that subcutaneous injection of the selective DOP agonist KNT-127 reduced immobility in the forced swimming test, and that this antidepressant-like response was reversed by intracerebroventricular injection of the selective mechanistic (or mammalian) target of rapamycin (mTOR) inhibitor rapamycin or the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002. KNT-127 also alleviated social avoidance and reduced sucrose consumption (anhedonia) among chronic vicarious social defeat stress model mice, which were similarly reversed by PI3K and mTOR inhibitors. In addition, KNT-127 increased phosphorylation levels of the mTOR signaling-related proteins Akt and p70S6 kinase in medial prefrontal cortex as revealed by immunoblotting. In the forced swimming test, a microinfusion of KNT-127 and another DOP agonist SNC80 in the infralimbic prefrontal cortex (IL-PFC) attenuated the immobility, which were blocked by rapamycin and LY294002. Perfusion of KNT-127 onto IL-PFC slices increased miniature excitatory postsynaptic current frequency and reduced miniature inhibitory postsynaptic current frequency in pyramidal neurons as measured by whole-cell patch-clamping, and both responses were reversed by rapamycin. Imaging of brain slices from transgenic mice with DOP-promoter-driven green fluorescent protein revealed that most DOPs were expressed in parvalbumin-positive interneurons in the IL-PFC. These findings suggest that DOP agonists exert antidepressant-like actions by suppressing GABA release from parvalbumin-positive interneurons via the PI3K-Akt-mTORC1-p70S6 kinase pathway, thereby enhancing IL-PFC pyramidal neuron excitation.

Potassium molybdate blocks APN-dependent coronavirus entry by degrading receptor via PIK3C3-mediated autophagy.

Swine enteric coronaviruses pose a significant challenge to the global pig industry, inflicting severe diarrhea and high mortality rates among piglets, and resulting in substantial economic losses. In our clinical practice, we observed that the addition of potassium molybdate (PM) to the feed could dramatically reduce diarrhea and diarrhea-related mortality in piglets. However, the underlying mechanisms remain elusive and merit further investigation. In this study, we revealed that PM effectively inhibited the infection of both aminopeptidase N (APN)-dependent coronaviruses, transmissible gastroenteritis virus (TGEV), and porcine respiratory coronavirus (PRCV), both in vitro and ex vivo. Specifically, PM was found to block TGEV and PRCV penetration by degrading the cell receptor APN through the upregulation of phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) expression. In addition, knockdown and knockout of PIK3C3 resulted in the attenuation of PM-induced autophagy, thereby rescuing APN expression and viral infection. Correspondingly, replenishment of PIK3C3 in PIK3C3-null ST cells restored PM-mediated APN degradation and successfully blocked viral entry. Furthermore, our findings demonstrated that PM promoted the assembly of the PIK3C3-BECN1-ATG14 complex, leading to induced autophagic degradation by upregulating PIK3C3 Ser249 phosphorylation. In vivo experiments further confirmed that PM-induced PIK3C3-mediated autophagic degradation of APN, thereby limiting the pathogenicity of TGEV. In summary, our study for the first time identified the mechanism by which PM blocked TGEV and PRCV internalization by degrading the cell receptor APN via PIK3C3-mediated autophagy. This study provides valuable insights and potential strategies for preventing APN-restricted coronavirus infection.IMPORTANCEAminopeptidase N (APN) is one of the most important host receptors of coronavirus. Modulating APN expression can represent a novel approach for controlling APN-dependent coronaviruses and their variants infection. Here we found that a chemical compound potassium molybdate (PM) negatively regulates APN expression by inducing phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3)-mediated autophagy against APN-dependent coronavirus internalization, including transmissible gastroenteritis virus (TGEV) and porcine respiratory coronavirus (PRCV). Furthermore, PM can promote PIK3C3-BECN1-ATG14 complex assembly to induce autophagic degradation of APN by upregulating PIK3C3 Ser249 phosphorylation. Lastly, results from pig experiments also confirmed that PM can trigger PIK3C3-mediated autophagic degradation of APN to restrict TGEV pathogenicity in vivo without toxicity. Our findings underscore the promising potential of PM as an effective agent against APN-dependent coronavirus and potentially emerging viral disease entry.

Synthesis of Novel Derivatives of 4,6-Diarylpyrimidines and Dihydro-Pyrimidin-4-one and In silico Screening of Their Anticancer Activity

: Derivatives of pyrimidinone, dihydropyrimidinone, and 2,4-diaryl-substituted pyrimidines were synthesized by cyclocondensation of α-aminoamidines with various sat-urated carbonyl derivatives and their analogs. The therapeutic potential of the newly syn-thesized derivatives for cancer treatment was evaluated using molecular docking calcula-tions. The molecular docking results indicate that some of the synthesized diaryl deriva-tives of pyrimidine exhibit high binding affinity towards PIK3γ. Aim and Objective: 4,6-Diaryl-substituted pyrimidines have shown high inhibitory poten-cy against phosphoinositide 3-kinases (PI3Ks), which are important targets in oncology. Inhibition of PI3Ks could potentially be a viable therapy for human cancers. Materials and Methods: The synthesis of pyrimidinone and dihydropyrimidinone deriva-tives as well as a series of 2,4-diaryl-substituted pyrimidines were described. These com-pounds were synthesized by cyclocondensation of α-aminoamidines with various saturated carbonyl derivatives and their analogs. Results: Derivatives of pyrimidinone, dihydropyrimidinone, and 2,4-diaryl-substituted py-rimidines were synthesized by combining α-aminoamidines with various saturated car-bonyl derivatives and their analogs. By adjusting the large substituents in the 2-position, we gained the ability to modify the therapeutic properties of the resulting compounds. The potential of the newly synthesized derivatives for cancer treatment was assessed using mo-lecular docking calculations. The results of the docking calculations suggest that some of the synthesized diaryl derivatives of pyrimidine have a strong binding affinity towards PIK3γ, making them promising candidates for the development of new anticancer medica-tions. Conclusion: We synthesized some pyrimidinones, dihydropyrimidinones, and 2,4-diaryl-substituted pyrimidines by combining α-aminoamidines with various saturated carbonyl derivatives and similar compounds. Molecular docking results suggest that certain diaryl derivatives of pyrimidine have a strong binding affinity for PIK3γ. Moreover, diphenyl de-rivatives of pyrimidine exhibited dual inhibitory activity against PI3K and tubulin, show-ing promise for the development of next-generation microtubule-targeting agents for use in combination therapies.

Discovery of CHF-6523, an Inhaled Selective PI3Kδ Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease.

The design of inhaled selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitors for the treatment of inflammatory lung diseases was pursued. Knowledge-based design of a novel isocoumarin scaffold that was able to adopt a propeller-shape topology ensured the desired PI3Kδ selectivity. Achievement of low nanomolar cellular potencies through hinge binder group optimization, reduction of intrinsic permeability through head group optimization to extend lung retention, and screening of crystalline forms suitable for administration as dry powders culminated in the identification of compound 18. This novel inhaled selective PI3Kδ inhibitor displayed durable anti-inflammatory activity in a disease-relevant rat model of Th-2-driven acute lung inflammation and safe in vitro and in vivo preclinical profiles. Therefore, compound 18 showed the appropriate discovery profile and was progressed to clinical trials in healthy volunteers and chronic obstructive pulmonary disease (COPD) patients as CHF-6523.

Genetic Etiologies and Outcomes in Malignancy and Mortality in Activated Phosphoinositide 3-Kinase Delta Syndrome: A Systematic Review.

This analysis evaluated literature on patients with activated phosphoinositide 3-kinase delta syndrome (APDS) to better understand the genetic etiologies and occurrence of mortality in this population. A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses approach, including all articles published in English prior to March 13, 2023, in PubMed and Embase. Patients included in the study had reported either (1) APDS diagnosis or (2) ≥ 1 clinical sign consistent with APDS and a first-degree relative with genetically confirmed APDS. Reported age at last observation was also a required outcome. Publications not meeting these criteria were excluded. Data were summarized using descriptive statistics. The search identified 108 publications describing 351 unique patients with 39 distinct disease-causing variants. Among these, 41 (12%) deaths were reported, with a mean age at last follow-up of 19.6 (range, 1-64) years. A cause of death was reported for 80% (33/41) of deaths; lymphoma (24%, 10/41) and infections (22%, 9/41) were the most common causes. Types of infections causing death were severe uncontrollable infections (n = 3), sepsis (n = 2), viral infection (varicella zoster pneumonitis [n = 1], cytomegalovirus and adenovirus [n = 1], and Epstein-Barr virus [n = 1]), and infection (n = 1). Mean age at death for lymphoma was 24.9 (range, 1-41) years, and all nine patients who died from infections died before the age of 15 years. The mean age at first APDS symptom was 2.0 (range, < 1-22) years, and mean age at APDS diagnosis was 13.4 (range, 0-56) years; the mean time between symptoms and diagnosis was 10.6 (range, 0-44) years. Limitations of the study were primarily related to the data source. Patients with APDS suffer early mortality, largely from lymphoma and infection, with large time gaps between symptoms and diagnosis. These findings highlight the need for improved diagnostics, earlier genetic testing for APDS, increased awareness of familial testing, and targeted therapies.

PDGFRα signaling regulates Srsf3 transcript binding to affect PI3K signaling and endosomal trafficking.

Signaling through the platelet-derived growth factor receptor alpha (PDGFRα) plays a critical role in craniofacial development. Phosphatidylinositol 3-kinase (PI3K)/Akt is the primary effector of PDGFRα signaling during mouse skeletal development. We previously demonstrated that Akt phosphorylates the RNA-binding protein serine/arginine-rich splicing factor 3 (Srsf3) downstream of PI3K-mediated PDGFRα signaling in mouse embryonic palatal mesenchyme (MEPM) cells, leading to its nuclear translocation. We further showed that ablation of Srsf3 in the murine neural crest lineage results in severe midline facial clefting and widespread alternative RNA splicing (AS) changes. Here, we demonstrated via enhanced UV-crosslinking and immunoprecipitation of MEPM cells that PDGF-AA stimulation leads to preferential binding of Srsf3 to exons and loss of binding to canonical Srsf3 CA-rich motifs. Through the analysis of complementary RNA-seq data, we showed that Srsf3 activity results in the preferential inclusion of exons with increased GC content and lower intron to exon length ratio. We found that Srsf3 activity downstream of PDGFRα signaling leads to retention of the receptor in early endosomes and increases in downstream PI3K-mediated Akt signaling. Taken together, our findings reveal that growth factor-mediated phosphorylation of an RNA-binding protein underlies gene expression regulation necessary for mammalian craniofacial development.

PDGFRα signaling regulates Srsf3 transcript binding to affect PI3K signaling and endosomal trafficking

Signaling through the platelet-derived growth factor receptor alpha (PDGFRα) plays a critical role in craniofacial development. Phosphatidylinositol 3-kinase (PI3K)/Akt is the primary effector of PDGFRα signaling during mouse skeletal development. We previously demonstrated that Akt phosphorylates the RNA-binding protein serine/arginine-rich splicing factor 3 (Srsf3) downstream of PI3K-mediated PDGFRα signaling in mouse embryonic palatal mesenchyme (MEPM) cells, leading to its nuclear translocation. We further showed that ablation of Srsf3 in the murine neural crest lineage results in severe midline facial clefting and widespread alternative RNA splicing (AS) changes. Here, we demonstrated via enhanced UV-crosslinking and immunoprecipitation of MEPM cells that PDGF-AA stimulation leads to preferential binding of Srsf3 to exons and loss of binding to canonical Srsf3 CA-rich motifs. Through the analysis of complementary RNA-seq data, we showed that Srsf3 activity results in the preferential inclusion of exons with increased GC content and lower intron to exon length ratio. We found that Srsf3 activity downstream of PDGFRα signaling leads to retention of the receptor in early endosomes and increases in downstream PI3K-mediated Akt signaling. Taken together, our findings reveal that growth factor-mediated phosphorylation of an RNA-binding protein underlies gene expression regulation necessary for mammalian craniofacial development.

The Mitochondrial Fusion Promoter M1 Mitigates Cigarette Smoke-Induced Airway Inflammation and Oxidative Stress via the PI3K-AKT Signaling Pathway.

This study investigated the efficacy and underlying mechanism of the mitochondrial fusion promoter M1 in mitigating cigarette smoking (CS)-induced airway inflammation and oxidative stress both in vitro and in vivo models. Cigarette smoke extract (CSE)-treated airway epithelial cells (BEAS-2B) and CS-exposed mice were pretreated with M1, followed by the measurement of proinflammatory cytokines, oxidative stress, mitochondrial fusion proteins (MFN2 and OPA1) and fission proteins (DRP1 and MFF). Molecular pathways were elucidated through transcriptomic analysis and Western blotting. M1 pretreatment in CSE-treated cells significantly reduced the release of inflammatory cytokines (interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-α); reduced malondialdehyde (MDA) and reactive oxygen species (ROS) levels; increased superoxide dismutase (SOD) activity; protected mitochondrial function by increasing the expression of mitochondrial fusion proteins (MFN2 and OPA1) and decreasing the expression of mitochondrial fission proteins (DRP1 and MFF). M1 attenuated CS-induced lung histologic damage and mucus hypersecretion in mice, relieved high oxidative stress and reduced the release of IL-6 and IL-8 in BALF. Similarly, it also protected mitochondrial function by regulating the CS-induced imbalance of mitochondrial dynamic proteins. Transcriptome sequencing and Western blotting showed that M1 inhibited CSE- or CS-induced activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway. M1 plays a protective role in inflammation, oxidative stress and mitochondrial dynamics dysfunction caused by CS by inhibiting the PI3K-AKT signaling pathway; thus, it has therapeutic potential for the treatment of CS-induced airway disorders.

Prognostic and clinicopathological significance of survivin in gynecological cancer.

Survivin belongs to the inhibitor of apoptosis protein (IAP) family and is encoded by the baculoviral inhibitor of apoptosis repeat-containing, or BIRC5, gene. It is preferentially expressed in cancers with functional complexity in cell signaling cascades such as extracellular signal-regulated kinases (ERK), mitogen-activated protein kinases (MAPK), heat shock protein-90 (HSP90), epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase (PI3K), signal transducer and activator of transcription (STAT), hypoxia-inducible factor-1 alpha (HIF-1α), vascular endothelial growth factor (VEGF), and others. Survivin plays a role in cell division and cell death, properties that have attracted a large body of research to decipher its therapeutic and prognostic significance in cancer. Survivin has tumor-promoting effects in endometrial (EC) and ovarian (OC) cancers, and its upregulation in endometrial cancer has been associated with poor overall survival (OS). While survivin protein is abundantly expressed in OC, it is barely detectable in normal ovarian tissue or benign ovarian tumors. Survivin expression is also a marker for cervical intraepithelial neoplasia (CIN) and high-risk human papillomavirus, and a predictor of viral clearance and prognosis in uterine cervical cancer (UCC). Furthermore, nuclear survivin expression is very low in normal vulvar squamous epithelium and increases to become abundant in vulvar invasive squamous cell carcinoma (ISCC), conferring resistance to apoptosis in vulvar carcinogenesis. In this review, we discuss in detail the impact of survivin signaling on gynecological cancers and provide insight on its therapeutic and diagnostic potential, existing research gaps, and areas for future research.

Sodium alginate based piezoelectric hydrogel for promoting healing of infected wounds at movable parts

The frequent movement is an obstacle to the healing of wounds at movable parts. It would be highly beneficial if this characteristic could be utilized to accelerate wound healing process. Herein, we developed a sodium niobate (NNO) hydrogel (NNO-Gel) for promoting healing process of wounds at movable parts based on its photodynamic and piezoelectric properties. NNO-Gel is formed through incorporating NNO into polyvinyl alcohol‑sodium alginate hydrogel using calcium chloride as a cross-linking agent. NNO-Gel could not only produce reactive oxygen species for bacteria inactivation with simulated sunlight irradiation, but also generate electric field for promoting cell migration and proliferation through the frequent movement of necks. With simulated sunlight irradiation, NNO-Gel could kill 95.6 % ± 1.4 % of bacteria, 9.3 % higher than NNO nanomaterials. The cell proliferation rate reaches 148.41 ± 6.37 % by NNO nanomaterials with ultrasound irradiation through activating and phosphorylating phosphoinositide 3-kinase and protein kinase B. For infected neck wounds, NNO NMs and NNO-Gel show 23.6 ± 5.1 % and 25.3 ± 6.1 % higher healing rate than PBS treated ones. The development of NNO-Gel provides an opportunity for transforming the negative frequent movement which prevents wound healing into motive power for promoting healing of wound at movable parts, as well as the possibility of clinic applications for piezoelectric nanomaterials.

Novel Natural Inhibitors for Glioblastoma by Targeting Epidermal Growth Factor Receptor and Phosphoinositide 3-kinase.

Glioblastoma is an extensively malignant neoplasm of the brain that predominantly impacts the human population. To address the challenge of glioblastoma, herein, we have searched for new drug-like candidates by extensive computational and biochemical investigations. Approximately 950 compounds were virtually screened against the two most promising targets of glioblastoma, i.e., epidermal growth factor receptor (EGFR) and phosphoinositide 3-kinase (PI3K). Based on highly negative docking scores, excellent binding capabilities and good pharmacokinetic properties, eight and seven compounds were selected for EGFR and PI3K, respectively. Among those hits, four natural products (SBEH-40, QUER, QTME-12, and HCFR) exerted dual inhibitory effects on EGFR and PI3K in our in-silico analysis; therefore, their capacity to suppress the cell proliferation was assessed in U87 cell line (type of glioma cell line). The compounds SBEH-40, QUER, and QTME-12 exhibited significant anti-proliferative capability with IC50 values of 11.97 ± 0.73 μM, 28.27 ± 1.52 μM, and 22.93 ± 1.63 μM respectively, while HCFR displayed weak inhibitory potency (IC50 = 74.97 ± 2.30 μM). This study has identified novel natural products that inhibit the progression of glioblastoma; however, further examinations of these molecules are required in animal and tissue models to better understand their downstream targeting mechanisms.

Neurotrophin-3 Rescues Striatal Synaptic Plasticity in Model of Neurodegeneration by PLC Signaling Activation.

Neurotrophins are essential factors for neural growth and function; they play a crucial role in neurodegenerative diseases where their expression levels are altered. Our previous research has demonstrated changes in synaptic plasticity and neurotrophin expression levels in a pharmacological model of Huntington's disease (HD) induced by 3-nitropropionic acid (3-NP). In the 3-NP-induced HD model, corticostriatal Long Term Depression (LTD) was impaired, but neurotrophin- 3 (NT-3) restored striatal LTD. This study delves into the NT-3-induced signaling pathways involved in modulating and restoring striatal synaptic plasticity in cerebral slices from 3-NPinduced striatal degeneration in mice in vivo. Phospholipase C (PLC), phosphatidylinositol-3-kinase (PI3K), and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways activated by NT-3 were analyzed by means of field electrophysiological recordings in brain slices from control and 3-NP treated in the presence of specific inhibitors of the signaling pathways. Using specific inhibitors, PLC, PI3K, and MEK/ERK signaling pathways contribute to NT-3-mediated plasticity modulation in striatal tissue slices recorded from control animals. However, in the neurodegeneration model induced by 3-NP, the recovery of striatal LTD induced by NT-3 was prevented only by the PLC inhibitor. Moreover, the PLC signaling pathway appeared to trigger downstream activation of the endocannabinoid system, evidenced by AM 251, an inhibitor of the CB1 receptor, also hindered NT-3 plasticity recovery. Our finding highlights the specific involvement of the PLC pathway in the neuroprotective effects of NT-3 in mitigating synaptic dysfunction under neurodegenerative conditions.

The role of protein kinase C and the glycoprotein Ibα cytoplasmic tail in anti-glycoprotein Ibα antibody-induced platelet apoptosis and thrombocytopenia

IntroductionImmune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts. ITP patients with anti-platelet glycoprotein (GP) Ibα (a subunit of GPIb-IX-V complex) autoantibodies, which induce Fc-independent signaling and platelet clearance, are refractory to conventional treatment. Protein kinase C (PKC) is activated by the binding of the ligand von Willebrand factor to GPIbα and regulates VWF-GPIbα-induced platelet activation. However, the role of PKC in anti-GPIbα antibody-induced thrombocytopenia remains unknown. Materials and methodsThe anti-GPIbα antibody-induced PKC activation and its underlying mechanisms were first detected by Western blot, and then the effects of PKC inhibitors, PKC knockout, or GPIbα C-terminal removal on anti-GPIbα antibody-induced platelet apoptosis, activation, aggregation, and clearance were investigated by flow cytometry, platelet aggregometry, and platelet posttransfusion, respectively. Meanwhile, platelet retention and co-localization with macrophages in the liver were detected by spinning disc intravital confocal microscopy. ResultsAnti-GPIbα antibody-induced PKC activation depends on GPIbα clustering and phosphoinositide 3-kinase (PI3K) activation and results in Akt phosphorylation. Pharmacologic inhibition or genetic ablation of PKC suppresses anti-GPIbα antibody-induced platelet apoptosis and activation. Moreover, the GPIbα cytoplasmic tail is required for antibody-induced PKC activation, platelet apoptosis, and activation. Inhibition or ablation of PKC and deletion of the GPIbα cytoplasmic tail protect platelets from clearance in vivo. ConclusionsOur study indicates the important role of PKC and the GPIbα cytoplasmic tail in anti-GPIbα antibody-mediated platelet signaling and clearance and suggests a novel therapeutic target for ITP and other thrombocytopenic diseases.

STING agonists and PI3Kγ inhibitor co-loaded ferric ion-punicalagin networks for comprehensive cancer therapy

Nanoparticles-based drug delivery system has been a promising approach for the treatment of colorectal cancer (CRC), which can be combined with chemotherapy, targeted therapy and immunotherapy to improve the treatment of CRC. 2′3’ cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) is an agonist of the STING signaling pathway activating antitumor immunity. IPI-549 is a small-molecule inhibitor for phosphatidylinositol 3-kinase γ (PI3Kγ), which can induce M1 macrophages polarization to provide pro-inflammatory microenvironment to suppress tumors. Here, we developed a ferric ion-punicalagin network (Fe-PU), which can be not only used as an inducer of ferroptosis, but also serve as a carrier to load cGAMP and IPI-549 to obtain nanohybrid (Fe-PU/CD-IPI). In order to improve the delivery effect and targeted ability to CRC, a cyclic arginine-glycine-aspartic acid peptide linked-bovine serum albumin were utilized to modify Fe-PU/CD-IPI to prepare nanohybrid Fe-PU/CD-IPI@cBSA. The therapeutic effect of various nanohybrids were validated in the mice with spontaneous tumor in the colorectal area and tumor-bearing mice, which lead to the increase of ferroptosis, the activation of STING signaling pathway, and the repolarization of macrophages. Collectively, the cGAMP and IPI-549 co-loaded nanohybrids effectively reshaped the tumor immune microenvironment, and exhibited prominent treatment effect of anti-colorectal cancer in vitro, patient-derived organoids, and in vivo.

Fhl1, a new spatially specific protein, regulates vein graft neointimal hyperplasia.

Vein grafts are commonly employed in revascularisation surgery for multivessel coronary artery disease, yet neointimal hyperplasia (NIH) remains a critical impediment to the long-term patency of these grafts. Despite this, effective methods to precisely identify and target interventions for the neointima are still inadequate. In this study, Sprague-Dawley (SD) rats were used to establish an external jugular vein transplantation model, and the NIH pathophysiological process was tracked across 11 time points (0-35 days) using various histological stains. Spatial transcriptomics was performed on normal veins and 19-day grafts to explore gene expression in neointimal regions. Immunohistochemical analysis identified neointima-specific markers, while NIH progression was assessed in SD rats with four and a half LIM domains protein 1 (Fhl1) knockout and in human saphenous veins (HSV) with adenovirus-mediated Fhl1 overexpression. Typical neointimal formation commenced by day 11 postgrafting and peaked at day 19. Neointimal cells originated from newly generated α-SMA(+) repair cells located outside the grafted vein, displaying a hybrid fibroblast-smooth muscle cell phenotype. Spatial transcriptomics identified stable and sustained Fhl1 expression within the neointima throughout the entire NIH phase. Systemic knockout of Fhl1 in SD rats via the phosphoinositide 3-kinase pathway exacerbated graft inflammation, heightened cell proliferation, and accelerated NIH. Conversely, FHL1 overexpression in cultured HSV suppressed NIH. These findings indicate that, following grafting into the arterial system, the newly formed repair cells external to the grafted vein play a pivotal role in NIH, with neointimal cells exhibiting stable and continuous Fhl1 expression. Fhl1 serves as a protective factor against NIH both in vivo and in HSV, likely due to its anti-inflammatory and anti-proliferative effects. This study firstly used spatial transcriptomics technique to analyse the neointima and generated a specific neointimal transcriptomic atlas. Fhl1 exhibits specific and stable expression in the spatial region of the neointima. It has thus far the highest enrichment of expression in the neointima in NIH phases, suggesting that it is a prominent molecular biomarker of neointima. We generated rats with a Fhl1 deletion and found that insufficient Fhl1 expression caused an increase in the severity of vascular inflammation and proliferation during neointimal hyperplasia. Adenovirus-mediated FHL1 overexpression in human saphenous vein have beneficial effects in preventing neointimal hyperplasia. These highlight its potential as a therapeutic target for mitigating vein graft failure associated with cardiovascular procedures. Spatial transcriptomics profiles and morphological observations demonstrated that a newly generated cell population outside the grafted vein with hybrid phenotype between SMCs and fibroblasts contributes to neointimal formation.