Current Molecular Pharmacology - Current Issue

Increasing evidence has highlighted the involvement of the imbalance of long non-coding RNAs in the development of gastric cancer (GC), which is one of the most common malignancies in the world. This study aimed to determine the role of lncRNA WT1-AS in the progression of GC and explore its underlying mechanism.

The expression of lncRNA WT1-AS in gastric cancer tissues was detected using RT-qPCR. We knocked down the expression of WT1-AS in GC cells or treated them with rapamycin or both. Then, transwell assay and scratch assay were carried out to determine the migration of GC cells, and flow cytometry was carried out to determine the cell cycle. The immunofluorescence technique was used to determine the autophagy, and a tumor formation experiment was carried out to determine tumor growth in vivo. The expression of factors related to the PI3K/Akt/mTOR pathway was also measured by Western Blotting.

In GC tissues and cells, lncRNA WT1-AS was underexpressed. Moreover, overexpression of lncRNA WT1-AS blocked the PI3K/Akt/mTOR pathway. Upregulation of lncRNA WT1-AS or inhibition of the PI3K/Akt/mTOR pathway suppressed cancer cell migration in vitro, leading to cell cycle arrest, and promoted autophagy while inhibiting tumor growth in vivo. It also reduced the expression levels of Ki-67, MMP2, MMP9, and VEGF. The WT1-AS+rapamycin group was the most prominent in all experiments.

The upregulation of lncRNA WT1-AS could suppress the PI3K/Akt/mTOR pathway, which inhibits cell migration and cell cycle arrest while promoting autophagy in gastric cancer cells.

Allergic Rhinitis (AR) is an inflammatory condition characterized by nasal mucosa remodeling, driven by Immunoglobulin E (IgE). Platycodin D (PLD) exhibits a wide range of bioactive properties.

The aim of this work was to investigate the potential protective effects of PLD on AR, as well as the underlying mechanisms.

The anti-allergic and anti-inflammatory potential of PLD was investigated in an ovalbumin-sensitized AR mouse model and human nasal mucosa cells (HNEpC) challenged with interleukin-13 combined with PLD. Our assessment included an examination of nasal symptoms, tissue pathology, and goblet cell hyperplasia. The levels of IgE, Interferon-gamma (IFN-γ), and interleukin-4 in the serum were detected using Enzyme-linked Immunosorbent Assay (ELISA). Furthermore, quantitative Real-time Polymerase Chain Reaction (RT-PCR) and ELISA were employed to determine the expressions of IL-1β, Tumor Necrosis Factor-alpha (TNF-α), and IL-6 in in vivo and in vitro settings. Western blot analysis was conducted to investigate the changes in DPP4/JAK2/STAT3 in vivo and in vitro.

Our results demonstrated that oral administration of PLD significantly ameliorated nasal symptoms in AR mice, improved histopathological changes in the nasal mucosa, raised the level of IFN-γ, and reduced IgE as well as IL-4 levels in the serum. PLD inhibited the expressions of IL-1β, IL-6, TNF-α, and DPP4 in in vivo and in vitro settings. Notably, PLD modulated the changes in DPP4, p-JAK2, and p-STAT3 induced by IL-13 in HNEpC cells and AR mice.

The findings suggested the potential of PLD as a therapeutic agent for the treatment of AR.

Finasteride and doxazosin are used for the treatment of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). Epithelial–mesenchymal transition (EMT) and TGF-β/Smad signaling pathway play an important role in BPH, little is known about the growth inhibition and anti-fibrosis effects of doxazosin on the regulation of EMT and morphology in the prostate.

The present study examined the effects of doxazosin on testosterone propionate (TP)-induced prostate growth in vivo and in vitro and its impact on the EMT and TGF-β/Smad signaling pathway.

Mice were treated with TP. Doxazosin (5 or 10 mg/kg) and finasteride (10 mg/kg) were administered orally for 28 days in TP-induced mice. The prostate index (prostate/body weight ratio), morphological characteristics and the protein expression of the prostate were examined. We further examined the effects of doxazosin and finasteride on the EMT and TGF-β/Smad signaling pathway in mice and in human prostate stroma cell (WPMY-1). The protein expressions of TGF-β1, TGFBR2, p-Smad2/3, N-cadherin, vimentin, fibronectin and α-SMA, E-cadherin and prostate specific antigen (PSA) were determined after treatment by western blot.

The prostate wet weight, prostate index decreased after treatment. Doxazosin (5 or 10 mg/kg), finasteride (10 mg/kg) or a combination treatment (doxazosin 10 mg/kg + finasteride 10 mg/kg) were shown to reverse the pathological and morphological characteristics of the prostate. Doxazosin and finasteride inhibited TP-induced prostate growth, EMT, and the TGF-β/Smad signaling pathway by downregulating the expression of TGF-β1, TGFBR2, p-Smad2/3, N-cadherin, vimentin, fibronectin and α-SMA, whereas expression of E-cadherin was increased after treatment with either doxazosin or finasteride. Doxazosin (1-50 μM) inhibited normal human prostate stroma cell growth (WPMY-1) after 48 h with or without testosterone treatment. Doxazosin also regulated the EMT and proteins related to the TGF-β/Smad signaling pathway in WPMY-1 cells after 24 h. Additionally, doxazosin decreased protein expression of the PSA both in vivo and in vitro.

This study demonstrated that doxazosin inhibits prostate growth by regulating the EMT and TGF-β/Smad signaling pathways in the prostate. This finding suggests that doxazosin has potential as a new signaling pathway for the treatment of BPH.

Autism is a neurodevelopmental disorder associated with mitochondrial dysfunction, apoptosis, and neuroinflammation. These factors can lead to the overactivation of c-JNK and p38MAPK.

In rats, stereotactic intracerebroventricular (ICV) injection of propionic acid (PPA) results in autistic-like characteristics such as poor social interaction, repetitive behaviours, and restricted communication. Research has demonstrated the beneficial effects of phytochemicals derived from plants in treating neurological disorders. Tanshinone-IIA (Tan-IIA) is a chemical found in the root of Salvia miltiorrhiza. It has neuroprotective potential by inhibiting c-JNK and p38MAPK against behavioral and neurochemical alterations in PPA-induced autistic rats. We observe behavioral changes, alterations in apoptotic markers, myelin basic protein (MBP), neurofilament-Light (NEFL), inflammatory cytokines, brain-derived neurotrophic factor (BDNF), and neurotransmitter imbalances using different brain regions (cerebral cortex, hippocampus, striatum), as well as biological samples, cerebrospinal fluid (CSF), and blood plasma.

Persistent administration of 30 mg/kg and 60 mg/kg Tan-IIA via intraperitoneal injection reduced these alterations dose-dependently. Anisomycin (3 mg/kg.,i.p.) as a SAPK (c-JNK and p38MAPK) agonist was administered to assess the neuroprotective effect of Tan-IIA in autistic rats. Tan-IIA's molecular interactions with c-JNK and p38MAPK were confirmed using silico analysis. We also observed gross morphological, histopathological, and Luxol Fast Blue (LFB) myelin straining changes in whole and coronal brain sections.

Thus, Tan-IIA has a neuroprotective potential by inhibiting the c-JNK and p38MAPK signalling pathways, which reduces the behavioral and neurochemical abnormalities induced by PPA in adult Wistar rats, indicating that current results should be studied further for the diagnosis and treatment of autism.

Cardiac fibrosis causes most pathological alterations of cardiomyopathy in diabetes and heart failure patients. The activation and transformation of cardiac fibroblasts (CFs) are the main pathological mechanisms of cardiac fibrosis. It has been established that Sirtuin1 (Sirt1) plays a protective role in the pathogenesis of cardiovascular disorders. This study aimed to ascertain the Sirt1 effect on the phenotypic transformation of CFs in diabetes and its possible mechanisms.

Type 1 diabetes was induced in 6-week-old male mice by subcutaneously injecting 50 mg/kg streptozotocin (STZ, i.p.). Western blotting, collagen staining, and echocardiography were performed to detect protein expression and assess cardiac fibrosis and function in vivo. We used high glucose (HG) to culture CFs prior to protein expression measurement in vitro.

Upregulation of Sirt1 expression effectively alleviated the degree of cardiac fibrosis by improving cardiac function in diabetic mice. In vitro experiments revealed that HG decreased the protein expression levels of Sirt1, but increased those of type I collagen and alpha-smooth muscle actin (α-SMA), as well as the transdifferentiation of fibroblasts into myofibroblasts. Further studies confirmed that downregulation of Sirt1 expression in the HG environment reduced the protein kinase-B (Akt) phosphorylation, thereby promoting the transdifferentiation of CFs into myofibroblasts coupled with the deterioration of cardiac function.

Diabetes mellitus leads to downregulation of Sirt1 protein expression in CFs and decreased Akt phosphorylation, which promotes the transdifferentiation of CFs into myofibroblasts, the pathological process of cardiac fibrosis, and mediates the incidence and development of diabetic cardiomyopathy.

This aims to assess the efficacy of 2', 3, 3, 5'-Tetramethyl-4'-nitro-2'H-1, 3'-bipyrazole (TMNB), a novel compound, in colitis treatment.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract with limited effective treatments available. The exploration of new therapeutic agents is critical for advancing treatment options.

To assess the effect of TMNB in alleviating symptoms of experimental colitis in mice and to compare its effectiveness with that of sulfasalazine, a standard treatment.

Experimental colitis was induced in mice, which were subsequently treated with TMNB at dosages of 50, 100, and 150 mg/kg. The outcomes were evaluated based on colitis symptoms, Colon damage, Disease Activity Index (DAI) scores, and inflammation markers, including nitric oxide (NO) and myeloperoxidase (MPO) levels. Additional assessments included spleen cell proliferation, pro-inflammatory cytokine production (TNF-α, IL-6, IL-1β), and inflammatory genes expression (IL-1β, IL-6, TNF-α, COX2, and iNOS).

TMNB treatment significantly alleviated colitis symptoms (100 and 150 mg/kg). These higher doses notably reduced colonic damage, inflammation, hyperemia, edema, and ulceration (p<0.01). The treatment also effectively decreased Disease Activity Index (DAI) scores, demonstrating a marked improvement in clinical signs of colitis (100 mg/kg, p<0.05; 150 mg/kg, p<0.01). Additionally, TMNB substantially lowered myeloperoxidase (MPO) levels, indicating reduced neutrophil activity and inflammation (100 mg/kg, p<0.05; 150 mg/kg, p<0.01), and nitric oxide (NO) levels, suggesting diminished oxidative stress (100 mg/kg, p<0.05; 150 mg/kg, p<0.01). The treatment also led to a significant reduction in spleen cell proliferation (100 mg/kg, p<0.05; 150 mg/kg, p<0.01) and pro-inflammatory cytokine levels, with TNF-α, IL-1β, and IL-6 all showing decreases comparable to those observed with sulfasalazine (p<0.01). Moreover, TMNB effectively downregulated IL-1β, IL-6, TNF-α, COX2, and iNOS (p<0.01), affirming its broad-spectrum anti-inflammatory and immunomodulatory effects.

TMNB exhibits potent anti-inflammatory and immunomodulatory activities, suggesting that TMNB could be a new therapeutic agent for managing inflammatory bowel disease. This study supports the need for further clinical trials to explore TMNB's efficacy and safety in human subjects.

Atherosclerosis is a chronic cardiovascular disease which is regarded as one of the most common causes of death in the elderly. Recent evidence has shown that atherosclerotic patients can benefit by targeting interleukin-1 beta (IL-1β). Aloperine (ALO) is an alkaloid which is mainly isolated from Sophora alopecuroides L. and has been recognized as an anti-inflammatory disease. Herein, the effect of ALO on atherosclerosis was investigated.

ApoE^-/- mice fed with western diet received ALO once daily. Plaques in the aortas were evaluated using oil red O and hematoxylin & eosin (H&E) staining. Inflammation, lipids and kinases phosphorylation levels were evaluated using ELISA assay and western blot. Pyroptosis was examined by THP-1 cells treated with oxidized low-density lipoprotein (ox-LDL).

Plaque development in aortic sinus and en face aortas were reduced after ALO treatment in ApoE^-/- miceTreatment with ALO ameliorated inflammation and profile of blood lipid. Western blot assay showed that ALO treatment substantially inhibited phosphorylation of p38 and Jun N-terminal kinase (JNK) in aorta of ApoE^-/- mice. Meanwhile, ALO significantly inhibited levels of IL-1β and IL-18 in serum and cleaved caspase-1 and IL-1β expression in aorta of ApoE^-/- mice. Interestingly, ALO mildly increased pro-caspase-1 expression in ApoE^-/- aorta in comparison with saline group. In a dose dependent fashion, ALO treatment markedly inhibited ox-LDL-induced IL-1β and IL-18 levels in THP-1 cells and reduced cleaved caspase-1 and IL-1β expression and caspase-1 activity, while ALO had little effect on nod-like receptor protein containing pyrin-3 (NLRP3), apoptosis associated speck-like protein containing a caspase-1 recruitment domain (ASC).

It is of great practical significance to find the natural product to regulate macrophage pyroptosis, which are key drivers to accelerate the progression of atherosclerosis. ALO could inhibit NLRP3 inflammasome activation in macrophages during atherogenesis, which may serve as a potential candidate for the treatment of atherosclerosis.

The escalating global concerns regarding reproductive health underscore the urgency of investigating the impact of environmental pollutants on fertility. This study aims to focus on Chlorpyrifos (CPF), a widely-used organophosphate insecticide, and explores its adverse influence on the hypothalamic-pituitary-testicular axis in Wistar male rats. This study explores the potential protective effects of chrysin nanocrystal (CHN), a flavonoid with known antioxidant and anti-inflammatory properties, against CPF-induced impairments in male Wistar rats.

Chrysin nanocrystals were prepared using a solvent precipitation method. Six sets of male Wistar rats were subjected to 30 days of treatment, comprising a control group, a group treated solely with CPF, groups treated with CHN at doses of 5 mg/kg and 10 mg/kg, and groups co-treated with CPF and CHN. Serum levels of reproductive hormones, enzyme biomarkers of testicular function, oxidative stress, and inflammatory biomarkers were assessed. Additionally, histological examinations were conducted on the hypothalamus, testes, and epididymis.

CHN exhibited antioxidant and anti-inflammatory properties, effectively counteracting CPF-induced reductions in Luteinizing Hormone (LH), serum testosterone, Follicle-Stimulating Hormone (FSH), and testicular enzyme biomarkers. Moreover, CHN enhanced antioxidant defenses, as evidenced by decreased malondialdehyde (MDA) and increased glutathione (GSH) levels in the hypothalamus, and testes, epididymis. Inflammatory markers, including nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), were significantly reduced in CHN co-treated groups compared to the CPF-only group. Histopathological analyses confirmed the protective effects of CHN on tissue integrity.

Chrysin nanocrystal demonstrated promising potential in mitigating CPF-induced reproductive deficits in male rats through its anti-inflammatory and antioxidant properties. This study provides valuable insights into therapeutic interventions against environmental toxin-induced reproductive toxicity, emphasizing the potential of chrysin nanocrystals as a protective agent in the context of CPF exposure.

Neuroinflammatory responses are strongly associated with the pathogenesis of progressive neurodegenerative conditions and mood disorders. Modulating microglial activation is a potential strategy for developing protective treatments for central nervous system (CNS)-related diseases. Fibrates, widely used in clinical practice as cholesterol-lowering medications, exhibit numerous biological activities, such as anticancer and anti-inflammatory activities. However, the mechanisms underlying their beneficial effects on the CNS remain unclear.

This study investigated the mechanisms through which fibrates influence inflammatory and anti-inflammatory homeostasis in microglial cells.

Cell viability assay, nitric oxide measurement, Western blot analysis,, real-time PCR, and cell transfection were used in this study.

Fenofibrate, a well-known fibrate, reduced the production of nitric oxide and interleukin-6 and the expression of inducible nitric oxide synthase and cyclooxygenase-2 in microglial cells. It also inhibited the expression of various proinflammatory cytokines and chemokines, including tumor necrosis factor-ɑ and interleukin-1β, and chemokine (C-C) motif ligand 2 and chemokine (C-X-C motif) ligand 10. Notably, treatment of fenofibrate dramatically activated the sonic hedgehog (SHH) and sirtuin-1 (SIRT1). Furthermore, the inhibition of SHH or SIRT1 mitigated the anti-inflammatory effects of fenofibrate in IMG microglial cells.

Our findings suggest that fenofibrate may inhibit inflammatory responses by activating SIRT1 and SHH in IMG microglial cells. Our study suggests that fenofibrate or targeting SHH molecule is a promising therapeutic strategy for neuroinflammation-associated conditions. Further research with additional cell lines and in vivo models is needed to understand its therapeutic potential.

Recent research has validated the efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in reducing glucose levels and exerting a nephroprotective role.

This study aimed to examine the impact of dapagliflozin in preventing sepsis-induced acute kidney injury (AKI) and related consequences. The study used both normal and diabetic rat models to investigate whether the effectiveness of dapagliflozin is influenced by glycemia levels.

Normal and diabetic Wistar albino rats were treated with dapagliflozin for two weeks and then received a single dose of lipopolysaccharide (LPS). After sepsis induction, skin and deep body temperatures were recorded every two hours. Blood and kidneys were collected for analysis using histological examination and biochemical assays.

Dapagliflozin attenuated the consequences of sepsis through mitigation of LPS-induced hypothermia and AKI in the normal and diabetic septic groups. Dapagliflozin regulated the serum levels of AKI markers, including creatinine and blood urea nitrogen, as well as ion levels. Dapagliflozin attenuated LPS-induced AKI through modulation of renal inflammation and oxidative stress, which showed well-abundant glomeruli. These results indicated the protective effect of dapagliflozin against LPS-induced hypothermia and AKI, which was likely unrelated to its glucose-lowering properties, as evidenced in the non-diabetic septic group.

The outcomes suggest that dapagliflozin has a potential impact in preventing sepsis-induced hypothermia and AKI via modulation of inflammation and oxidative stress, irrespective of glycemic levels.

This study aimed to explore the repair effect of siRNA-mediated double silencing of the mechanically sensitive ion channels Piezo1 and TRPV4 proteins on a rat model of osteoarthritis.

Piezo1 and TRPV4 interference plasmids were constructed using siRNA technology. Sprague Dawley (SD) rats were divided into four groups: the model group, siRNA-Piezo1, siRNA-TRPV4, and double gene silencing groups. Improved Mankin and OARSI scores were calculated based on H&E staining and Safranin O-fast green staining. Immunohistochemical staining was used to determine expression levels of aggrecan and Collagen II proteins. Piezo1, TRPV4, Aggrecan, and Collagen II mRNA expression in knee joint cartilage tissue were assessed using qRT-PCR.

Lentivirus-mediated siRNA plasmids (siRNA-Piezo1, siRNA-TRPV4, and double-gene siRNA silencing plasmids) achieved > 90% transfection efficiency in chondrocytes. RT-PCR results indicated that double-gene siRNA silencing plasmids silenced Piezo1 and TRPV4 mRNA expression (P < 0.05). Modified Mankin and OARSI scores revealed that the repair effect in the double gene silencing group was significantly better than that of the siRNA-Piezo1 and siRNA-TRPV4 groups (P < 0.05). Relative expression of aggrecan and collagen II mRNA in the double gene-silenced group was significantly higher than in the siRNA-Piezo1 and siRNA-TRPV4 groups (P < 0.05).

Double silencing Piezo1 and TRPV4 plays a key role in cartilage repair in an osteoarthritic rat model by promoting the expression of Aggrecan and Collagen II.

Momordica cochinchinensis is a dried and mature seed of Cucurbitaceae plants, which has the effect of dispersing nodules, detumescence, attacking poison, and treating sores, and is used in the treatment of tumors in the clinic. P-hydroxylcinnamaldehyde (CMSP) is an ethanol extract of cochinchina momordica seed (CMS). Our previous studies have found that CMSP is an effective anti-tumor component with good anti-tumor effects on melanoma and esophageal tumors. However, the inhibitory effect of CMSP on gastric cancer (GC) and its potential mechanism remain to be further elucidated.

First, we utilized network pharmacology to predict potential targets and mechanisms of action for the treatment of GC. Subsequently, a series of biological function experiments were conducted to assess the effects of CMSP on the proliferation and apoptosis of GC cells in vitro. To elucidate the molecular mechanism of CMSP, bioinformatics and high-efficiency liquid chromatography tandem mass spectrometry (HPLC-MS/MS) were employed for analysis. Additionally, a resistant cell line of the chemotherapy drug paclitaxel for GC was established, and the impact of 10μg/mL CMSP on the sensitivity of GC-resistant cells was examined.

The network pharmacology results demonstrated that the active components of CMS exert an anti-GC effect through multi-target and multi-pathway mechanisms. The main pathways involved included the PI3K/Akt pathway, p53 signaling pathway, multi-species apoptosis pathway, as well as ADRB2 and CAV1 genes. Cell experiments revealed that CMSP can effectively inhibit the proliferation and induce apoptosis of GC cells in vitro. However, it did not show any sensitizing effect on paclitaxel-resistant cells. Importantly, CMSP exhibited no toxic or side effects on normal gastric epithelial cells. Furthermore, differential protein expression patterns following CMSP treatment were elucidated using HPLC-MS/MS and western blot analysis, highlighting its role in regulating apoptosis signaling pathways.

Our study presents novel evidence regarding pertinent potential target genes and signaling pathways through which CMSP mediates its anti-GC effects, with a particular emphasis on its role in modulating apoptotic signaling pathways. Collectively, these findings underscore the promising candidacy of CMSP as a therapeutic agent for GC that merits further investigation in clinical contexts.

Reduced bedaquiline (BDQ) sensitivity to antimycobacterial drugs has been linked to mutations in the Rv0678, pepQ, and Rv1979c genes of Mycobacterium tuberculosis (MTB). Resistance-causing mutations in MTB strains under treatment may have an impact on novel BDQ-based medication regimens intended to reduce treatment time. Due to this, we investigated the genetic basis of BDQ resistance in Turkish TB patients with MTB clinical isolates. Furthermore, mutations in the genes linked to efflux pumps were examined as a backup resistance mechanism.

We scrutinized 100 MTB clinical isolates from TB patients using convenience sampling. Eighty MDR and twenty pan-drug susceptible MTB strains were among these isolates. Sequencing was performed on all strains, and genomic analyses were performed to find mutations in BDQ resistance-associated genes, including Rv0678 and pepQ(Rv2535c), which correspond to a putative Xaa-Pro aminopeptidase, and Rv1979c. Of the 74 isolates with PepQ (Rv2535c) mutations, four isolates (2.96%) exhibited MGIT-BDQ susceptibility.

Twenty-one (19.11%) of the ninety-one isolates carrying mutations, including Rv1979c, were MGIT-BDQ-sensitive. Nonetheless, out of the 39 isolates with Rv0678 mutations, four (2.96%) were sensitive to MGIT-BDQ. It was found that resistance-associated variants (RAVs) in Rv0678, pepQ, and Rv1979c are often linked to BDQ resistance.

In order to include variations in efflux pump genes in genome-based diagnostics for drug-resistant MTB, further evidence about their involvement in resistance is needed.

Status Epilepticus (SE) leads to the development of epilepsy with the contribution of endoplasmic reticulum (ER) stress. Uridine, a pyrimidine nucleoside, has been shown to have neuroprotective and antiepileptogenic effects in animal models. This study aimed to determine whether uridine ameliorates ER stress and apoptosis following epileptogenic insult. Secondly, this study aimed to establish the effect of uridine on inflammatory and oxidative stress parameters that contribute to ER stress.

Status epilepticus was induced using lithium-pilocarpine in adult male Sprague-Dawley rats. Following SE termination, rats were treated with uridine, 4-phenylbutyric acid (4-PBA), or saline twice daily for 48 h. Expressions of hippocampal glucose-regulated protein 78 (GRP78), Inositol-Requiring Protein 1 (IRE1α), Protein kinase RNA-like Endoplasmic Reticulum Kinase (PERK), and C/EBP Homologous Protein (CHOP) were determined by western blotting 48 h after SE. Uridine's effects on apoptosis, inflammation or oxidation were evaluated by analyses of cleaved caspase-3 and poly(ADP-ribose) polymerase 1 (PARP1) protein expressions or pro-inflammatory cytokine levels or levels of oxidative stress markers, respectively.

Expressions of all ER stress-related proteins significantly increased 48 h after SE. Uridine treatment markedly decreased GRP78, IRE1α, and CHOP levels. A decrease in the PERK level was observed following the administration of 4-PBA; however, uridine had no effect. Cleaved caspase-3 and PARP1 levels were increased in the SHAM group, while uridine and 4-PBA treatment effectively decreased their expressions. Treatment with uridine significantly reduced Myeloperoxidase (MPO) and Malondialdehyde (MDA) levels while tending to increase Catalase (CAT) and Glutathione Peroxidase (GPx) levels. Uridine treatment also significantly attenuated levels of TNF-α and IL-1β, the pro-inflammatory cytokines, which increased 48 h post-SE.

Our data indicate that uridine alleviates ER stress after SE. This effect may be attributed to the regulation of inflammation and oxidative stress. Uridine shows promise as a potential preventive agent for epilepsy.

This study investigates whether phloretin, a brain-edema inhibitor, can enhance the therapeutic effects of human-derived platelet-rich plasma (hPRP) in reducing brain hemorrhagic volume (BHV) and preserving neurological function in rodents following acute traumatic brain damage (TBD).

Forty rats were divided into five groups: sham-control, TBD, TBD + phloretin (80 mg/kg/dose intraperitoneally at 30 minutes and on days 2/3 post-TBD), TBD + hPRP (80μL by left intra-carotid-artery injection at 3 hours post-TBD), and TBD + phloretin + hPRP. Cerebral tissues were harvested on day 28 post-TBD for analysis.

Brain MRI on day 28 showed the lowest BHV in the sham-control group and the highest in the TBD group. BHV was significantly lower in the phloretin + hPRP group compared to the phloretin or hPRP alone groups, which had similar BHV. Neurological function followed an inverse pattern to BHV. By day 28, protein levels of upstream (HGMB1, TLR-2, TLR-4, MyD88, Mal, TRAM, TRIF, TRAF6, IKK-α, IKK-ß, p-NF-κB) and downstream (IL-1ß, TNF-α, iNOS) inflammation signalings, apoptosis (caspase3, PARP), and fibrosis (Smad3, TGF-ß) biomarkers, as well as flow cytometric assessment of inflammatory cells (CD11b/c+, Ly6G+, PMO+) and early (AN-V+/PI-) and late (AN-V+/PI+) mononuclear-cell apoptosis, displayed patterns similar to BHV. The number of inflammatory (CD68+, MMP9+) and brain-swelling/myelin-damaged (AQP4+, GFAP+) mediators also followed this pattern, while neuronal-myelin (Doublecortin+, NeuN, nestin) mediators showed an inverse relationship with BHV (all p<0.0001).

Combined phloretin and hPRP therapy is superior to either treatment alone in protecting the brain against TBD, primarily by suppressing inflammatory signaling and brain-swelling biomarkers.

Increasing ratio of bone fragility, and susceptibility to fractures constitutes a major health problem worldwide. Therefore, we aimed to identify new compounds with a potential to increase proliferation and differentiation of bone forming osteoblasts.

Cellular and molecular assays, such as ALP activity, alizarin staining, and flow cytometry were employed to study effect of 7,3′,4′-Trimethoxyflavone (TMF) on osteogenesis. Moreover, gene expression analysis of certain important genes and transcriptional factors was also performed.

Our findings report for the first time that natural product TMF is capable of enhancing proliferation, and differentiation in osteoblast cells. Results from flow cytometry analysis also indicated that TMF increases the number of cells in S-phase. Furthermore, treatment with TMF altered the expression of osteogenic genes, OCN and Axin-2, indicating possible activation of Wnt signaling pathway.

Taken together, this study identified that 7,3′,4′-Trimethoxyflavone has the potential to enhance osteoblast proliferation and differentiation, possibly through the activation of Wnt/β-catenin pathway. Thus, TMF promotes osteogenesis and thus can contribute in the prevention of bone fragility, and related disorders.