Uroprotective Potential of Campesterol in Cyclophosphamide Induced Interstitial Cystitis; Molecular Docking Studies.

Cyclophosphamide (CYP) is commonly used to treat cancer of the ovaries, breast, lymph, and blood system and produces interstitial cystitis (IC) via its urotoxic metabolite: i. e., acrolein. The present study was aimed to investigate the uroprotective effect of campesterol (a steroidal phytochemical) in cyclophosphamide induced IC. IC was induced by CYP (150 mg/kg, i. p.) in rats. The Enzyme linked immunosorbent assays for oxidative stress markers and Polymerase Chain Reaction (PCR) for inflammatory cytokines were carried out. The Tissue Organ Bath Technique was used for the evaluation of the spasmolytic effect of campesterol. Different pharmacological antagonists have been used to explore the mechanism of action of campesterol. Treatment with campesterol (70 mg/kg) reduced nociception (55 %), edema (67 %), hemorrhage (67 %), and protein leakage significantly (94 %). The antioxidant activity of campesterol was exhibited by a fall in MDA, NO, and an elevation in SOD, CAT, and GPX levels. Campesterol presented anti-inflammatory potential by decreasing IL-1, TNF-α, and TGF-ß expression levels. Histologically, it preserved urothelium from the deleterious effect of CYP. Campesterol showed a spasmolytic effect by reducing bladder overactivity that was dependent on muscarinic receptors, voltage-gated calcium and KATP channels, and cyclo-oxygenase pathways. In silico studies confirmed the biochemical findings. The findings suggest that campesterol could be valorized as a possible therapeutic agent against cyclophosphamide-induced interstitial cystitis.

In-vivo anti-epileptic study of newly synthesized pregabalin derivatives based on docking studies.

OBJECTIVE: The goal of the present study is to examine pretreatment with Schiff bases and derivatives of pregabalin along with their metal (Zn and Cu) complexes on the severity of epilepsy, latency time, duration of convulsions, seizure score and survival rate in mice. METHODS: To achieve the goal, a molecular docking study of analogues was carried out on a specific molecular target, such as the alpha-2δ receptor (PDB ID: 6ND9); which revealed the significant binding affinity of the analogs to their respective target. Based on the docking information, all pregabalin derivatives were synthesized and in-vivo antiepileptic effect was confirmed by applying the PTZ model that prioritized the most crucial significant points responsible for biological activity. RESULTS: The test compounds markedly increased the latency of the first seizure and reduced the frequency of seizures throughout the body and frequent spinning and jumps. Additionally, treatment with pregabalin derivatives in mice that received PTZ significantly reduced the duration of seizures and seizure score. However, it increased the survival rate of the mice. DISCUSSION: Since the newly synthesized compounds were more active as compared to the parent drug in some respects; therefore, the expansion of the project can be planned to explore clinical side of the drugs in the future.

Docking studies of Schiff bases and derivatives of Pregabalin along with their Zn and Cu metal complexesPretreatment with Schiff bases and derivatives of pregabalin along with their metal (Zn and Cu)PTZ Model of epilepsyObservation of different parameters including; the severity of epilepsy, latency time, duration of convulsions, seizure score and survival rate in miceNewly synthesized compounds were more active as compared to the parent drug.

Spasmolytic and Uroprotective Effects of Apigenin by Downregulation of TGF-ß and iNOS Pathways and Upregulation of Antioxidant Mechanisms: In Vitro and In Silico Analysis.

Apigenin is a phytochemical obtained from Chamomilla recutita. Its role in interstitial cystitis is not yet known. The present study is aimed at understanding the uroprotective and spasmolytic effects of apigenin in cyclophosphamide-induced interstitial cystitis. The uroprotective role of apigenin was analyzed by qRT-PCR, macroscopic analysis, Evans blue dye leakage, histological evaluation, and molecular docking. The spasmolytic response was measured by adding cumulative concentrations of apigenin to isolated bladder tissue pre-contracted with KCl (80 mM) and carbachol (10-9-10-4) on non-incubated and pre-incubated tissues with atropine, 4DAMP, methoctramine, glibenclamide, barium chloride, nifedipine, indomethacin, and propranolol. Apigenin inhibited pro-inflammatory cytokines (IL-6, TNF-α and TGF 1-ß) and oxidant enzymes (iNOS) while increasing antioxidant enzymes (SOD, CAT, and GSH) in CYP-treated groups compared to the control. Apigenin restored normal tissue of the bladder by decreasing pain, edema, and hemorrhage. Molecular docking further confirmed the antioxidant and anti-inflammatory properties of apigenin. Apigenin produced relaxation against carbachol-mediated contractions, probably via blockade of M3 receptors, KATP channels, L-type calcium channels, and prostaglandin inhibition. While the blockade of M2 receptors, KIR channels, and ß-adrenergic receptors did not contribute to an apigenin-induced spasmolytic effect, apigenin presented as a possible spasmolytic and uroprotective agent with anti-inflammatory, antioxidant effects by attenuating TGF-ß/iNOS-related tissue damage and bladder muscle overactivity. Thus, it is a potential agent likely to be used in treatment of interstitial cystitis.

Caftaric Acid Ameliorates Oxidative Stress, Inflammation, and Bladder Overactivity in Rats Having Interstitial Cystitis: An In Silico Study.

Interstitial cystitis (IC) is the principal unwanted effect associated with the use of cyclophosphamide (CYP). It results in increased oxidative stress, overexpression of proinflammatory cytokines, and bladder overactivity. Patients receiving CYP treatment had severely depreciated quality of life, as the treatment available is not safe and effective. The goal of this study was to assess the protective effect of caftaric acid in CYP-induced IC. IC was induced in female Sprague Dawley by injecting CYP (150 mg/kg, i.p.). In the present study, oral administration of caftaric acid (20, 40, and 60 mg/kg) significantly decreased inflammation. Caftaric acid significantly increased SOD (93%), CAT (92%), and GSH (90%) while decreased iNOS (97%), IL-6 (90%), TGF 1-ß (83%), and TNF-α (96%) compared to the diseased. DPPH assay showed the antioxidant capacity comparable to ascorbic acid. Molecular docking of caftaric acid with selected protein targets further confirmed its antioxidant and anti-inflammatory activities. The cyclophosphamide-induced bladder overactivity had been decreased possibly through the inhibition of M3 receptors, ATP-sensitive potassium channels, calcium channels, and COX enzyme by caftaric acid. Therefore, our findings demonstrate that caftaric acid has a considerable protective role against CYP-induced IC by decreasing the oxidative stress, inflammation, and bladder smooth muscle hyperexcitability. Thus, caftaric acid signifies a likely adjuvant agent in CYP-based chemotherapy treatments.

The anti-cancer potential of 2,4,6 tris-methyphenylamino1,3,5-triazine compound against mammary glands cancer: Via down-regulating the hormonal, inflammatory mediators, and oxidative stress.

AIM OF THE STUDY: Breast cancer is caused by abnormal growth of the cells and progressed due to the over-expression of estrogen (ER) and progesterone (PR). The current study was designed to evaluate the anti-tumor activity of 2,4,6 tris-methyphenylamino1,3,5-triazine compound (MPAT) in N-nitroso, N-methyl urea (NMU)-induced mammary gland cancer. METHODS: Molecular docking and in-vitro studies were conducted before the in-vivo analysis. Female Albino rats were divided into 5 groups (n = 6). Group I received Carboxymethylcellulose (CMC) (1 mL/100 g). Group II (diseased group) received NMU 50 mg/kg. Group III (standard group) received tamoxifen (5 mg/kg). Group IV-V received MPAT at doses of 30 and 60 mg/kg respectively. All groups received NMU intraperitoneally except the control group at 3 weeks intervals for 12 weeks. After 12 weeks of NMU dosing, MPAT was given for 15 consecutive days. Biochemical, oxidative stress markers, hormonal profile, and inflammatory mediators were analyzed. KEY FINDINGS: MPAT showed significant interaction with the selected targets in docking studies. An over-expression of ER and PR was observed in NMU-treated rats which were restored significantly after MPAT administration. Nitrite and MDA levels were high in the diseased group and MPAT treatment attenuated the oxidative damage after treatment. Antioxidants such as superoxide dismutase (SOD), Catalase (CAT), total sulfhydryl (TSH), glutathione (GSH), and Lactate dehydrogenase (LDH) values were low in NMU-treated rats. SIGNIFICANCE: This study concluded that MPAT can be used as an anticancer agent due to its significant effects on down-regulating the hormonal profile and oxidative stress markers.

Schiff-Based Metal Complexes of Lamotrigine: Design, Synthesis, Characterization, and Biological Evaluation.

In the current study, a series of Schiff base derivatives of lamotrigine are complexed with zinc, copper, silver, and tin and characterized by spectroscopic techniques and biological assays. Docking analyses revealed six complexes with favorable binding interactions, which were further subjected to in vitro anticancer activity. The complexes 6b and 6c displayed the most potent antiproliferative activity against MCF-7 cell lines with an IC50 value of 11.9 ± 0.27 and 12.0 ± 0.14 µM, respectively, as compared with the standard doxorubicin with an IC50 value of 0.90 ± 0.14 µM. In vivo anticonvulsant activities of the compounds were evaluated by the subcutaneous pentylenetetrazole model and neurotoxic activities by the minimal motor impairment model. The neurotoxicity of targeted compounds was measured using the rotating rod (ROT) method. Computational studies were carried out using the reported crystal structures of multidrug-resistant protein (PDB-ID: 2KAV) and dihydrofolate reductase (PDB-ID: 3GHW), indicating that the compound 6c showed significant interactions at the voltage-gated sodium ion channel in the brain and at dihydrofolate reductase enzyme in the breast. Certain metal complexes of Schiff base ligands (e.g., 6c) were found to possess the most potent anticancer, anticonvulsant, and neurotoxic potential than lamotrigine alone.

In-silico computational analysis of [6-(2, 3-Dichlorophenyl)-1, 2, 4-Triazine-3, 5-Diamine] metal complexes on voltage gated sodium channel and dihydrofolate reductase enzyme.

Epilepsy is the disease associated with seizures and convulsions. Various antiepileptic drugs have been used widely to treat these disorders. Lamotrigine [6-(2,3-Dichlorophenyl)-1,2,4-triazine-3,5-diamine] shows certain adverse effects at small doses, to evaluate its efficacy lamotrigine schiff based metal complexes were screened in-silico at voltage gated sodium channel for antiepileptic effect and dihydrofolate reductase enzyme for anticancer activity. Post docking analysis revealed that lamotrigine shows greater antiepileptic effect with its Schiff base complex of tin, with greater binding affinities on voltage gated sodium channel. However, anticancer effect of lamotrigine with its Schiff base silver complex shows highest binding affinity on dihydrofolate reductase enzyme. Study concluded that Schiff base derivative and its metal complexes express significant binding interactions with voltage gated sodium channel and dihydrofolate reductase enzyme.