Down-regulation Of Bcl-2 Research Articles

Rhodium complex [RhLI2]I: a novel anticancer agent inducing tumor inhibition and apoptosis

Numerous chemotherapeutic agents are currently employed in cancer treatment, but many are associated with significant side effects. This study aims to identify a novel anticancer drug that minimizes or eliminates these adverse effects. The anticancer activity of the Rhodium (III) complex cis-[RhLI2]I was evaluated through both in vivo and in vitro functional assays. Apoptosis in cancer cells post-treatment was assessed using microscopy and gene expression analysis. In cytotoxicity screening via the brine shrimp lethality bioassay, the compound exhibited an LC50 value of 25.90 µg/mL (P < 0.001). It also achieved an 88.96% inhibition of cell growth (P < 0.001), an 82.39% increase in lifespan (P < 0.001), and a significant reduction in tumor weight at a dosage of 200 µg/kg in Ehrlich ascites carcinoma (EAC)-bearing Swiss albino mice. Restoration of hematological parameters, such as RBC, WBC, and hemoglobin levels, was observed in treated tumor-bearing mice compared to untreated EAC-bearing mice. The compound inhibited the growth and proliferation of breast cancer (MCF7) cells in a dose-dependent manner, achieving a maximum inhibition of 88.9% at 200 µg/mL. Apoptotic induction in MCF7 cells occurred through the upregulation of p53, Bax, caspase-3, -8, and -9, alongside the downregulation of the anti-apoptotic protein Bcl-2. No long-term adverse effects on hematological or biochemical parameters or tissue levels were observed in the mice. Given these findings, this compound demonstrates significant cytotoxic effects and has the potential to serve as a promising chemotherapeutic agent, warranting further investigation at more advanced stages.

Protective effects of naringenin against methamphetamine-induced cell death in dopaminergic SH-SY5Y cells

ABSTRACT Background: Methamphetamine is a psychoactive substance that competes with the dopamine transporter, disrupting its flow and storage. This can trigger oxidative stress, finally resulting in neural cell death. Due to the increasing prevalence of methamphetamine use, extensive research has been devoted to finding treatments that ameliorate its detrimental effects. Naringenin, a dietary flavonoid found in citrus fruits, has shown several neuroprotective and pharmacological properties. Objectives: This study was aimed to assess the protective effects of naringenin against methamphetamine-induced dopaminergic cell death. Methods: Before exposure to methamphetamine, human neuroblastomaSH-SY5Y cells were either pretreated or not treated (controls) with naringenin. Cell viability, level of oxidative stress markers, and expression of some genes involved in apoptosis and autophagy processes were then assessed using MTT, ROS, and MMP assays, and qRT-PCR and Western blotting techniques. Results: Naringenin pretreatment significantly enhanced cell viability following methamphetamine exposure (p < .01). It significantly decreased ROS levels (p < .001), preserved mitochondrial membrane potential, and moderated upregulation of apoptotic (CytC, Casp3, and Bax) and autophagic genes (Beclin-1, and LC-3) and down-regulation of Bcl-2 as an anti-apoptotic gene. Similar naringenin-mediated patterns were observed for cytochrome C and caspase 3 proteins. Conclusion: Naringenin administration can be considered for treating the neurotoxic effects of methamphetamine.

Synthesis, DPPH Radical Scavenging, Cytotoxic Activity, and Apoptosis Induction Efficacy of Novel Thiazoles and Bis-thiazoles.

Heterocyclic materials-containing thiazoles exhibited incredible importance in pharmaceutical chemistry and drug design due to their extensive biological properties. Synthesis of thiazoles and bis-thiazoles from the reaction of 2-((6-Nitrobenzo[ d][1,3]dioxol-5-yl)methylene)hydrazine-1-carbothioamide with hydrazonoyl chlorides in dioxane and in the existence of triethylamine as basic catalyst. The antioxidant, in vitro antiproliferative, and cytotoxicity efficacy of thiazoles and bis-thiazoles were measured. In this work, novel series of 5-methyl-2-(2-(-(6-nitrobenzo[d][1,3]dioxol-5-yl)methylene) hydrazinyl)-4-(aryldiazenyl)thiazoles (4a-f) were prepared via the reaction of hydrazonoyl chlorides 2a-f with 2-((6-nitrobenzo[d][1,3]dioxol-5-yl)methylene)hydrazine-1-carbothioamide (1) in dioxane and employing triethylamine as basic catalyst. Following the same procedure, bisthiazoles (6, 8, and 10) have been synthesized by utilizing bis-hydrazonoyl chlorides (5, 7, and 9) and carbothioamide 1 in a molar ratio (1:2), respectively. The distinctive features in the structure of isolated products were elucidated by spectroscopic tools and elemental analyses. The antioxidant, in vitro anti-proliferative, cytotoxicity, and anti-cancer efficacy of thiazoles and bis-thiazoles were evaluated. Compounds 4d and 4f were the most potent antioxidant agents. Gene expression of apoptosis markers and fragmentation assay of DNA were assessed to explore the biochemical mechanism of synthesized products. Thiazoles significantly inhibited cell growth and proliferation more than bis-thiazoles. They induced apoptosis through induction of apoptotic gene expression P53 and downregulation of antiapoptotic gene expression Bcl-2. Moreover, they induced fragmentation of DNA in cancer cells, indicating that they could be employed as anticancer agents by inhibiting tumor growth and progression and can be considered effective compounds in the strategy of anti-cancer agents' discovery. Synthesis, DPPH Radical Scavenging, Cytotoxic activity, and Apoptosis Induction Efficacy based on Novel Thiazoles and Bis-thiazoles.

New thiadiazolopyrimidine-ornamented pyrazoles as prospective anticancer candidates via suppressing VEGFR-2/PI3K/Akt signaling pathway: Synthesis, characterization, in-silico, and in-vitro studies.

New thiadiazolopyrimidine-ornamented pyrazoles (4a-8b) have been synthesized by a cyclocondensation reaction of 3a, b with different active methylene compounds. The structure of our products was confirmed via different physical and spectroscopic data. We assessed all newly thiadiazolopyrimidine-ornamented pyrazoles' potential to inhibit angiogenesis, metastasis, and cancer growth by utilizing in-silico investigations focused on the VEGFR2 signaling pathway. Based on our results, compound 8b was chosen for in vitro evaluation since it had the highest binding energy of -10.252 kcal/mol using molecular docking. Compound 8b significantly damaged the T47D (IC50 = 33.01 ± 2.2 μM) cells in comparison to Cisplatin (IC50 = 3.163 ± 1.7 μM). Additionally, compound 8b significantly suppressed the VEGFR-2 receptor protein that triggers the inhibition of PI3K/Akt genes which causes mitochondrial membrane malfunction resulting in Bax overexpression and Bcl-2 downregulation levels. Besides, compound 8b showed a notable decrease in the levels of nitric oxide (NO) production levels and stopped the cell cycle in the G0/G1 stage. These outcomes demonstrated that compound 8b adhered to Lipinski's rules and may serve as a potential candidate for future breast cancer treatments via obstructing the VEGFR2/PI3K/Akt signaling pathway, which in turn prevents metastasis, angiogenesis, and proliferation.

N-3 polyunsaturated fatty acids enhanced efficacy of cytarabine in iron-overloaded NALM-6 cells via apoptotic and oxidative pathways

Despite progress in treating acute lymphoblastic leukemia (ALL), the adverse effects of chemotherapy toxicity and iron overload from transfusions continue to affect patients' quality of life. Polyunsaturated fatty acids (PUFAs) exhibit both antitumor and anti-inflammatory properties in leukemia. This study investigated the influence of n-3 PUFA on the efficacy of cytarabine in cells with iron overload. Iron overload was induced in NALM-6 cells using ferric ammonium citrate (FAC) and quantified through atomic absorption spectroscopy (AAS). The impact of n-3 PUFA on NALM-6 cells' response to cytarabine was evaluated using MTT, lactate dehydrogenase (LDH), apoptosis, and cell cycle assays. Additionally, gene expression analyses were performed on apoptotic, anti-apoptotic, and inflammatory genes, along with oxidative stress markers such as reactive oxygen species (ROS) and malondialdehyde (MDA) levels. The administration of n-3 PUFA significantly enhanced the effectiveness of cytarabine in iron-overloaded NALM-6 cells, leading to increased LDH secretion, elevated apoptosis rates, and G1 phase cell cycle arrest. These effects were associated with the upregulation of apoptotic genes such as P53 and caspase-8, the downregulation of the anti-apoptotic gene Bcl2, and a decrease in the inflammatory gene TNF-α. Furthermore, there was a notable increase in ROS and MDA levels. Overall, n-3 PUFA treatment improved cytarabine's efficacy in iron-overloaded NALM-6 cells by activating apoptotic processes and oxidative stress pathways.

The effects of hesperidin on valproic acid-induced reduction in hippocampal neurogenesis through the antioxidant and apoptotic pathways in adult rats

Treatment with valproic acid (VPA) can induce oxidative stress, leading to neuronal degeneration. Hesperidin (HSD) has an antioxidant function that can mitigate oxidative stress, thereby promoting hippocampal neurogenesis. Because brain function and memory are reliant on hippocampal neurogenesis, this work is planned to elucidate the effects of HSD on the VPA-induced alterations in hippocampal neurogenesis and apoptosis via oxidative damage. Twenty-four male Sprague-Dawley rats were grouped into the vehicle, VPA, HSD, and VPA + HSD groups. After administration, the hippocampi and prefrontal cortex were harvested for p21 staining, assessment of MDA, CAT, SOD, and GPx, and Western blotting analysis of Nrf2, Bax, caspase3, and Bcl-2 proteins. The results exhibited a significantly elevated level of p21-positive cells in VPA-treated rats, indicating cell cycle arrest in hippocampal neurogenesis. Additionally, our findings demonstrated a notable rise in oxidative stress, a decrease in antioxidant enzyme activity and the transcription factor Nrf2 in VPA-treated rats. Furthermore, VPA induced apoptotic activities, as substantiated by the upregulation of Bax and caspase3, and the downregulation of Bcl-2. These findings demonstrate that HSD can reduce oxidative stress levels, thereby mitigating the arrest of the cell cycle and apoptotic activity induced by VPA treatment in both the hippocampus and prefrontal cortex.

Anticancer Potential Of Psoralea Corylifolia L. Ethanol Extract: Cytotoxicity, Apoptosis Mechanisms, And Gene Expression Analysis In Mcf7 Breast Cancer Cells Via qPCR

Aim: The aim of this study was to evaluate the phytochemical profile and anticancer potential of Psoralea corylifolia L. extract, specifically focusing on its effects on breast cancer cells (MCF7) and its underlying molecular mechanisms. Methods: The seeds of P. corylifolia were extracted using ethanol and chloroform through Soxhlet extraction. The extracts were analyzed for bioactive compounds through standard phytochemical tests. The anticancer activity of the ethanol extract was assessed using the MTT assay to determine cell viability and IC50 values. Further molecular analysis of apoptosis was performed by quantifying the expression of the Bcl-2 gene using semi-quantitative PCR and evaluating marker of apoptosis. Results: Phytochemical screening revealed that both ethanol and chloroform extracts contained alkaloids, carbohydrates, and terpenoids, with ethanol extract showing a broader range of bioactive compounds, including flavonoids, phenols, saponins, and proteins. The ethanol extract exhibited significant cytotoxicity against MCF7 cells, with an IC50 value of 10.1 µg/ml. Molecular analysis showed that the extract induced apoptosis through down-regulation of the anti-apoptotic protein Bcl-2 and activation of caspase-3 and PARP, suggesting the involvement of the mitochondrial pathway. Conclusion: The results demonstrate the anticancer potential of P. corylifolia ethanol extract against breast cancer cells, primarily through cell cycle arrest and apoptosis induction. These findings highlight P. corylifolia as a promising candidate for further investigation as a safer, plant-based alternative in cancer treatment, particularly for breast cancer, though clinical studies are needed to confirm its therapeutic efficacy in humans.

Proteome modulation triggers potent antiviral response in Japanese Encephalitis Virus infected human macrophages.

Japanese encephalitis virus (JEV) is a mosquito-borne neurotropic virus that claims thousands of children's lives globally every year, causing neuropsychiatric sequelae. While neuronal cell pathogenesis is a terminal consequence of JEV infection, the virus hijacks macrophages during initial replication and propagation, making macrophages critical cells of host immune defense that dictate the outcomes of infection. Though a plethora of studies have been reported using various neuronal and immune cells, a global response of human macrophages to JEV infection is yet to be explored. In this study, we assessed the kinetics of global proteome dysregulation employing an in vitro JEV infection model using human monocyte-derived macrophages (THP-1). A comparative assessment of the proteome of the infected THP-1 cells revealed differential regulation of 428 proteins at 24h post-infection (hpi), which was later increased to 443 by 48h post-infection. Global gene ontology analysis of the differentially expressed proteins highlighted several critical pathways related to immune and metabolic processes that are known to play either proviral or antiviral effects during infection. Notably, several antiviral proteins, including STAT2, OAS1, MX1, MX2, RIG-I, ISG15, and ISG20, were significantly upregulated at both time points post-infection. In contrast, a considerable downregulation of BCL-2, an anti-apoptotic protein at 48hpi indicates the activation of cell death pathways. Further, gene set enrichment analysis identified the type I interferon signaling pathway as one of the top upregulated pathways following JEV infection in human macrophages. Altogether, this study demonstrates human macrophage responses to JEV infection at the proteome level for the first time, highlighting several critical and novel antiviral proteins and pathways that not only advance our understanding of anti-JEV immunity but also aid in developing strategies to control this acute global public health menace.

Design, in silico studies and biological evaluation of novel chalcones tethered triazolo[3,4-a]isoquinoline as EGFR inhibitors targeting resistance in non-small cell lung cancer

A novel series of six [1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-3-(1,3-diphenyl-1H-pyrazol-4-yl)prop-2-en-1-ones (3a–3f) was designed and synthesized. They were characterized based on spectral and elemental analyses. In silico studies were also committed to provide insights and a better understanding of their structural features. The six compounds were screened for their antiproliferative activity using the MTT assay against five human cancer cell lines, namely, A549, HCT116, PC3, HT29, and MCF-7 in parallel with the non-cancerous human lung cell line WI-38. The results showed that 3e and 3f have potential cytotoxic activities, especially on A549 cells with IC50 = 2.3 µM and 1.15 µM, respectively. Meanwhile, they recorded a minimal cytotoxic effect on WI-38 cells. Concerning the molecular mechanism of action, the present study showed the inhibitory effect of the six compounds against total EGFR. The most potent EGFR inhibitors were 3e and 3f with IC50 = 0.031 µM and 0.023 µM, respectively. The selectivity index of 3f for EGFRT790M was 1.81 times more selective than that of lapatinib. In addition, 3e and 3f initiated cell cycle arrest at the G2/M and pre-G1 phases along with the downregulation of anti-apoptotic protein Bcl2 and the upregulation of pro-apoptotic proteins: p53, Bax, and caspases 3, 8, and 9. Further studies are recommended to evaluate animal models’ promising anticancer activity and molecular mechanism of triazolo[3,4-a]isoquinoline derivatives 3e and 3f.

Diltiazem Hydrochloride Protects Against Myocardial Ischemia/Reperfusion Injury in a BNIP3L/NIX-Mediated Mitophagy Manner.

Mitochondrial calcium uptake-induced mitophagy may play an essential role in myocardial ischemia/reperfusion (MI/R) injury. Diltiazem hydrochloride (DIL), a traditional calcium channel blocker, can alleviate MI/R injury by blocking calcium overload. However, whether the protective mechanism of DIL involves mitophagy remains elusive. This study aimed to clarify the underlying molecular mechanism by which DIL ameliorates MI/R injury by downregulating mitophagy in vivo and in vitro. Thirty rats were randomized into three groups: the sham, MI/R, and MI/R+DIL (1 mg/kg) groups (n = 10/per group). MI/R injury was induced by ligating the left anterior descending (LAD) artery for 30min followed by 60min of reperfusion in vivo. H9C2 cells were selected to establish an oxygen-glucose deprivation/recovery (OGD/R) model to simulate MI/R injury in vitro. The potential mechanism by which DIL alleviates MI/R injury was analyzed based on tissue morphology, mitophagy-related gene transcription, and protein expression. According to histological and immunohistochemical evaluations, DIL significantly alleviated myocardial damage in vivo. Moreover, DIL significantly increased cell viability, attenuated OGD/R-induced apoptosis, and inhibited mitochondrial autophagy in vitro. Mechanistically, DIL attenuated mitochondrial autophagy through the upregulation of dual-specificity protein phosphatase 1 (DUSP1) and the downregulation of c-Jun N-terminal kinase (JNK) and Bcl2 interacting protein 3-like (BNIP3L, also known as NIX) expression. Diltiazem hydrochloride protects against myocardial ischemia/reperfusion injury in a BNIP3L/NIX-mediated mitophagy manner in vivo and in vitro.

Gamma irradiation green synthesis of (polyacrylamide/chitosan/silver nanoparticles) hydrogel nanocomposites and their using as antifungal against Candida albicans and anti-cancer modulator

Silver nanoparticles-loaded hydrogel nanocomposites are exploited for medicinal and pharmaceutical applications. Hydrogel nanocomposites were prepared from acrylamide (Am), chitosan (CS) and AgNO3 utilizing gamma rays. Diverse variables were applied in preparation of silver nanoparticles-laoded hydrogel nanocomposites of (PAm/CS)-AgNPs such as influence of radiation dose and influnece of CS concentration. Diverse techniques were utilized to characterize hydrogel nanocomposites; Fourier transform infrared spectroscopy (FTIR), thermal gravimetric analysis (TGA), X-ray diffraction (XRD), Transmission electron microscopy (TEM), energy dispersive X-ray (EDX) and scanning electron microscopy (SEM). Results confirmed formation of silver nanoparticles-loaded hydrogel nanocomposites of (PAm/CS)-AgNPs. Antifungal activity of (PAm/CS)-AgNPs hydrogel nanocomposites on viability of C. albicans was esitmated. Results displayed the efficient microbial inhibition activity of treatment against C. albicans compared to control. Furthermore, (PAm/CS)-AgNPs hydrogel nanocomposite against cervical cancer HeLa cell line was investigated. Cytotoxicity of (PAm/CS)-AgNPs hydrogel nanocomposites on prior cancer cell line empolyed to prohibition of cell growth assesssed by MTT test. HeLa cancer cell is treated by (PAm/CS)-AgNPs for 48 h exposed a potential apoptotic activity by noticeable up-regulation of p53 gene expression. Moreover, anticancer activity was investigated by down-regulation of platelet-based growth variable receptor beta (PDGFR-β), Bcl2, Cathepsine, and MMP-2 gene expression. antioxidant activity was investigated and results showed antioxidant activity of (PAm/CS) hydrogel and (PAm/CS)-AgNPs hydrogel nanocomposite are 87.8% and 62.9%, respectively.

Japanese encephalitis virus infection induces mitochondrial-mediated apoptosis through the proapoptotic protein BAX.

The Japanese encephalitis virus (JEV), a zoonotic flavivirus, is Asia's primary cause of viral encephalitis. JEV induces apoptosis in a variety of cells; however, the precise mechanisms underlying this apoptosis resulting from JEV infection remain to be elucidated. Our previous studies showed that the proapoptosis gene BAX may have a role in JEV proliferation. In this study, we constructed a PK-15 cell line (BAX.KO) with a knockout of the BAX gene using CRISPR/Cas9. The knockout of the BAX gene effectively inhibited the proliferation of JEV, resulting in a 39.9% decrease in viral protein levels, while BAX overexpression produced the opposite effect. We confirmed that JEV induces apoptosis of PK-15 using 4',6-diamidino-2-phenylindole (DAPI) staining and Annexin V-FITC/PI staining. Furthermore, we found that the phosphorylation of P53 and the expression levels of BAX, NOXA, PUMA, and cleaved-caspase-3/9 were significantly upregulated after JEV infection. Moreover, we found that JEV infection not only caused mitochondrial damage, the release of mitochondrial cytochrome C (Cyt C), and the downregulation of the apoptosis-inhibiting protein BCL-2 but also reduced the mitochondrial membrane potential (MOMP) and the accumulation of intracellular reactive oxygen species (ROS). These factors collectively encourage the activation of the mitochondrial apoptosis pathway. In contrast, BAX gene knockout significantly reduces the apoptotic changes caused by JEV infection. Treatment with the caspase3 inhibitor attenuated JEV-induced viral proliferation and release, leading to a decrease in viral protein levels of 46% in PK-15 cells and 30% in BAX.KO cells. In conclusion, this study clarified the molecular mechanisms of JEV-induced apoptosis and provided a theoretical basis for revealing the pathogenic mechanisms of JEV infection.

Potential Protective Effect of Orlistat: A Formulation of Nanocrystals Targeting Inflammation, Oxidative Stress, and Apoptosis in an Experimental Model of Doxorubicin-Induced Cardiotoxicity.

Background: Doxorubicin (DOX) is a widely used chemotherapeutic agent; nevertheless, cardiotoxicity limits its effectiveness. Orlistat (Orli) is an irreversible lipase enzyme inhibitor with poor solubility and bioavailability. Furthermore, Orli has a favorable impact on the decrease in cardiometabolic risk variables. Thus, this study aimed to investigate the novel use of Orlistat Nanocrystals (Orli-Nanocrystals) to mitigate DOX-induced cardiotoxicity and to identify probable pathways behind the cardioprotective effects. Methods: The pharmacokinetic parameters-area under % dose/g heart time curve (AUC0→4h), Drug targeting index (DTI), and relative targeting efficiency (RTE)-were calculated. Furthermore, experimental design mice were categorized into six groups: a (1) Normal control group, (2) Orli-Free group, (3) Orli-Nanocrystals group, (4) DOX group, (5) Orli-Free-DOX group, and (6) Orli-Nanocrystals-DOX group. All treatments were intraperitoneally injected once daily for 14 days with a single dose of DOX (15 mg/kg) on the 12th day for 4, 5, and 6 groups. Results: The pharmacokinetic parameters (Cmax, AUC) following oral administration of Orli-Nanocrystals presented a significant difference (higher values) in comparison to Orli due to the enhanced extent of the absorption of nanocrystals and, subsequently, their distribution to the heart. The study results indicated that DOX caused significant cardiotoxicity, as revealed by a remarkable rise in cardiac function biomarkers like LDH and CK-MB, which involve enzyme activities. Additionally, cardiac MDA content also increased; however, glutathione peroxidase, catalase, and superoxide dismutase activities were decreased. In the same context, DOX was found to have a remarkable downregulation in Nrf2, HO-1, Sirt-1, and Bcl2, while the upregulation of NF-κB, TNF-α, and BAX gene and protein expression occurred. Pretreatment with Orli-Nanocrystals displayed the most notable recovery of the altered immunohistochemical, histological, and biochemical characteristics as compared to the Orli-Free group. Conclusions: This work is the first investigation into the potential use of antioxidant, anti-inflammatory, and anti-apoptotic characteristics of Orli-Nanocrystals to protect against DOX-induced cardiotoxicity in vivo.

Nucleophosmin 1 overexpression enhances neuroprotection by attenuating cellular stress in traumatic brain injury

BackgroundTraumatic Brain Injury (TBI) is a multifaceted injury that can cause a wide range of symptoms and impairments, leading to significant effects on brain function. Nucleophosmin 1 (NPM1), a versatile phosphoprotein located in the nucleolus, is being recognized as a possible controller of cellular stress reactions and could be important in reducing neuro dysfunction caused by TBI. However the critical roles of NPM1 in cellular stress in TBI remains unclear. MethodsWe employed a control cortical impact mouse model and a scratch-induced primary neuronal culture model. Hematoxylin and eosin staining was used to evaluate tissue damage and cellular changes, with NPM1 expression in the cortical area assessed through immunofluorescence staining and Western blot analysis. Neuronal morphology was assessed using Nissl staining. Behavioral assessments were performed to evaluate the impact of NPM1 overexpression on neurobehavioral results in TBI mice. Mitochondrial function was assessed using an Extracellular Flux Analyzer. ResultsFollowing TBI, an increase in NPM1 expression was observed, with a peak at 72 h post-injury. Increased levels of NPM1 resulted in decreased neuronal cell death, as shown by Nissl staining, and lower levels of Caspase 8, APE1, H2AX, and 8-OHDG expression, indicating a reduction in DNA damage. NPM1 overexpression also resulted in improved neurobehavioral outcomes, characterized by decreased neurological deficits and enhanced motor function post-TBI. Additionally, in vitro, scratch-induction experiments revealed that NPM1 overexpression mitigated mitochondrial damage, as evidenced by the downregulation of P53, BCL2, and Cyto C expression levels and improvements in mitochondrial respiratory function. ConclusionThese findings suggest NPM1 as a promising target for developing interventions to alleviate TBI-related cellular stress and promote neuronal survival.

Evaluation of Anti-Proliferative and Apoptosis-Inducing Activities of the New Ciprofloxacin Derivative on Human Leukemia NB4 Cells

Backgrounds:: Leukemic stem cells are considered to be the main cause of treatment failure and disease recurrence due to their resistance to most common therapies. Apoptosis induction is one of the highly effective methods for treating cancer. Ciprofloxacin is among the compounds whose antitumor effects have been confirmed. Objectives: In this study, we investigated the anti-proliferative effect and induction of apoptosis by one of the derivatives of this family called 1-Cyclopropyl-6-fluoro-7-[4-(2-{[(1R,2S,5R)- 2- isopropyl-5-methylcyclohexyl]oxy}-2-oxoethyl)-piperazin-1-yl]-4-oxo-1,4-dihydroquinoline-3- carboxylic acid (ICH-CP) on NB4 cell line as an in vitro model of Acute promyelocytic leukemia (APL). NB4 cells were treated using the ICH-CP combination in various concentrations. Methods: The viability of NB4 cells was evaluated by MTT assay, and their morphology of apoptosis was examined by fluorescence microscopy. Flow cytometry and Annexin V/PI staining were used to quantify apoptosis. Finally, the expression of three genes, Bax, Bcl-2, and Survivin was inquired by real-time PCR. Results: According to the results, ICH-CP was able to destroy about 60% of NB4 cells in a dose and time-dependent manner. Light microscopy and fluorescence microscopy studies on treated cells confirmed the induction of apoptosis. Also, the real-time PCR analysis showed that ICH-CP induces apoptosis in the NB4 cell line via the down-regulation of Survivin and Bcl-2, in contrast to the up-regulation of the Bax gene. Conclusion: Based on the present data, it seems that the novel compound can be a good candidate for the treatment of acute myeloid leukemia. Furthermore, it is recommended to evaluate the qualification of ICH-CP as an adjunctive agent for other cancer cell lines.

Combinational delivery of berbamine and 5-fluorouracil in cerium oxide nanoparticles for colon cancer therapy: Insights from in vitro and in silico studies

Colon cancer is traditionally treated by an antimetabolite drug 5-fluorouracil (5FU) but has been linked to several drawbacks and systemic toxicity. To overcome drug associated toxicity, combination therapy is a promising strategy that synergistically enhances the therapeutic effects of co-delivered drugs while minimizing administration doses. Therefore, the current study aims to investigate the anti-colon cancer potency of 5FU co-delivered with a phytochemical i.e., berbamine (BERB) in a Cerium oxide nanoparticles (CONPs) delivery system. CONPs loaded 5FU (5FU-CONPs) and BERB (BERB-CONPs) were prepared and characterized using different analytical techniques. Successful entrapment of both drugs into CONPs formulations was detected under X-ray diffraction (XRD) observations. Drug-loaded CONPs in combination showed effective anti-oxidant activity by preventing reactive oxygen species (ROS) generations and had superior cytotoxic effects on HT-29 cell lines compared to treatment with native drugs singly or in combination. They also triggered apoptosis through p21, p53, Bax upregulation, and Bcl-2 downregulation, as confirmed by Western blot studies. Additionally, in silico analysis was performed using molecular docking and molecular dynamics simulation (MDS) to validate the in vitro results. Results of the study suggest that 5FU and BERB CONPs in combination could be taken as a possible therapeutic approach for colon cancer treatment.

Application of XBP1s Decoy Oligodeoxynucleotide Attenuates Cancerous Phenotype in Huh-7 Hepatocellular Carcinoma Cells.

The spliced form of X-box binding protein 1 (XBP1s) is a key transcription factor in the unfolded protein response (UPR), an adaptive mechanism for cell survival. Many studies demonstrated the induced expression of XBP1s in various cancers, including hepatocellular carcinoma (HCC). Such upregulated expression is linked to an enhancement of cell proliferation, migration, and improvement of the survival rate. In this study, we aimed to assess the therapeutic potential of targeting XBP1s, by specific decoy oligodeoxynucleotide (ODN) and evaluated the cancerous phenotypes in Huh-7 cells. In this experimental study, we transfected Huh-7 cells with XBP1s decoy oligonucleotide (ODN). Subsequently, we assess some cellular features, including viability, migration capacity, proliferation potential, and apoptosis. Therefore, various techniques included wound healing test, BrdU, and annexin/PI assays. Additionally, the colony formation capacity was evaluated. The mRNA expression levels of BAX, BCL-2, c-MYC, CCND1, MMP-9, CDH1, and CD133 were quantified by the reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Transfection of Huh-7 cells by XBP1s decoy ODN led to significant down-regulation of c-Myc, CCND1, MMP-9, BCL-2 and CD133 and up-regulation of CDH1 and BAX transcriptional expressions in comparison with the vehicle group. Our results also demonstrated that transfection of XBP1s-decoy reduced HCC cell viability, proliferation, migration capacity as well as colonization ability in comparison with the vehicle group. These findings proposed the potential application of XBP1s-decoy ODN to reduce cancerous phenotypes such as cell proliferation, cell migration and apoptosis induction in the Huh-7 cell line. More experiments on other cell lines and primary cells could validate our results.

Oral toxicity assessment and the mitigation of lung carcinogenesis by phytol and α-bisabolol combination treatment in swiss albino mice: insights into redox enzyme modulation and caspase-dependent cell death mechanisms.

This study examined the safety and potential anti-lung cancer effects of combinations of phytol and α-bisabolol in Swiss albino mice. Both acute and subacute toxicity assessments showed that the combination of phytol and α-bisabolol is safe, with no adverse effects observed at higher concentrations. Hematological, biochemical, and histopathological tests showed no signs of toxicity in the heart, lungs, liver, spleen, and kidneys. The LD50 was greater than 2000mg/kg, indicating a large safety margin. Histopathological analysis confirmed cancer induction in the B(a)P-induced group, which had significantly altered relative lung weights. Lung weight increased slightly pre and post-treatment, but histopathology showed normal alveolar epithelium. GSH and SOD levels increased significantly in B(a)P-exposed groups, indicating an adaptive antioxidant response. CAT levels increased significantly in the post-treatment group, demonstrating the role of combination of phytol and α-bisabolol in protecting against B(a)P-induced oxidative damage. Upregulation of Bax and downregulation of Bcl-2 caused a pro-apoptotic environment, suggesting a way to inhibit malignant cell survival. Modulation of caspase-3 and caspase-9 showed the complexity of carcinogen-induced apoptotic signaling. In conclusion, phytol and α-bisabolol were found to be safe and organ-protective, and demonstrated no acute or subacute toxicity. They modulate antioxidant defenses and apoptotic pathways, which may help prevent and treat lung cancer.

Folate-Functionalized Chitosan-PLGA Nanoparticles: A Novel approach for targeted osthole delivery in pancreatic cancer

Efficient drug delivery systems targeting cancer cells are crucial for enhancing cancer therapy. In this study, we developed PLGA nanoparticles coated with folate-conjugated chitosan (osthole-PLGA-NPs/CS-FA) to deliver osthole to cancer cells and investigated its inhibitory and molecular signaling mechanisms in the PANC-1 pancreatic cancer cell line. Field emission scanning electron microscopy (FESEM) revealed that osthole-PLGA-NPs/CS-FA had a spherical structure with a uniform size distribution. Dynamic light scattering (DLS) analysis showed an average size of 171.76 nm, a dispersion index 0.26, and a surface charge of + 33.08 mV, indicating stability and uniform dispersion. Fourier-transform infrared (FTIR) spectrum analysis confirmed the successful incorporation of osthole into the PLGA nanoparticles, with an encapsulation efficiency of 93.12 %. These physicochemical properties suggest efficient cellular uptake and targeted delivery. The antioxidant potential of osthole-PLGA-NPs/CS-FA was evaluated using the ABTS assay, showing concentration-dependent inhibition of free radicals with an IC50 value of 172.95 μg/mL. The anticancer properties were assessed using the MTT assay, demonstrating a significant and concentration-dependent cytotoxic effect on PANC-1 cells (IC50 = 31.2 μg/mL) with minimal impact on normal human foreskin fibroblast (HFF) cells. DAPI staining and flow cytometry analyses confirmed a concentration-dependent increase in apoptosis in PANC-1 cells. The nanoparticles induced upregulation of Bax and downregulation of Bcl2, indicating activation of the intrinsic mitochondrial apoptotic pathway. The anti-angiogenic activity of osthole-PLGA-NPs/CS-FA was evaluated using the chick chorioallantoic membrane (CAM) assay. The results showed significant inhibition of angiogenesis in a concentration-dependent manner, starting at 40 μg/mL and increasing up to 120 μg/mL. In conclusion, osthole-PLGA-NPs/CS-FA nanoparticles exhibit promising potential for targeted pancreatic cancer therapy by enhancing cellular uptake, inducing apoptosis, and inhibiting angiogenesis.

New application of ombuoside in protecting auditory cells from cisplatin-induced ototoxicity via the apoptosis pathway

Hearing loss is caused by many factors including ototoxic drug-induced hair cell damage. Ombuoside, an antioxidant isolated from Gynostemma pentaphyllum, has been suggested to serve as a new neuroprotective drug. However, the role of ombuoside in protecting inner ear hair cells from ototoxic drug-induced damage has not been investigated. Here, we demonstrated the protective potential of ombuoside in mitigating drug-induced ototoxicity in vivo and in vitro. We used cisplatin, a highly ototoxic anti-tumor drug, to induce hair cell damage. Our results showed that ombuoside significantly increased the survival of cisplatin-treated HEI-OC1 cells. Further mechanism research suggested that ombuoside protects HEI-OCI cells from cisplatin-induced apoptosis by reducing the cisplatin-induced upregulation of apoptosis-promoting proteins Bax, Bak, as well as apoptosis indicator proteins cytochrome C and cleaved-caspase-3, and the downregulation of apoptosis-inhibiting proteins Bcl-2. Ombuoside also protects the cells from the excessive ROS production and mitochondrial membrane depolarization triggered by cisplatin. These results demonstrated the potential for ombuoside in protecting hair cells from cisplatin by suppressing ROS generation and the mitochondrial apoptotic cascade. Ombuoside showed promise in protecting hair cells from cisplatin-induced apoptosis by suppressing ROS generation and the mitochondrial apoptotic cascade. Furthermore, ombuoside co-treatment in mouse cochlear explants and zebrafish lateral neuromasts rescued the decreased number and deformed morphology of hair cells resulting from cisplatin exposure. These findings further validated our conclusions and indicated that ombuoside is a potential protector against hearing loss caused by ototoxicity as a clinical side effect of cisplatin.