Exploring the Antiproliferative and Modulatory Effects of 1-Methoxyisobrassinin on Ovarian Cancer Cells: Insights into Cell Cycle Regulation, Apoptosis, Autophagy, and Its Interactions with NAC.

Ovarian cancer, a highly lethal malignancy among reproductive organ cancers, poses a significant challenge with its high mortality rate, particularly in advanced-stage cases resistant to platinum-based chemotherapy. This study explores the potential therapeutic efficacy of 1-methoxyisobrassinin (MB-591), a derivative of indole phytoalexins found in Cruciferae family plants, on both cisplatin-sensitive (A2780) and cisplatin-resistant ovarian cancer cells (A2780 cis). The findings reveal that MB-591 exhibits an antiproliferative effect on both cell lines, with significantly increased potency against cisplatin-sensitive cells. The substance induces alterations in the distribution of the cell cycle, particularly in the S and G2/M phases, accompanied by changes in key regulatory proteins. Moreover, MB-591 triggers apoptosis in both cell lines, involving caspase-9 cleavage, PARP cleavage induction, and DNA damage, accompanied by the generation of reactive oxygen species (ROS) and mitochondrial dysfunction. Notably, the substance selectively induces autophagy in cisplatin-resistant cells, suggesting potential targeted therapeutic applications. The study further explores the interplay between MB-591 and antioxidant N-acetylcysteine (NAC), in modulating cellular processes. NAC demonstrates a protective effect against MB-591-induced cytotoxicity, affecting cell cycle distribution and apoptosis-related proteins. Additionally, NAC exhibits inhibitory effects on autophagy initiation in cisplatin-resistant cells, suggesting its potential role in overcoming resistance mechanisms.

Investigations of Ni(II)Cysteine-Tyrosine Dithiocarbamate Complex: Synthesis, Characterization, Molecular Docking, Molecular Dynamic, and Anticancer Activity on MCF-7 Breast Cancer Cell Line.

OBJECTIVE: Breast cancer ranks second in terms of the highest number of cancer deaths for women worldwide and is one of the leading causes of death from cancer in women. The drug that is often used for chemotherapy is cisplatin. However, cisplatin drugs have a number of problems, including lack of selectivity, unwanted side effects, resistance, and toxicity in the body. In this work, we investigated Ni(II) cysteine-tyrosine dithiocarbamate complex against breast cancer. METHODS: Research on the new complex compound Ni(II) cysteine-tyrosine dithiocarbamate have several stages including synthesis, characterization, in-silico and in-vitro testing of MCF-7 cells for anticancer drugs. The synthesis involved reacting cysteine, CS2, KOH and tyrosine with Mn metal. The new complex compound Ni(II) cysteine-tyrosine dithiocarbamate has been synthesized, characterized, and tested in vitro MCF-7 cells for anticancer drugs. Characterization tests such as melting point, conductivity, SEM-EDS, UV Vis, XRD, and FT-IR spectroscopy have been carried out. RESULT: The synthesis yielded a 60,16%, conversion with a melting point of 216-218 oC and a conductivity value of 0.4 mS/cm. In vitro test results showed morphological changes (apoptosis) in MCF-7 cancer cells starting at a sample concentration of 250 µg/mL and an IC50 value of 618.40 µg/mL. Molecular docking study of Ni(II) cysteine-tyrosine dithiocarbamate complex identified with 4,4',4''-[(2R)-butane-1,1,2-triyl]triphenol - Estrogen α showing active site with acidic residue amino E323, M388, L387, G390 and I389. Hydrophobic and hydrophobic bonds are seen in Ni(II) cysteine-tyrosine dithiocarbamate - Estrogen α has a binding energy of -80.9429 kJ /mol. CONCLUSION: there were 5 residues responsible for maintaining the ligand binding stable. The compound had significant Hbond contact intensity, however, it was not strong enough to make a significant anticancer effect. Though the synthesized compound shows low bioactivity, this research is expected to give valuable insight into the effect of molecular structure on anticancer activity.

Molinate induces organ defects by promoting apoptosis, inflammation, and endoplasmic reticulum stress during the developmental stage of zebrafish.

Molinate is classified as a thiocarbamate herbicide and is mainly used in paddy fields to culture rice. However, the toxic effects of molinate and the associated mechanisms in the process of development have not been completely elucidated. Therefore, in the present study, we demonstrated that molinate reduced the viability of zebrafish larvae and the probability of successful hatching using zebrafish (Danio rerio), one of the remarkable in vivo models for testing the toxicity of chemicals. In addition, molinate treatment triggered the occurrence of apoptosis, inflammation, and endoplasmic reticulum (ER) stress response in zebrafish larvae. Furthermore, we identified that an abnormal cardiovascular phenotype through wild type zebrafish, neuronal defects through transgenic olig2:dsRed zebrafish, and developmental toxicity in the liver through transgenic lfabp:dsRed zebrafish. Collectively, these results provide evidence of the hazardous effects of molinate on the developmental stage of non-target organisms by elucidating the toxic mechanisms of molinate in developing zebrafish.

Role of nuclear factor kappa-B in TNF-induced cytoprotection.

Ischaemic heart disease (IHD) is a leading cause of death worldwide. Understanding prosurvival signalling pathways that protect against ischaemia-reperfusion injury (IRI) may assist in the development of novel cardioprotective strategies against IHD. In this regard, the transcription factor, nuclear factor kappa-B (NFκB) is activated by tumour necrosis factor (TNF), but its role in TNF-induced cytoprotection is unknown. Therefore, to investigate the role of NFκB in TNF-induced cytoprotection, C2C12 cells were pretreated with TNF (0.5 ng/ml) in the presence and absence of an NFκB inhibitor, pyrrolidine derivative of dithiocarbamate (PDTC; 100 µM). Cells were subjected to simulated IRI and treated with PDTC, either during TNF exposure or at reperfusion. Phosphorylation of IkB was measured after the TNF stimulus. Cytoprotection by TNF in cells subjected to IRI (cell viability: 43.7 ± 8.1% in control vs 70.6 ± 6.1% with TNF, p < 0.001) was abrogated by co-administration of PDTC (40.6 ± 1.9%, p < 0.001 vs TNF) but not by exposure to PDTC at reperfusion (70.7 ± 1.7%). Cytosolic IkB phosphorylation [1.5 ± 0.2 arbitrary units (AU) for TNF vs 1.0 ± 0.0 for untreated, p < 0.01]) was increased after TNF exposure and this increase was abolished by co-administration with PDTC (0.8 ± 0.3 AU, p < 0 01 vs TNF). Our data suggest that NFκB acts as a key component in TNF-induced cytoprotection. These findings may pave the way for the development of novel therapeutic drugs that target TNF/NFκB signalling to protect against IHD.

Pyrrolidine Dithiocarbamate-loaded Electrospun Membranes for Peritendinous Anti-adhesion through Inhibition of the Nuclear Factor-κB Pathway.

Peritendinous adhesion is a major cause of limb dysfunction and disability in clinical practice. Numerous studies suggest that activation of nuclear factor-κB (NF-κB) pathway in macrophages could be the pivotal figure in excessive collagen synthesis and thus peritendinous adhesion formation. In this study, we assumed this pathological process could be suppressed by inhibiting NF-κB phosphorylation and nuclear translocation using pyrrolidine dithiocarbamate (PDTC), a specific NF-κB inhibitor with the ability to penetrate cell membranes, in macrophages. Then, we conducted electrospinning process to incorporate PDTC into poly(L-lactic) acid (PLA) electrospinning membranes, that is, the PDTC-PLA membranes. Further, with integral film quality and stable drug release property, the PDTC-PLA membranes were subsequently analyzed in the capability and mechanism of preventing adhesion formation both in vitro and in vivo. Our results showed inhibition of macrophage proliferation as well as NF-κB pathway activation from in vitro assays and outstanding promotion in inhibiting NF-κB p65 phosphorylation and reducing adhesion formation from in vivo assays of PDTC-PLA compared to PLA membranes. In conclusion, our findings suggested that PDTC-PLA as an alternative therapeutic approach alleviated inflammation and peritendinous adhesion formation through NF-κB signaling pathway. STATEMENT OF SIGNIFICANCE: Pyrrolidine dithiocarbamate (PDTC) can be blended into poly-L-lactic acid (PLA) fibrous membranes by electrospinning process. This incorporation of PDTC into PLA is an effective way to inhibit proinflammatory activation of macrophages and to achieve advanced anti-adhesion outcome after tendon repair.

D609 inhibition of phosphatidylcholine-specific phospholipase C attenuates prolonged insulin stimulation-mediated GLUT4 downregulation in 3T3-L1 adipocytes

Glucose uptake is stimulated by insulin via stimulation of glucose transporter 4 (GLUT4) translocation to the plasma membrane from intracellular compartments in adipose tissue and muscles. Insulin stimulation for prolonged periods depletes GLUT4 protein, particularly in highly insulin-responsive GLUT4 storage vesicles. This depletion mainly occurs via H2O2-mediated retromer inhibition. However, the post-receptor mechanism of insulin activation of oxidative stress remains unknown. Here, we show that phosphatidylcholine-specific phospholipase C (PC-PLC) plays an important role in insulin-mediated downregulation of GLUT4. In the study, 3T3-L1 adipocytes were exposed to a PC-PLC inhibitor, tricyclodecan-9-yl-xanthogenate (D609), for 30 min prior to the stimulation with 500 nM insulin for 4 h, weakening the depletion of GLUT4. D609 also prevents insulin-driven H2O2 generation in 3T3-L1 adipocytes. Exogenous PC-PLC and its product, phosphocholine (PCho), also caused GLUT4 depletion and promoted H2O2 generation in 3T3-L1 adipocytes. Furthermore, insulin-mediated the increase in the cellular membrane PC-PLC activity was observed in Amplex Red assays. These results suggested that PC-PLC plays an important role in insulin-mediated downregulation of GLUT4 and that PCho may serve as a signaling molecule. (AU)

The Versatility in the Applications of Dithiocarbamates.

Dithiocarbamate ligands have the ability to form stable complexes with transition metals, and this chelating ability has been utilized in numerous applications. The complexes have also been used to synthesize other useful compounds. Here, the up-to-date applications of dithiocarbamate ligands and complexes are extensively discussed. Some of these are their use as enzyme inhibitor and treatment of HIV and other diseases. The application as anticancer, antimicrobial, medical imaging and anti-inflammatory agents is examined. Moreover, the application in the industry as vulcanization accelerator, froth flotation collector, antifouling, coatings, lubricant additives and sensors is discussed. The various ways in which they have been employed in synthesis of other compounds are highlighted. Finally, the agricultural uses and remediation of heavy metals via dithiocarbamate compounds are comprehensively discussed.

D609 inhibition of phosphatidylcholine-specific phospholipase C attenuates prolonged insulin stimulation-mediated GLUT4 downregulation in 3T3-L1 adipocytes.

Glucose uptake is stimulated by insulin via stimulation of glucose transporter 4 (GLUT4) translocation to the plasma membrane from intracellular compartments in adipose tissue and muscles. Insulin stimulation for prolonged periods depletes GLUT4 protein, particularly in highly insulin-responsive GLUT4 storage vesicles. This depletion mainly occurs via H2O2-mediated retromer inhibition. However, the post-receptor mechanism of insulin activation of oxidative stress remains unknown. Here, we show that phosphatidylcholine-specific phospholipase C (PC-PLC) plays an important role in insulin-mediated downregulation of GLUT4. In the study, 3T3-L1 adipocytes were exposed to a PC-PLC inhibitor, tricyclodecan-9-yl-xanthogenate (D609), for 30 min prior to the stimulation with 500 nM insulin for 4 h, weakening the depletion of GLUT4. D609 also prevents insulin-driven H2O2 generation in 3T3-L1 adipocytes. Exogenous PC-PLC and its product, phosphocholine (PCho), also caused GLUT4 depletion and promoted H2O2 generation in 3T3-L1 adipocytes. Furthermore, insulin-mediated the increase in the cellular membrane PC-PLC activity was observed in Amplex Red assays. These results suggested that PC-PLC plays an important role in insulin-mediated downregulation of GLUT4 and that PCho may serve as a signaling molecule.

Dithiocarbamates effectively inhibit the α-carbonic anhydrase from Neisseria gonorrhoeae.

Recently, inorganic anions and sulphonamides, two of the main classes of zinc-binding carbonic anhydrase inhibitors (CAIs), were investigated for inhibition of the α-class carbonic anhydrase (CA, EC 4.2.1.1) from Neisseria gonorrhoeae, NgCA. As an extension to our previous studies, we report that dithiocarbamates (DTCs) derived from primary or secondary amines constitute a class of efficient inhibitors of NgCA. KIs ranging between 83.7 and 827 nM were measured for a series of 31 DTCs that incorporated various aliphatic, aromatic, and heterocyclic scaffolds. A subset of DTCs were selected for antimicrobial testing against N. gonorrhoeae, and three molecules displayed minimum inhibitory concentration (MIC) values less than or equal to 8 µg/mL. As NgCA was recently validated as an antibacterial drug target, the DTCs may lead to development of novel antigonococcal agents.

Association between increased inflammatory cytokine expression in the lateral habenular nucleus and depressive-like behavior induced by unpredictable chronic stress in rats.

Depression induced by unpredictable chronic stress (UCS) has been widely studied using animal models. However, its underlying pathological mechanisms remain unclear. Increased inflammatory cytokines (ICs) in the central nervous system (CNS) are closely related to depressive disorder. UCS was used as an animal model in this study to investigate how UCS-induced changes in cytokine signaling lead to depression. We found that UCS could increase ICs in the CNS, especially in the habenular nucleus (Hb). UCS resulted in decreased expression of Menin in Hb and increased the activation of the NF-κB signaling pathway. Local administration of tumor necrosis factor-α in the lateral Hb (LHb) could induce depressive-like behavior in rats. The anti-inflammatory drug aspirin and the NF-κB inhibitor pyrrolidine dithiocarbamate could alleviate depressive-like behavior. This phenomenon was not observed for local administration in the dorsal raphe nucleus and paraventricular nucleus. These results indicate that LHb is the main central target for ICs to regulate depressive-like behaviors. We also found that LHb lesions could improve the inflammatory response in the hippocampus, reduce the activation of the NF-κB signaling pathway and the expression of ICs, and increase the expression of brain-derived neurotrophic factor and its receptor tropomyosin receptor kinase B, collectively improving the neuroinflammation caused by UCS. Moreover, LHb lesions improve not only hippocampal neurogenesis damage caused by UCS by activating the PI3K/mTOR signaling pathway but also hippocampal function by reducing the expression of apoptosis-related proteins, including phosphorylated p53, Bax, Bcl2, and cleaved-caspase3. In conclusion, our study sheds light on the pathogenesis of ICs-induced depression. Anti-inflammation in the CNS could be a new strategy in the treatment of depression.

Design, synthesis and evaluation of novel bis-substituted aromatic amide dithiocarbamate derivatives as colchicine site tubulin polymerization inhibitors with potent anticancer activities.

As the continuation of our work on the development of tubulin inhibitors with potential anticancer activities, novel bis-substituted aromatic amide dithiocarbamate derivatives were designed by contacting bis-substituted aryl scaffolds (potential anti-tubulin fragments) with N-containing heterocycles (potential anti-tubulin fragments) in one hybrid using the anticancer dithioformate unit as the linker. The antiproliferative activity against three digestive tract tumor cells was evaluated and preliminary structure activity relationships were summarized. Among these compounds, compound 20q exhibited most potent antiproliferative activity against MGC-803, HCT-116, Kyse30 and Kyse450 cells with IC50 values of 0.084, 0.227, 0.069 and 0.078 µM, respectively. In further studies, compound 20q was identified as a novel tubulin inhibitor targeting the colchicine binding site. Compound 20q could inhibit the microtubule assembly and disrupt cytoskeleton in Kyse30 and Kyse450 cells. The results of molecular docking suggested that compound 20q could tightly bind into the colchicine binding site of tubulin by hydrogen bonds and hydrophobic interactions. Compound 20q dose-dependently inhibited the cell growth and colony formation, effectively arrested cells at the G2/M phase and induce mitochondrial apoptosis in Kyse30 and Kyse450 cells. In addition, Compound 20q could regulate the expression of G2/M phase and mitochondrial apoptosis related proteins. Collectively, compound 20q was here reported as a novel tubulin inhibitor with potential anticancer activities.

Dithiocarbamates combined with copper for revitalizing meropenem efficacy against NDM-1-producing Carbapenem-resistant Enterobacteriaceae.

The worldwide prevalence of NDM-1-producing Gram-negative pathogens has drastically undermined the clinical efficacy of carbapenems, prompting a need to devise an effective strategy to preserve their clinical value. Here we constructed a focused compound library of dithiocarbamates and systematically evaluated their potential synergistic antibacterial activities combined with copper. SA09-Cu exhibited excellent inhibition against a series of clinical NDM-1-producing carbapenem-resistant Enterobacteriaceae (CRE) in restoring meropenem effect, and slowed down the development of carbapenem resistance. Enzymatic kinetic and isothermal titration calorimetry studies demonstrated that SA09-Cu was a noncompetitive NDM-1 inhibitor. The electron paramagnetic resonance (EPR) and X-ray photoelectron spectroscopy (XPS) revealed a novel inhibition mechanism, which is that SA09-Cu could convert NDM-1 into an inactive state by oxidizing the Zn(II)-thiolate site of the enzyme. Importantly, SA09-Cu showed a unique redox tuning ability, and avoided to be reduced by intracellular thiols of bacteria. In vivo experiments indicated that SA09 combined with CuGlu could effectively potentiate MER's effect against NDM-1-producing E. coli (EC23) in the murine infection model. This study provides a highly promising scaffold in developing novel inhibitors to combat NDM-1-producing CREs.

Facile green approach towards the synthesis of some phenyl piperazine based dithiocarbamates as potent hemolytic and thrombolytic agents.

The facile and efficient protocol for the synthesis of N-phenyl piperazine based di-thio-carbamates has been reported under neat conditions. A library of novel piperazine based di-thio-carbamates (3a-h) in excellent yields has been prepared. Solvent free, catalyst free and easy work up conditions make this protocol an attractive synthetic protocol to achieve novel biologically active di-thio-carbamates. The synthesized molecules have been characterized by FT-IR, 1HNMR and 13CNMR spectroscopic techniques. The pharmacological aspects of these derivatives have been evaluated via hemolysis and thrombolysis. All the target molecules (3a-h) exhibit mild to medium potential as hemolytic and thrombolytic agents. Among the synthesized derivatives, compound 3c showed least cytotoxicity and better thrombolytic potential.

Ferritinophagy-Mediated ROS Production Contributed to Proliferation Inhibition, Apoptosis, and Ferroptosis Induction in Action of Mechanism of 2-Pyridylhydrazone Dithiocarbamate Acetate.

Reactive oxygen species (ROS) production is involved in the mechanism of action of a number of drugs, but the biological effects of ROS remain to be clarified. Furthermore, ferroptosis involves iron-dependent ROS production that may be derived from ferritinophagy; however, the association between ferroptosis and ferritinophagy has not been fully established. The present study demonstrated that dithiocarbamate derivatives (iron chelators) exhibited antineoplastic properties involving ferritinophagy induction, but whether the underlying mechanisms involved ferroptosis was unknown. To gain insight into the underlying mechanism, a dithiocarbamate derivative, 2-pyridylhydrazone dithiocarbamate s-acetic acid (PdtaA), was prepared. An MTT assay demonstrated that PdtaA inhibited proliferation involving ROS production (IC50 = 23.0 ± 1.5 µM for HepG2 cells). A preliminary mechanistic study revealed that PdtaA induced both apoptosis and cell cycle arrest. Notably, PdtaA also induced ferroptosis via downregulation of GPx4 and xCT, which was first reported for a dithiocarbamate derivative. Moreover, these cellular events were associated with ROS production. To explore the origin of ROS, expression of the ferritinophagy-related genes, ferritin, and nuclear receptor coactivator (NCOA4) were measured. Immunofluorescence and western blotting analysis indicated that PdtaA-induced ferritinophagy may contribute to ROS production. To investigate the role of ferritinophagy, autophagy inhibitor 3-methyladenin or genetic knockdown of NCOA4 was employed to inhibit ferritinophagy, which significantly neutralized the action of PdtaA in both apoptosis and ferroptosis. Taken together, PdtaA-induced cell cycle arrest, apoptosis, and ferroptosis were associated with ferritinophagy.

Amyloid Beta-Peptide 25-35 (Aß25-35) Induces Cytotoxicity via Multiple Mechanisms: Roles of the Inhibition of Glucosylceramide Synthase by Aß25-35 and Its Protection by D609.

Sphingolipids (SLs), such as ceramide, glucosylceramide (GlcCer), and sphingomyelin, play important roles in the normal development/functions of the brain and peripheral tissues. Disruption of SL homeostasis in cells/organelles, specifically up-regulation of ceramide, is involved in multiple diseases including Alzheimer's disease (AD). One of the pathological features of AD is aggregates of amyloid beta (Aß) peptides, and SLs regulate both the formation/aggregation of Aß and Aß-induced cellular responses. Up-regulation of ceramide levels via de novo and salvage synthesis pathways is reported in Aß-treated cells and brains with AD; however, the effects of Aß on ceramide decomposition pathways have not been elucidated. Thus, we investigated the effects of the 25-35-amino acid Aß peptide (Aß25-35), the fundamental cytotoxic domain of Aß, on SL metabolism in cells treated with the fluorescent nitrobenzo-2-oxa-1,3-diazole-labeled C6-ceramide (NBD-ceramide). Aß25-35 treatment reduced the formation of NBD-GlcCer mediated by GlcCer synthase (GCS) without affecting the formation of NBD-sphingomyelin or NBD-ceramide-1-phosphate, and reduced cell viability. Aß25-35-induced responses decreased in cells treated with D609, a putative inhibitor of sphingomyelin synthases. Aß25-35-induced cytotoxicity significantly increased in GCS-knockout cells and pharmacological inhibition of GCS alone demonstrated cytotoxicity. Our study revealed that Aß25-35-induced cytotoxicity is at least partially mediated by the inhibition of GCS activity.

Antiproliferative activity and electrochemical oxygen evolution by Ni(II) complexes of N'-(aroyl)-hydrazine carbodithioates.

The electrochemical water splitting by transition metal complexes is emerging very rapidly. The nickel complexes also play a very vital role in various biological activities. Here, three new ligands {H2mbhce = N'-(4-methyl-benzoyl), H2pchce = N'-(pyridine-carbonyl) and H2hbhce = N'-(2-hydroxy-benzoyl) hydrazine carbodithioic acid ethyl ester} and their corresponding Ni(II) complexes [Ni(Hmbhce)2(py)2] (1), [Ni(pchce)(o-phen)2]·CH3OH·H2O (2) and [Ni(hbhce)(o-phen)2]·1.75CHCl3·H2O (3) have been synthesized and fully characterized by various physicochemical and X-ray crystallography techniques. The photoluminescence study and thermal degradations were also examined. The treatment of K562 cells with the increasing concentrations of the nickel salts, ligands, and complexes 1, 2, and 3 showed dose-dependent cytotoxicity. The cytotoxic activity of ligands reveals that ligand H2mbhce is more potent in inhibiting the growth of tumor cells in comparison to other ligands H2pbhce and H2hbhce. Cytotoxicity assay results indicate that all complexes have remarkable cytotoxic potential in comparison to either nickel salts or the free ligands. Among these complexes, complex 1 has significantly better anti-tumor activity as compared to complexes 2 and 3. The electrochemical study of complexes 1, 2, and 3 for water oxidation reveals that all the complexes possess admirable electrocatalytic activity towards oxygen evolution reaction (OER) and have lower overpotential (328, 338, and 370 mV, respectively) than many previously reported complexes and RuO2 (390 mV). Among complexes 1, 2, and 3, complex-2 shows a better water oxidation response. Consequently, these complexes have great potential to be utilized in fuel cells. The more reliable electrochemical parameter TOF is also calculated for all three complexes.

Protective effect of pyrrolidine dithiocarbamate against methotrexate-induced testicular damage.

The aim of the study was to investigate the protective effect of pyrrolidine dithiocarbamate (PDTC) against methotrexate (MTX)-induced testicular damage in rats. Forty Wistar albino male rats were divided into equally four groups: Control group (saline solution, IP), PDTC group (100 mg/kg PDTC,IP, 10 days), MTX group (20 mg/kg MTX, IP, single dose, on the 6th day) and MTX + PDTC group (100 mg/kg PDTC, IP, 10 days and 20 mg/kg MTX, IP, single dose, on the 6th day). After 10 days, testicular tissues were excised for morphometric, histological and immunohistochemical evaluations. Serum testosterone, follicle stimulating hormone (FSH), luteinizing hormone (LH) and prokineticin 2 (PK2) levels were determined. Body and testicular weights were measured. Testicular damage was assessed by histological evaluation. Nuclear factor kappa B (NFkB), nuclear factor erythroid 2 related factor 2 (Nrf2) and PK2 immunoreactivities were evaluated by HSCORE. Body and testicular weights, serum FSH, LH, testosterone levels, seminiferous tubule diameter and germinal epithelial thickness were significantly decreased in the MTX group. However, serum PK2 level, histologically damaged seminiferous tubules and interstitial field width were significantly increased. Additionally, there was an increase in NFkB and PK2 immunoreactivity, whereas there was a significant decrease in Nrf2 immunoreactivity. PDTC significantly improved hormonal, morphometric, histological and immunohistochemical findings. Taken together, we conclude that PDTC may reduce MTX-induced testicular damage via NFkB, Nrf2 and PK2 signaling pathways.

Pyridazinones containing dithiocarbamoyl moieties as a new class of selective MAO-B inhibitors.

A novel class of potential MAO-B inhibitors was designed and synthesized in good yield by combining the pyridazinone moiety with the dithiocarbamate framework, two relevant pharmacophores for drug discovery. The biological results obtained for the different pyridazinone/dithiocarbamate hybrids (compounds 8-14) indicated that most of them reversibly and selectively inhibit the hMAO-B in vitro with IC50 values in the µM range and exhibit not significant cellular toxicity. The analogues 9a1, 11a1, 12a2, 12b1 and 12b2, which present the dithiocarbamate fragment derivatized with a piperidin-1-yl or pyrrolidin-1-yl group and placed at C3 or C4 of the diazine ring, were the most attractive compounds of these series. Molecular modeling studies were performed to analyze the binding mode to the enzyme and the structure activity relationships of the titled compounds, as well as to predict their drug-like properties.

Intraperitoneal injection of PDTC on the NF-kB signaling pathway and osteogenesis indexes of young adult rats with anterior palatal suture expansion model.

In recent years, many studies have found that mechanical tension can activiate NF-kB signal pathway and NF-kB plays an important role in the process of osteogenesis. However, it is still unclear whether this process exists in the anterior palatal suture expansion. In this paper, we mainly studied the effect of intraperitoneal injection of PDTC on the NF-kB signaling pathway and osteogenesis index of the anterior palatal suture expansion model in young adult rats. The expansion model is grouped and established: 45 male 8-week-old Sprague-Dawley rats were randomly divided into three groups, an expansion only (EO) group, an expansion plus PDTC (PE) group, and a control group. The results revealed that PDTC inhibited the activity of NF-kB signaling pathway and promote one morphogenetic protein 2 (BMP-2), steocalatin (OCN) expression. Compared with the control group, the optical density (OD) value of BMP in the EO group and PE group rats increased significantly from the first day to the seventh day, and the difference was statistically significant (P<0.05). After 6.0Gy irradiation, PDTC administration group could slightly increase the total SOD level in the liver and serum of rats, and reduce the MDA level in the liver and serum, especially the effect of 60mg/kg and 90mg/kg was the most obvious.

Synthesis and anticancer evaluation of 2-oxo-2-(arylamino) ethyl 4-phenylpiperazine-1-carbodithioates.

Piperazine moiety is found as an efficient pharmacological scaffold in various drugs. To explore the anticancer potential of piperazine framework, a series of novel N-acetamides derivatives of phenyl piperazine containing di-thio-carbamate moiety was designed and synthesized. 1HNMR, 13CNMR, FT-IR and mass spectrometry were used for the structures elucidation of these derivatives. In-vitro cytotoxic evaluation of the prepared novel compounds against lung carcinoma A-549 was carried out using standard MTT assay. All the di-thio-carbamate-piperazine derivatives exhibited moderate to excellent cytotoxic potential against A-549 cell line based on cell viability. Particularly, 6e was found to be the most potent derivative with cell viability 34.12±0.73 % at 100 µg/mL concentration and represents promising lead compound for future progress.