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The present study deals with developing novel 1,3,5‐triazine‐nicotinohydrazide derivatives as potent CDK9 inhibitors in a straightforward synthetic route with potent anti‐osteosarcoma activity. The most potent CDK9 inhibitor compound 5k inhibits proliferation of MG‐63 cells via induction of apoptosis and G2/M cell cycle arrest. It reduces tumor progression in the patient‐derived orthotopic xenograft (PDOX) mouse model with significant antioxidant and anti‐inflammatory activity. In tumor tissue homogenates, it caused significant inhibition of CDK9 and inhibited the phosphorylation of RNAPII ser2 and reduced MCL‐1 expression in Western blot analysis. Compound 5k also showed considerable bioavailability in SD mice. Our results demonstrated that compound 5k inhibits growth of OS in vitro and in vivo via inhibition of CDK9 which attenuated the downstream phosphorylation of RNAPII ser2 and represses expression of the anti‐apoptotic protein, MCL‐1 for the induction of apoptosis in OS. [ABSTRACT FROM AUTHOR]

Unc-51 like autophagy activating kinase 1 (Ulk1) is a serine/threonine kinase that plays a key role in regulating autophagy processes. We attempted to investigate the effects of Ulk1 on traumatic brain injury (TBI) progression by using wild type (WT) mice and Ulk1-knockout (KO) mice suffered with or not TBI. The results were verified using LPS-treated primary astrocyte (AST). Here, Ulk1 was over-expressed in hippocampus of WT mice after TBI, as well as in lipopolysaccharide (LPS)-stimulated AST. Ulk1-deletion improved cognitive ability and hippocampus histological changes in TBI mice. Nissl and neuronal nuclei (NeuN) staining indicated that Ulk1-deletion increased the number of surviving neurons in hippocampus of TBI mice. Ulk1-ablation alleviated neuroinflammation, as evidenced by the reduced expression of hippocampus pro-inflammatory cytokines in TBI mice. TBI-induced apoptosis was also ameliorated by Ulk1-ablation, as proved by the reduced number of TUNEL-staining cells, and cleaved Caspase-3 and poly (ADP-ribose) polymerase (PARP) expressions. Moreover, Ulk1-knockout suppressed TBI-stimulated activation of astrocytes and microglia cells. Additionally, hippocampus autophagy induced by TBI was attenuated by Ulk1-knockout. Further, TBI-activated p38/c-Jun N-terminal Kinase (JNK) pathway was repressed by Ulk1-deletion in hippocampus of mice. The findings above were confirmed in LPS-stimulated AST with or without Ulk1 siRNA transfection. Intriguingly, pre-treatment of p38 or JNK activator markedly abolished the anti-inflammation, anti-apoptosis and anti-autophagy effects of Ulk1-knockdown on LPS-incubated AST. In conclusion, our results demonstrated that Ulk1 might be a potential target for developing therapeutic strategy against TBI in future. [ABSTRACT FROM AUTHOR]

Thyroid hormone (TH) is essential for the proper development of mammalian central nervous system. TH deficiency during the critical period of brain development results in permanent cognitive and neurological impairments. Members of the protein kinase C (PKC) family play a key role in the regulation of cellular functions in the nervous system. Alteration of PKC can be involved in the pathogenesis of neuronal disorders. This review details recent progress made in determining the roles played by PKC isoforms in developing hypothyroid rat brain. Evidence indicates that hippocampus down-regulation of PKCβ and PKCγ may be related to impaired learning and memory observed in perinatal hypothyroid rats. Enhanced PKCα activity in neonatal hypothyroid brain may bring about oxidative stress and cause brain damage. The activated pro-apoptotic PKCs including PKCδ can cause extensive apoptosis in the hypothyroid rat brain. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to study the effects of angiotensin receptor (AT1R) on proliferation, cell cycle progression, and apoptosis of estrogen-induced ishikawa cell by the transfection of AT1R-siRNA. Methods: Immunofluorescence method was used to detect AT1R in ishikawa cell. Western blot was used to detect the expression of AT1R protein in ishikawa cell before and after the transfection of AT1R-siRNA. MTT method was used to test the cell proliferation of estrogen-induced ishikawa cell before and after the transfection. Western blot was used to detect the expression of extracellular regulated protein kinase1/2(ERK1/2). Results: The result of immunofluorescence shows that AT1R was expressed in ishikawa cell. The expression of AT1R protein was inhibited obviously by 72 h after the transfection of AT1R-siRNA. The results of MTT show that estrogen could induce the cell proliferation of ishikawa cell. The expression of ERK1/2 was down-regulated after the transfection of AT1R-siRNA. Conclusion: AT1R can promote the cell proliferation of estrogen-induced ishikawa cell. The possible mechanism may be down-regulating the expression of ERK1/2 protein. [ABSTRACT FROM AUTHOR]

Background: Current cancer therapies often fall short in addressing the complexities of malignancies, underscoring the urgent need for innovative treatment strategies. RNA interference technology, which specifically suppresses gene expression, offers a promising new approach in the fight against tumors. Recent studies have identified a novel immunostimulatory small-interfering RNA (siRNA) with a unique sequence (sense strand, 5'-C; antisense strand, 3'-GGG) capable of activating the RIG-I/IRF3 signaling pathway. This activation induces the release of type I and III interferons, leading to an effective antiviral immune response. However, this class of immunostimulatory siRNA has not yet been explored in cancer therapy. Methods: IsiBCL-2, an innovative immunostimulatory siRNA designed to suppress the levels of B-cell lymphoma 2 (BCL-2), contains a distinctive motif (sense strand, 5'-C; antisense strand, 3'-GGG). Glioblastoma cells were subjected to 100 nM isiBCL-2 treatment in vitro for 48 h. Morphological changes, cell viability (CCK-8 assay), proliferation (colony formation assay), migration/invasion (scratch test and Transwell assay), apoptosis rate, reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were evaluated. Western blotting and immunofluorescence analyses were performed to assess RIG-I and MHC-I molecule levels, and ELISA was utilized to measure the levels of cytokines (IFN-β and CXCL10). In vivo heterogeneous tumor models were established, and the anti-tumor effect of isiBCL-2 was confirmed through intratumoral injection. Results: IsiBCL-2 exhibited significant inhibitory effects on glioblastoma cell growth and induced apoptosis. BCL-2 mRNA levels were significantly decreased by 67.52%. IsiBCL-2 treatment resulted in an apoptotic rate of approximately 51.96%, accompanied by a 71.76% reduction in MMP and a 41.87% increase in ROS accumulation. Western blotting and immunofluorescence analyses demonstrated increased levels of RIG-I, MAVS, and MHC-I following isiBCL-2 treatment. ELISA tests indicated a significant increase in IFN-β and CXCL10 levels. In vivo studies using nude mice confirmed that isiBCL-2 effectively impeded the growth and progression of glioblastoma tumors. Conclusions: This study introduces an innovative method to induce innate signaling by incorporating an immunostimulatory sequence (sense strand, 5'-C; antisense strand, 3'-GGG) into siRNA, resulting in the formation of RNA dimers through Hoogsteen base-pairing. This activation triggers the RIG-I signaling pathway in tumor cells, causing further damage and inducing a potent immune response. This inventive design and application of immunostimulatory siRNA offer a novel perspective on tumor immunotherapy, holding significant implications for the field. [ABSTRACT FROM AUTHOR]

Background: Recent studies revealed that long noncoding RNAs (lncRNAs) play critical regulatory roles in cancer biology. PlncRNA-1 is one of lncRNAs that is associated with cell apoptosis and proliferation of prostate cancer. Aim: This study aimed to assess the potential role of PlncRNA-1 in the pathogenesis of esophageal squamous cell carcinoma (ESCC). Materials and Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression level of PlncRNA-1 in 73 pairs of ESCC and their matched normal tissues. The correlation of PlncRNA-1 with clinicopathological features and clinical stages was also analyzed. Cancer cell proliferation and apoptosis were assessed following knock-down of PlncRNA-1 by MTT, colony formation assay, and flow cytometry. Results: The expression of PlncRNA-1 was significantly higher in human ESCC compared with the adjacent noncancerous tissues (69.8 %, p < 0.05), and the high level of PlncRNA-1 expression was significantly correlated with advanced clinical stage ( p < 0.01) and lymph node metastasis ( p < 0.05). Furthermore, knockdown of PlncRNA-1 reduced cell proliferation and increased the apoptosis in vitro. Conclusions: PlncRNA-1 plays an important role in ESCC cell proliferation. Overexpression of PlncRNA-1 is correlated with advanced tumor stage and lymph node metastasis, and may serve as a potential prognostic marker and therapeutic target for ESCC. [ABSTRACT FROM AUTHOR]

• PPZM exhibited significant scavenging activity of DPPH and OH free radicals in vitro. • PPZM effectively against H 2 O 2 -induced cell damage by decreasing LDH and MDA release, and increasing SOD activity. • The neuroprotective effects of PPZM may be involved in the inhibition of mitochondria-dependent apoptosis. • PPZM can be used as the source of natural antioxidants and neuroprotective agents. The pericarp of Zanthoxylum bungeanum Maxim (PZM) is one of eight fascinating condiments and also used as a traditional herbal medicine to treat a variety of diseases. In this study, ultrasound-assisted extraction (UAE) was applied for the extraction of polysaccharides from PZM (PPZM) and the extraction conditions were optimized by response surface methodology (RSM). The obtained PPZM yield (2.60 ± 0.06%) was closely agreed with the predicted value (2.58%), and the optimal extraction conditions obtained were: liquid to solid ratio of 32 mL/g, extraction time of 42 min, and extraction temperature of 61 °C. PPZM was determined to be composed of mannose (Man), rhamnose (Rha), galacturonic acid (GalA), glucose (Glu), galactose (Gal), arabinose (Ara) with a molar ratio of 4.93: 5.03: 71.01: 16.01: 24.87: 18.79, and the average molecular weight (Mw) of PPZM was 1.72 × 105 Da. Typical polysaccharide characteristics were determined by fourier transform infrared spectroscopy (FT-IR). PPZM exhibited remarkable antioxidant activities in vitro. More importantly, PPZM effectively protected adrenal phaeochromocytoma PC12 cells against H 2 O 2 -induced damage by inhibiting the release of lactate dehydrogenase (LDH) and malondialdehyde (MDA), increasing the level of superoxide dismutase (SOD), and inhibiting abnormal apoptosis. Further experiments indicated that the anti-apoptotic effects of PPZM were closely related to down-regulating the expressions of Bax and Caspase-3, and up-regulating the expression of Bcl-2. Therefore, PPZM can be used as the source of natural antioxidants and neuroprotective agents. [ABSTRACT FROM AUTHOR]

Two new mixed-ligand coordination polymers (CPs) with the chemical formulae of [Co(L)(phen)]n (1, phen = 1,10-phenanthroline and [Co(L)(4,4′-bipy)4·2H2O]n (2, 4,4′-bipy = 4,4′-bipyridine) have been successfully synthesized by the solvothermal reaction of 1,4-bis(3-carboxylbenzyl)piperazine acid (H2L) and different N-donor co-ligands with Co(II) salt. In the biological function study, the treatment effect of compounds 1 and 2 on the Alzheimer's disease (AD) was evaluated and the detail mechanism was explored in this research. Firstly, the AD animal model was constructed, and the content of the Amyloid (Aβ) in the brain after compounds 1 and 2 treatment was detected. Then the protective activity of compounds 1 and 2 on neurons was evaluated after Aβ stimulation. Two new mixed-ligand coordination polymers have been synthesized. In the biological function study, the treatment effect of compounds 1 and 2 on the Alzheimer's disease (AD) was evaluated and the detail mechanism was explored in this research. Firstly, the AD animal model was constructed, and the content of the Amyloid (Aβ) in the brain after compounds 1 and 2 treatment was detected. Then the protective activity of compounds 1 and 2 on neurons was evaluated after Aβ stimulation. [ABSTRACT FROM AUTHOR]

Fuzheng Qingjie (FZQJ) recipe is a polyherbal Chinese medicine capable of suppressing tumor growth and is used as an adjuvant therapy for various types of cancer. However, its anticancer mechanisms are yet to be fully elucidated. In the present study, we explored whetherp38mitogen-activatedprotein kinase (MAPK) was involved in FZQJ-mediated mitochondria-dependent apoptosis in human hepatocellular carcinoma cells. 3-(4,5TJ)imethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were used to measure the viability of HepG2 cells. 4,6-Diamidino-2-phenylindole (DAPI) and Annexin-V fluorescein isothiocyanate (FITC) were used to analyze the apoptosis of HepG2 cells. The mitochondrial membrane potential (Δψ) and phosphorylated P38 MAPK protein were examined by a flow cytometer following 5,5',6,6'-tetrachloro-1,1',3,3'-tetraeth-ylbenzimidazolcarbocyanine iodide (JC-1) and Alexa Fluor® 647 mouse anti-phosphorylated P38 MAPK antibody staining, respectively. The activation of caspase-9 and caspase-3 were measured using colorimetric assays. Additionally, Bcl-2 and Bax expression were examined using reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis. The results demonstrated that water extract of FZQJ was able to induce apoptosis of HepG2 cells in vitro. FZQJ-induced apoptosis was accompanied by the loss of Δψ, downregulation of Bcl-2 and upregulation of Bax expression, and the activation of caspase-3, -9 and P38 MAPK. These results indicated that FZQJ induced apoptosis in HepG2 cells at least via P38 MAPK activation and the mitochondria-dependent apoptotic pathway. [ABSTRACT FROM AUTHOR]

Using K562 and HL60 cell lines, we have investigated the anti-tumoral activity of d-limonene, a monocyclic monoterpene, in human leukemia cells. Apoptosis was evaluated by Hoechst staining and by the annexin V/propidium iodide binding assay. d-Limonene induced apoptosis in a dose- and time-dependent manner in both cell lines. Our findings and data, demonstrating an increase in Bax protein expression, the release of cytochrome c from mitochondria, and an increase in caspase-9 and cleaved caspase-3, but not caspase-8, after the treatment of d-limonene, all suggest that the mitochondrial death pathway is primarily involved in the development of d-limonene-induced apoptosis. [ABSTRACT FROM AUTHOR]