Bacterial Tyrosinase Inhibition, Hemolytic and Thrombolytic Screening, and In Silico Modeling of Rationally Designed Tosyl Piperazine-Engrafted Dithiocarbamate Derivatives.

Piperazine is a privileged moiety that is a structural part of many clinical drugs. Piperazine-based scaffolds have attracted the attention of pharmaceutical and medicinal scientists to develop novel, efficient therapeutic agents owing to their significant and promising biological profile. In the current study, an ecofriendly ultrasonic-assisted synthetic approach was applied to achieve a novel series of 1-tosyl piperazine dithiocarbamate acetamide hybrids 4a-4j, which was evaluated for in vitro tyrosinase inhibition and thrombolytic and hemolytic cytotoxic activities. Among all the piperazine-based dithiocarbamate acetamide target molecules 4a-4j, the structural analogs 4d displayed excellent tyrosinase inhibition efficacy (IC50 = 6.88 ± 0.11 µM) which was better than the reference standard drugs kojic acid (30.34 ± 0.75 µM) and ascorbic acid (11.5 ± 1.00 µM), respectively, which was further confirmed by in silico induced-fit docking (IFD) simulation Good tyrosinase activities were exhibited by 4g (IC50 = 7.24 ± 0.15 µM), 4b (IC50 = 8.01 ± 0.11 µM) and 4c (IC50 = 8.1 ± 0.30 µM) dithiocarbamate acetamides, which were also better tyrosinase inhibitors than the reference drugs but were less active than the 4d structural hybrid. All the derivatives are less toxic, having values in the 0.29 ± 0.01% to 15.6 ± 0.5% range. The scaffold 4b demonstrated better hemolytic potential (0.29 ± 0.01%), while a remarkably high thrombolytic chemotherapeutic potential was displayed by analog 4e (67.3 ± 0.2%).

In silico targeting of colony-stimulating factor-1 receptor: delineating immunotherapy in cancer.

Aim: Delineate structure-based inhibition of colony-stimulating factor-1 receptor (CSF1R) by small molecule CSF1R inhibitors in clinical development for target identification and potential lead optimization in cancer therapeutics since CSF1R is a novel predictive biomarker for immunotherapy in cancer. Methods: Compounds were in silico modelled by induced fit docking protocol in a molecular operating environment (MOE, MOE.v.2015). The 3-dimensional (3D) X-ray crystallized structure of CSF1R kinase (Protein Databank, ID 4R7H) was obtained from Research Collaboratory for Structural Bioinformatics (RSCB) Protein Databank. The 3D conformers of edicotinib, DCC-3014, ARRY-382, BLZ-945, chiauranib, dovitinib, and sorafenib were obtained from PubChem Database. These structures were modelled in Amber10:EHT molecular force field, and quick prep application was used to correct and optimize the structures for missing residues, H-counts, termini capping, and alternates. The binding site was defined within the vicinity of the co-crystallized ligand of CSF1R kinase. The compounds were docked by the triangular matcher placement method and ranked by the London dG scoring function. The docked poses were further refined by the induced fit method. The pose with the lowest binding score (ΔG) was used to model the ligand interaction profile in Discovery Studio Visualizer v17.2. The co-crystallized ligand was docked in its apo conformation, and root-mean-square deviation was computed to validate the docking protocol. Results: All 7 CSF1R inhibitors interact with residue Met637 exhibiting selectivity except for edicotinib. The inhibitors maintain CSF1R in an auto-inhibitory conformation by interacting with Asp797 of the Asp-Phe-Gly (DFG) motif and/or hindering the conserved salt bridge formed between Glu633 and Lys616 thus stabilizing the activation loop, or interacting with tryptophan residue (Trp550) in the juxtamembrane domain. DCC-3014, ARRY-382, BLZ-945, and sorafenib bind with the lowest binding energy with CSF1R kinase. Conclusions: Pyrimidines are potent inhibitors that interact with CSF1R residues. DCC-3014 and ARRY-382 exhibit exceptional pharmaceutical potential exhibiting great structural stability and affinity.

Unfolding the Antibacterial Activity and Acetylcholinesterase Inhibition Potential of Benzofuran-Triazole Hybrids: Synthesis, Antibacterial, Acetylcholinesterase Inhibition, and Molecular Docking Studies.

In this study, a series of novel benzofuran-based 1,2,4-triazole derivatives (10a-e) were synthesized and evaluated for their inhibitory potential against acetylcholinesterase (AChE) and bacterial strains (E. coli and B. subtilis). Preliminary results revealed that almost all assayed compounds displayed promising efficacy against AChE, while compound 10d was found to be a highly potent inhibitor of AChE. Similarly, these 5-bromobenzofuran-triazoles 10a-e were screened against B. subtilis QB-928 and E. coli AB-274 to evaluate their antibacterial potential in comparison to the standard antibacterial drug penicillin. Compound 10b was found to be the most active among all screened scaffolds, with an MIC value of 1.25 ± 0.60 µg/mL against B. subtilis, having comparable therapeutic efficacy to the standard drug penicillin (1 ± 1.50 µg/mL). Compound 10a displayed excellent antibacterial therapeutic efficacy against the E. coli strain with comparable MIC of 1.80 ± 0.25 µg/mL to that of the commercial drug penicillin (2.4 ± 1.00 µg/mL). Both the benzofuran-triazole molecules 10a and 10b showed a larger zone of inhibition. Moreover, IFD simulation highlighted compound 10d as a novel lead anticholinesterase scaffold conforming to block entrance, limiting the swinging gate, and disrupting the catalytic triad of AChE, and further supported its significant AChE inhibition with an IC50 value of 0.55 ± 1.00 µM. Therefore, compound 10d might be a promising candidate for further development in Alzheimer's disease treatment, and compounds 10a and 10b may be lead antibacterial agents.

Protease inhibition, in vitro antibacterial and IFD/MM-GBSA studies of ciprofloxacin-based acetanilides.

In this study, we have investigated ciprofloxacin-based acetanilides for their in-vitro inhibitory study against gram +ve, -ve bacteria and serine protease activity. The compounds 4e and 4g showed excellent antibacterial activity against Bacillus subtilis with a zone of inhibition (ZI) values of 40 ± 0.9 mm, 37 ± 1.4 mm and with MIC values of 4.0 ± 0.78 mg/mL, 3.0 ± 0.98 mg/ML respectively, while 4a and 4i were found most active against Escherichia coli, with ZI values 38 ± 0.1 mm, 46 ± 1.8 mm and with MIC values of 1.0 ± 0.25 mg/mL, 1.0 ± 0.23 mg/mL respectively. All derivatives (4a-j) significantly inhibited the catalytic activity of serine protease, while 4a exhibited a maximum (100%) inhibitory effect at 96 minutes having 22.50 minutes [Formula: see text], and non-competitive inhibition with 0.1±0.00µM Ki. The IFD/MM-GBSA studies highlighted the binding mode of 4a for protease inhibition and indicated improved binding affinity with -107.62 kcal/mol of ΔGbind.

Ultrasound-Assisted Synthesis and In Silico Modeling of Methanesulfonyl-Piperazine-Based Dithiocarbamates as Potential Anticancer, Thrombolytic, and Hemolytic Structural Motifs.

Piperazine-based dithiocarbamates serve as important scaffolds for numerous pharmacologically active drugs. The current study investigates the design and synthesis of a series of dithiocarbamates with a piperazine unit as well as their biological activities. Under ultrasound conditions, the corresponding piperazine-1-carbodithioates 5a-5j were synthesized from monosubstituted piperazine 2 and N-phenylacetamides 4a-4j in the presence of sodium acetate and carbon disulfide in methanol. The structures of the newly synthesized piperazines were confirmed, and their anti-lung carcinoma effects were evaluated. A cytotoxic assay was performed to assess the hemolytic and thrombolytic potential of the synthesized piperazines 5a-5j. The types of substituents on the aryl ring were found to affect the anticancer activity of piperazines 5a-5j. Piperazines containing 2-chlorophenyl (5b; cell viability = 25.11 ± 2.49) and 2,4-dimethylphenyl (5i; cell viability = 25.31 ± 3.62) moieties demonstrated the most potent antiproliferative activity. On the other hand, piperazines containing 3,4-dichlorophenyl (5d; 0.1%) and 3,4-dimethylphenyl (5j; 0.1%) rings demonstrated the least cytotoxicity. The piperazine with the 2,5-dimethoxyphenyl moiety (5h; 60.2%) showed the best thrombolytic effect. To determine the mode of binding, in silico modeling of the most potent piperazine (i.e., 5b) was performed, and the results were in accordance with those of antiproliferation. It exhibits a similar binding affinity to PQ10 and an efficient conformational alignment with the lipophilic site of PDE10A conserved for PQ10A.

Interspecific Differences in Physiological and Biochemical Traits Drive the Water Stress Tolerance in Young Morus alba L. and Conocarpus erectus L. Saplings.

Mitigating climate change requires the identification of tree species that can tolerate water stress with fewer negative impacts on plant productivity. Therefore, the study aimed to evaluate the water stress tolerance of young saplings of C. erectus and M. alba under three soil water deficit treatments (control, CK, 90% field capacity, FC, medium stress MS, 60% FC and high stress, HS, 30% FC) under controlled conditions. Results showed that leaf and stem dry weight decreased significantly in both species under MS and HS. However, root dry weight and root/shoot ratio increased, and total dry weight remained similar to CK under MS in C. erectus saplings. Stomatal conductance, CO2 assimilation rate decreased, and intrinsic water use efficiency increased significantly in both species under MS and HS treatments. The concentration of hydrogen peroxide, superoxide radical, malondialdehyde and electrolyte leakage increased in both the species under soil water deficit but was highest in M. alba. The concentration of antioxidative enzymes like superoxide dismutase, peroxidase, catalase, and ascorbate peroxidase also increased in both species under MS and HS but was highest in C. erectus. Therefore, results suggest that C. erectus saplings depicted a better tolerance to MS due to an effective antioxidative enzyme system.

Synthesis, Hemolytic Studies, and In Silico Modeling of Novel Acefylline-1,2,4-Triazole Hybrids as Potential Anti-cancer Agents against MCF-7 and A549.

A series of novel theophylline-7-acetic acid (acefylline)-derived 1,2,4-triazole hybrids with N-phenyl acetamide moieties (11a-j) have been synthesized and tested for their inhibitory (in vitro) potential against two cancer cell lines, A549 (lung) and MCF-7 (breast), using MTT assay. Among these derivatives, 11a, 11c, 11d, 11g, and 11h displayed remarkable activity against both cancer cell lines having cell viability values in the 21.74 ± 1.60-55.37 ± 4.60% range compared to acefylline (86.32 ± 1.75%) using 100 µg/µL concentration of compounds. These compounds were further screened against the A549 cancer cell line (lung) to find their half-maximal inhibitory concentration (IC50) by applying various concentrations of these compounds. Compound 11g (2-(5-((1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)methyl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-p-tolylacetamide) with the least IC50 value (1.25 ± 1.36 µM) was discerned as a strong inhibitor of cancer cell multiplication in both cell lines (A549 and MCF-7). Their hemolytic studies revealed that all of them had very low cytotoxicity. Finally, in silico modeling was carried out to find the mode of binding of the highly active compound (11g), which was according to the results of anti-cancer activity.

Drotaverine Inhibitor of PDE4: Reverses the Streptozotocin Induced Alzheimer's Disease in Mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with decline in memory and cognitive impairments. Phosphodiesterase IV (PDE4) protein, an intracellular cAMP levels regulator, when inhibited act as potent neuroprotective agents by virtue of ceasing the activity of Pro-inflammatory mediators. The complexity of AD etiology has ever since compelled the researchers to discover multifunctional compounds to combat the AD and neurodegeneration. The aim of this study was to probe into role of drotaverine a PDE4 inhibitor in the management of AD. Albino mice were divided into seven groups (n = 10). Group 1 control group received carboxy methyl cellulose (CMC 1 mL/kg), group II diseased group treated with streptozotocin (STZ 3 mg/kg) by intracerebroventricular (ICV) route, group III administered standard drug Piracetam 200 mg/kg and groups IV-VII were given drotaverine (10, 20, 40, and 80 mg/kg i/p respectively). Groups II-VII were given STZ (3 mg/kg, ICV) on 1st and 3rd day of treatment to induce AD. All the groups were given their respective treatments for 23 days. Improvement in learning and memory was evaluated by using behavioral tests like open field test, elevated plus maze test, Morris water maze test and passive avoidance test. Furthermore, brain levels of biochemical markers of oxidative stress, neurotransmitters, ß-amyloid and tau protein were also measured. Drotaverine showed statistically significant dose dependent improvement in behavioral and biochemical markers of AD: the maximum response was achieved at a dose level of 80 mg/kg. The Study concluded that drotaverine ameliorates cognitive impairment and as well as exhibited modulated the brain levels of neurotransmitters.

Antiparkinsonian activity of Cucurbita pepo seeds along with possible underlying mechanism.

Cucurbita pepo is used as a vegetable in Pakistan and its seeds are also rich in tocopherol. Data showed the pivotal role of tocopherol in the treatment of Parkinson's disease (PD). The current study was designed to probe into the antiparkinson activity of methanolic extract of C. pepo (MECP) seeds in the haloperidol-induced Parkinson rat model. Behavioral studies showed improvement in motor functions. The increase in catalase, superoxide dismutase, glutathione levels whereas the decreases in the malondialdehyde and nitrite levels were noted in a dose-dependent manner. Acetylcholine-esterase (AchE) activity was increased. Molecular docking results revealed significant binding interaction of selected phytoconstituents within an active site of target protein AchE (PDB ID: 4EY7). Furthermore, α-synuclein was up regulated with down regulation of TNF-α and IL-1ß in the qRT-PCR study. Subsequently, ADMET results on the basis of structure to activity predictions in terms of pharmacokinetics and toxicity estimations show that selected phytochemicals exhibited moderately acceptable properties. These properties add knowledge towards the structural features which could improve the bioavailability of selected phytochemicals before moving towards the initial phase of the drug development. Our integrated drug discovery scheme concluded that C. pepo seeds could ameliorate symptoms of PD and may prove a lead remedy for the treatment of PD.

Anti-Parkinson's Activity of Tribulus terrestris via Modulation of AChE, α-Synuclein, TNF-α, and IL-1ß.

Tribulus terrestris (T.T.) is a rich source of flavonoids and saponins, which have been reported to have neuroprotective and antioxidant potential. The current study was planned to investigate the anti-Parkinson's activity of T. terrestris methanol extract (TTME). It was hypothesized that TTME possessed antioxidant potential and can ameliorate Parkinson's disease (PD) via modulation of α-synuclein, acetylcholinesterase (AChE), TNF-α, and IL-1ß. To test this hypothesis, in silico and in vivo studies were performed. The PD model in rats was prepared by giving haloperidol, 1 mg/kg, i.p. Rats were divided into six groups: control, disease control, standard, and treatment groups receiving TTME orally at 100, 300, and 1000 mg/kg dose levels for 21 days. Behavioral observations and biochemical analyses were done. The TTME modulatory effect on mRNA expression of α-synuclein, AChE, TNF-α, and interleukins in the brain homogenate was estimated by RT-PCR. Compounds detected in HPLC analysis disrupted the catalytic triad of AChE in in silico studies. Behavioral observations showed significant (p < 0.05) improvement in a reversal of catatonia, muscular strength, locomotor functions, stride length, and exploration in a dose-dependent manner (1000 >300 >100 mg/kg) of PD rats. Endogenous antioxidant enzyme levels CAT, SOD, GSH, and GPx were significantly restored at a high dose (p < 0.05) with a notable (p < 0.05) decrease in the MDA level in TTME-treated groups. TTME at a high dose significantly (p < 0.05) decreased the level of acetylcholinesterase. RT-PCR results are showing down-regulation in the mRNA expression levels of IL-1ß, α -synuclein, TNF-α, and AChE in TTME-treated groups compared to the disease control group, indicating neuroprotection. It is concluded that TTME has potential to ameliorate the symptoms of Parkinson's disease.

Antiarthritic Potential of Comprehensively Standardized Extract of Alternanthera bettzickiana: In Vitro and In Vivo Studies.

Alternanthera bettzickiana is being used as a folk remedy for treating arthritis by conventional healers in Thailand. The current research was undertaken to explore the antiarthritic potential of A. bettzickiana ethanolic extract (ABEE). Plant characterization, molecular docking, and in vitro and in vivo (ABEE at 250, 500, and 1000 mg/kg was administered orally to rats once daily for 28 days) studies to explore the antiarthritic effect and enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (RT-PCR) analyses were performed. Oxidative stress biomarkers (superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA)) in the serum and histopathological and radiographic assessment of joints were also carried out. Gallic acid, catechin, chlorogenic acid, sinapic acid, quercetin, and γ- and α-tocopherol were identified in high-performance liquid chromatography (HPLC). Molecular docking revealed a strong interaction between these compounds and cyclooxygenase (COX) enzymes. The extract significantly subdued paw swelling and arthritic scoring, inhibited cachexia, and considerably improved biochemical and hematological modifications. SOD and CAT levels increased and the MDA level decreased in ABEE-treated rats dose-dependently. Radiographic and histopathological analyses also supported the antiarthritic effect of ABEE, which was linked with the downregulation of nuclear factor (NF)-kB, COX-2, interleukin (IL)-6, tumour necrosis factor (TNF)-α, and IL-1ß and upregulation of IL-10, I-kB, and IL-4 as compared to disease control rats. Results suggested that A. bettzickiana possessed antiarthritic potential, supporting its folkloric use for treating rheumatoid arthritis.

In Silico Study and Pharmacological Evaluation of Eplerinone as an Anti-Alzheimer's Drug in STZ-Induced Alzheimer's Disease Model.

Alzheimer's disease (AD) is the neurodegenerative disorder characterized by impairment of higher intellectual dysfunctions associated with changes in the cognitive, behavioral, and social activities. AIM OF THE STUDY: The current study was designed to evaluate the potential of aldosterone antagonist in the treatment of AD. METHODOLOGY: The study was conducted on albino mice of either sex (n = 60). Mice were subcategorized into six groups, each group having 10 mice. Group I-normal control (CMC 1 mL/kg), group II-diseased [streptozotocin (STZ), 3 mg/kg, intracerebroventricular (i.c.v.)], group III-standard (piracetam, 200 mg/kg, i.p.), and groups IV-VI designated as the treatment group (eplerinone at dose levels of 4, 8, and 16 mg/kg, orally), respectively. The study was carried out for 14 consecutive days. STZ was administered through the i.c.v. route on first and third days of the study for memory impairment. The molecular docking was performed to investigate the chemical behavior of compounds to inhibit the AChE. Anti-Alzheimer's effect was assessed by using the behavioral paradigms such as passive avoidance, elevated plus maze, Morris water maze, open field, and balance beam. Various endogenous antioxidants such as SOD, GSH, nitrite, MDA, CAT, and AChE were identified in brain tissues of treated mice to assess the oxidative stress index. Biochemical markers for AD such as norepinephrine, dopamine, and serotonin, Aß 1-40, Aß 1-42, NF-κB, and tumor necrosis factor alpha were analyzed in brain tissues of mice. Expression of beta amyloid was observed by PCR. RESULTS: The in silico study indicated the distinct mechanism of eplerinone to inhibit the AChE. The outcomes of the in vivo study manifested that eplerinone at the highest dose was found to be more effective in the treatment of AD. CONCLUSION: It may be concluded from the research work that eplerinone can be effective for cognitive improvement which proposes its therapeutic effect in many neurodegenerative disorders such as AD.

Sphingosine 1-phosphate signaling in ischemia and reperfusion injury.

Ischemia and reperfusion injury is a complex hemodynamic pathological phenomenon that engages the metabolic to inflammatory machinery in development of disease conditions like heart failure, stroke and acute kidney failure. Target specific therapeutic approaches for ischemia reperfusion injury remains critical despite the extensive studies contributing to the understanding of its pathogenesis. Ischemic or pharmacological conditionings have been long established manipulations to harness the endogenous protective mechanisms against ischemia reperfusion injury that fostered the development of potential therapeutic targets such as sphingolipids signaling. Sphingosine 1-phosphate has been emerged as a crucial metabolite of sphingolipids to regulate the cell survival, vascular integrity and inflammatory cascades in ischemia reperfusion injury. Sphingosine 1-phosphate signaling process has been implicated to downgrade the mitochondrial dysfunction, apoptotic assembly along with upregulation of RISK and SAFE pro-survival pathways. It also regulates the endothelial dysfunction and immune cells behavior to control the vascular permeability and immune cells infiltration at ischemia reperfusion injury site. Targeting the signaling of this single moiety holds the vast potential to extensively influence the detrimental signaling of ischemia reperfusion injury. This review highlights the role and significance of S1P signaling that can be therapeutically exploit to treat ischemia reperfusion injury mediated pathological conditions in different organs.

Melatonin ameliorates the drug induced nephrotoxicity: Molecular insights / La melatonina mejora la nefrotoxicidad inducida por medicamentos: datos moleculares

BACKGROUND: Drug-induced nephrotoxicity is a frequent adverse event that can lead to acute or chronic kidney disease and increase the healthcare expenditure. It has high morbidity and mortality incidence in 40-70% of renal injuries and accounts for 66% cases of renal failure in elderly population. OBJECTIVE: Amelioration of drug-induced nephrotoxicity has been long soughed to improve the effectiveness of therapeutic drugs. This study was conducted to review the melatonin potential to prevent the pathogenesis of nephrotoxicity induced by important nephrotoxic drugs. METHODS: We analyzed the relevant studies indexed in Pubmed, Medline, Scielo and Web of science to explain the molecular improvements following melatonin co-administration with special attention to oxidative stress, inflammation and apoptosis as key players of drug-induced nephrotoxicity. RESULTS: A robust consensus among researchers of these studies suggested that melatonin efficiently eradicate the chain reaction of free radical production and induced the endogenous antioxidant enzymes which attenuate the lipid peroxidation of cellular membranes and subcellular oxidative stress in drug-induced nephrotoxicity. This agreement was further supported by the melatonin role in disintegration of inflammatory process through inhibition of principle pro-inflammatory or apoptotic cytokines such as TNF-alfa and NF-κB. These studies highlighted that alleviation of drug-induced renal toxicity is a function of melatonin potential to down regulate the cellular inflammatory and oxidative injury process and to stimulate the cellular repair or defensive mechanisms. CONCLUSION: The comprehensive nephroprotection and safer profile suggests the melatonin to be a useful adjunct to improve the safety of nephrotoxic drugs

ANTECEDENTES: La nefrotoxicidad inducida por medicamentos es un acontecimiento adverso frecuente que puede conducir a una nefropatía aguda o crónica, e incrementar los costes sanitarios. Presenta una incidencia elevada de morbimortalidad en el 40-70% de las lesiones renales y es responsable del 66% de los casos de insuficiencia renal entre la población de edad avanzada. OBJETIVO: La mejora de la nefrotoxicidad inducida por medicamentos es un objetivo anhelado desde hace mucho tiempo, para mejorar la eficacia de los fármacos terapéuticos. Este estudio se llevó a cabo con el propósito de revisar el potencial de la melatonina para prevenir la patogenia de la nefrotoxicidad inducida por medicamentos nefrotóxicos importantes. MÉTODOS: Analizamos los estudios relevantes indexados en Pubmed, Medline, Scielo y Web of Science, para explicar las mejoras moleculares posteriores a la administración concomitante de melatonina; prestando especial atención al estrés oxidativo, la inflamación y la apoptosis como actores fundamentales de la nefrotoxicidad inducida por medicamentos. RESULTADOS: Un sólido consenso entre los investigadores de estos estudios sugirió que la melatonina erradica de forma eficiente la reacción en cadena de producción de radicales libres e induce las enzimas antioxidantes endógenas que atenúan la peroxidación lipídica de las membranas celulares y el estrés oxidativo subcelular en la nefrotoxicidad inducida por medicamentos. Este consenso se vio respaldado por el papel de la melatonina en la desintegración del proceso inflamatorio a través de la inhibición de las principales citocinas proinflamatorias o apoptóticas, como el TNF-α y el NF-κB. Estos estudios subrayan que la mitigación de la nefrotoxicidad inducida por medicamentos se deriva del potencial de la melatonina para regular a la baja el proceso celular de lesión inflamatoria y oxidativa, y estimular la reparación celular o los mecanismos defensivos de las células. CONCLUSIÓN: La nefroprotección exhaustiva y el perfil de seguridad más favorable sugieren que la melatonina es un complemento útil para mejorar la seguridad de los fármacos nefrotóxicos

Melatonin ameliorates the drug induced nephrotoxicity: Molecular insights.

BACKGROUND: Drug-induced nephrotoxicity is a frequent adverse event that can lead to acute or chronic kidney disease and increase the healthcare expenditure. It has high morbidity and mortality incidence in 40-70% of renal injuries and accounts for 66% cases of renal failure in elderly population. OBJECTIVE: Amelioration of drug-induced nephrotoxicity has been long soughed to improve the effectiveness of therapeutic drugs. This study was conducted to review the melatonin potential to prevent the pathogenesis of nephrotoxicity induced by important nephrotoxic drugs. METHODS: We analyzed the relevant studies indexed in Pubmed, Medline, Scielo and Web of science to explain the molecular improvements following melatonin co-administration with special attention to oxidative stress, inflammation and apoptosis as key players of drug-induced nephrotoxicity. RESULTS: A robust consensus among researchers of these studies suggested that melatonin efficiently eradicate the chain reaction of free radical production and induced the endogenous antioxidant enzymes which attenuate the lipid peroxidation of cellular membranes and subcellular oxidative stress in drug-induced nephrotoxicity. This agreement was further supported by the melatonin role in disintegration of inflammatory process through inhibition of principle pro-inflammatory or apoptotic cytokines such as TNF-α and NF-κB. These studies highlighted that alleviation of drug-induced renal toxicity is a function of melatonin potential to down regulate the cellular inflammatory and oxidative injury process and to stimulate the cellular repair or defensive mechanisms. CONCLUSION: The comprehensive nephroprotection and safer profile suggests the melatonin to be a useful adjunct to improve the safety of nephrotoxic drugs.

Systems pharmacology based approach to investigate the in-vivo therapeutic efficacy of Albizia lebbeck (L.) in experimental model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons in substantia nigra pars compacta and clinically manifested mainly with motor dysfunctions. Plants are rich source of medicinally important bioactive compounds and inhabitants of underdeveloped countries used plants for treatment of various ailments. Albizia lebbeck has been reported to possess antioxidant and neuroprotective properties that suggest the evaluation of its traditional therapeutic potential in neurodegenerative diseases. The aim of present study was to validate the traditional use of Albizia lebbeck (L.) and delineate its mechanism of action in PD. The systems pharmacology approach was employed to explain the Albizia lebbeck (L.) mechanism of action in PD. METHODS: The haloperidol-induced catalepsy was adopted as experimental model of PD for in-vivo studies in wistar albino rats. The systems pharmacology approach was employed to explain the Albizia lebbeck (L.) mechanism of action in PD. RESULTS: In-vivo studies revealed that Albizia lebbeck improved the motor functions and endurance as demonstrated in behavioral studies which were further supported by the rescue of endogenous antioxidant defense and reversal of ultrastructural damages in histological studies. System pharmacology approach identified 25 drug like compounds interacting with 132 targets in a bipartite graph that revealed the synergistic mechanism of action at system level. Kaemferol, phytosterol and okanin were found to be the important compounds nodes with prominent target nodes of TDP1 and MAPT. CONCLUSION: The therapeutic efficiency of Albizia lebbeck in PD was effectively delineated in our experimental and systems pharmacology approach. Moreover, this approach further facilitates the drug discovery from Albizia lebbeck for PD.

ß-Carotene: A Natural Compound Improves Cognitive Impairment and Oxidative Stress in a Mouse Model of Streptozotocin-Induced Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by a cascade of changes in cognitive, behavioral, and social activities. Several areas of the brain are involved in the regulation of memory. Of most importance are the amygdala and hippocampus. Antioxidant therapy is used for the palliative treatment of different degenerative diseases like diabetes, cirrhosis, and Parkinson's, etc. The objective of this study was to assess the effectiveness of exogenous antioxidants, in particular, ß carotene (1.02 and 2.05 mg/kg) against intracerebroventricular injected streptozotocin-induced memory impairment in mice. Streptozotocin (3 mg/kg, i.c.v) was administered in two separate doses (on 1st and 3rd days of treatment) for neurodegeneration. Fifty Albino mice (male) were selected in the protocol, and they were classified into five groups (Group I-control, Group II-disease, Group III-standard, Group IV-V-ß-carotene-treated) to investigate the cognitive enhancement effect of selected antioxidants. The cognitive performance was observed following the elevated plus-maze, passive avoidance, and open field paradigms. Acetylcholine esterase, ß-amyloid protein, and biochemical markers of oxidative stress such as glutathione peroxidase, superoxide dismutase, and catalase were analyzed in brain homogenates. In silico activity against acetylcholinesterase (AChE) was determined by the molecular modeling of ß-carotene. ß-carotene at a dose of 2.05 mg/kg was found to attenuate the deleterious effects of streptozotocin-induced behavioral and biochemical impairments, including the inhibition of acetylcholinesterase activity. The in silico studies confirmed the binding capacity of ß-carotene with the acetylcholinesterase enzyme. The administration of ß-carotene attenuated streptozotocin-induced cognitive deficit via its anti-oxidative effects, inhibition of acetylcholinesterase, and the reduction of amyloid ß-protein fragments. These results suggest that ß-carotene could be useful for the treatment of neurodegenerative diseases such as Alzheimer's disease.

Experimental and Computational Studies to Characterize and Evaluate the Therapeutic Effect of Albizia lebbeck (L.) Seeds in Alzheimer's Disease.

Background and Objectives: Alzheimer's disease (AD) is a neurodegenerative disorder that deteriorates daily life due to loss of memory and cognitive impairment. It is believed that oxidative stress and cholinergic deficit are the leading causes of AD. Disease-modifying therapies for the treatment of AD are a challenging task for this century. The search for natural and synthetic agents has attracted the attention of researchers. The objective of this study was a scientific approach to search for most suitable remedy for AD by exploiting the potential of Albizia lebbeck (L.) seeds. Materials and Methods: Hydromethanolic extract of Albizia lebbeck seeds (ALE) was prepared by maceration. The plant was characterized by physico-chemical, phyto-chemical, and high-performance liquid chromatography (HPLC). Thirty-six Wistar albino rats were used in this study and divided into six groups (n = 6). Group I: normal control; Group II: disease control (AlCl3; 100 mg/Kg); Group III: standard control (galantamine; 0.5mg/Kg); Groups IV-VI were treated ALE at 100, 200 and 300 mg/Kg dose levels, respectively. All the treatments were given orally for 21 consecutive days. Y-maze, T-maze, Morris water maze, hole board, and open field behavioral tests were performed to analyze the cognitive impairment. Biochemical, histological, and computational studies were performed to support the results of behavioral tests. Results: HPLC analysis indicated the presence of quercetin, gallic acid, m-coumaric acid, and sinapic acid. ALE significantly improved the memory and cognitive impairments. Endogenous antioxidant stress biomarker levels and histopathological outcomes supported the therapeutic potential of A. lebbeck in AD. Cholinergic deficits were also ameliorated by ALE co-administration, possibly by the inhibition of hyperactive acetylcholinesterase (AChE). Docking studies supported the potential of ALE against AD. Conclusions: The data suggested that ALE has neuroprotective potential that can be exploited for beneficial effects to treat AD.

Design, synthesis, in-silico study and anticancer potential of novel n-4- piperazinyl-ciprofloxacin-aniline hybrids.

Synthesis and characterization of novel structural hybrids of ciprofloxacin linked with a variety of anilides have been described in this paper. Antitumor activity of these derivatives was assessed against liver cell line (Huh-7) using MTT assay. Among the synthesized derivatives, compound 6a inhibited the growth of tumor cells by displaying 68.36% cell viability at 100 µg/mL concentration which was then in-silico modelled to delineate the potential mechanistic insights for its antiproliferative activity. The PASS prediction indicated the TopII as potential anticancer target of compound 6a. The induced fit docking revealed that compound 6a inhibits the TopII with superior binding affinity and forms stronger contacts with active site's key residues responsible for DNA-TopII intercalation and catalytic inhibition consistent with its cytotoxic potential. Therefore, compound 6a can be considered as a potential lead for further optimization in the development of ciprofloxacin-derived anticancer drugs.