Mixed Ligand-metal Complexes of 2-(butan-2-ylidene) Hydrazinecarbothioamide- Synthesis, Characterization, Computer-Aided Drug Character Evaluation and in vitro Biological Activity Assessment.

BACKGROUND: Mixed ligand-metal complexes are efficient chelating agents because of their flexible donor ability. Mixed ligand complexes containing hetero atoms sulphur, nitrogen and oxygen have been probed for their biological significance. METHODS: Nine mixed ligand-metal complexes of 2-(butan-2-ylidene) hydrazinecarbothioamide (2- butanone thiosemicarbazone) with pyridine, bipyridine and 2-picoline as co-ligands were synthesized with Cu, Co and Zn salts. The complexes were tested against MDA-MB231 (MDA) and A549 cell lines. Antibacterial activity was tested against Staphylococcus aureus and Escherichia coli. The drug character of the complexes was evaluated on parameters viz. physicochemical properties, bioactivity scores, toxicity assessment and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) profile using various automated softwares. Molecular docking was performed against Ribonucleotide Reductase (RR) and topoisomerase II (topo II). RESULTS: The mixed ligand-metal complexes were synthesized by condensation reaction for 4-5 h. The characterization was done by elemental analysis, 1H-NMR, FT-IR, molar conductance and UV spectroscopic techniques. Molecular docking results showed that [Cu(C5H11N3S)(py)2(CH3COO)2], [Zn(C5H11N3S)(bpy)(SO4)] and [Zn(C5H11N3S)(2-pic)2(SO4)] displayed the lowest binding energies with respect to RR. Against topo II [Cu(C5H11N3S)(py)2(CH3COO)2], [Cu(C5H11N3S)(bpy)(CH3COO)2] and [Zn(C5H11N3S)(2-pic)2(SO4)] had the lowest energies. The druglikness assessment was done using Leadlikeness and Lipinski's rules. Not more than two violations were obtained in case of each filtering rule showing drug-like character of the mixed ligand complexes. Some of the complexes exhibited positive bioactivity scores and almost all the complexes were predicted to be safe with no hazardous effects as predicted by the toxicity assessment. Ames test predicted the non-mutagenic nature of the complexes. CONCLUSION: In vitro activity evaluation showed that [Zn(C5H11N3S)(py)2(SO4)], [Co(C5H11N3S(bpy) (Cl)2] and [Cu(C5H11N3S)(2-pic)2(CH3COO)2] were active against MDA. Against A549 [Co(C5H11N3S)(py)2(Cl)2], [Cu(C5H11N3S)(py)2(CH3COO)2] and [Co(C5H11N3S(bpy)(Cl)2] were active. Antibacterial evaluation showed that [Co(C5H11N3S)(bpy)(Cl)2], [Zn(C5H11N3S)(2-pic)2(SO4)] and [Cu(C5H11N3S)(2-pic)2(CH3COO)2] were active against S. aureus. Against E. coli, [Zn(C5H11N3S)(2- pic)2(SO4)] showed activity at 18-20 mg dose range.

Phenanthridine derivatives as promising new anticancer agents: synthesis, biological evaluation and binding studies.

Aim: Phenanthridines are an essential class of nitrogenous heterocycles with extensive applications in medicinal chemistry. The development of efficient and eco-friendly methods for the preparation of chirally pure dihydropyrrolo[1,2-f]phenanthridines (5a-h), and their in vitro evaluation and modeling studies as potential anticancer, antioxidant and DNA cleavage agents is reported. Methodology & results: Compounds 5a-h were prepared through a facile one-pot synthesis and characterized by infrared, high resolution mass spectrometry, 1H and 13C nuclear magnetic resonance. The molecules were subjected to virtual screening and docking analysis against selected human molecular targets. Compound 5g displayed good binding properties as well as significant anticancer and DNA cleavage activity. Conclusion: Compound 5g has been identified as a potential lead candidate for further testing against additional cancer cell lines and animal models in future.

Comparison and Clinical Evaluation of Two Pit and Fissure Sealants on Permanent Mandibular First Molars: An In Vivo Study.

AIM: The aim of the study was to compare and evaluate the clinical efficacy of a microfilled pit and fissure sealant and a nanofilled pit and fissure sealant at 3, 6, and 12 months of interval. MATERIALS AND METHODS: Samples consisting of 55 healthy 8- to 12-year-old children with deep pits and fissures in mandibular first permanent molars were selected for the study. It was a split mouth design and randomized clinical trial. A total of 110 mandibular first molars were divided into two groups of 55 each: group I Fissurit FX sealant and group II Grandioseal nanofilled fissure sealant. The sealed teeth were clinically evaluated at 3, 6, and 12 months of interval to assess marginal adaptation, sealant retention, fissure caries development, roughness of sealant surface, and change of color around the sealant. RESULTS: The results showed that both Fissurit FX and Grandioseal pit and fissure sealants were effective in preventing dental caries. Marginal adaptation was significantly better with Fissurit FX when compared to Grandioseal pit and fissure sealant. There was no difference in sealant retention between the two groups. The surface roughness of Fissurit FX was high when compared to that of Grandioseal. Statistical analysis was done using the Chi-squared test for intra-group comparison and Fisher's exact test for inter-group comparison. Results were considered statistically significant if p ≤ 0.05. CONCLUSION: Fissurit FX and Grandioseal pit and fissure sealants provided similar caries preventive effects and there was no difference in retention of sealants over a period of 1 year. However, surface roughness was better with Grandioseal fissure sealants. CLINICAL SIGNIFICANCE: This study is significant because there is limited evidence about the efficacy of nanofilled pit and fissure sealants in vivo. It will also provide dental practitioners an insight into the clinical efficacy of nanofilled pits and fissure sealant when compared to micro-filled sealant enabling them to make the right choice for the betterment of their dental practice. How to cite this article: Smitha M, Paul ST, Nagaraj T, et al. Comparison and Clinical Evaluation of Two Pit and Fissure Sealants on Permanent Mandibular First Molars: An In Vivo Study. J Contemp Dent Pract 2019;20(10):1151-1158.

Imbalance between neutrophil elastase and its inhibitor α1-antitrypsin in obesity alters insulin sensitivity, inflammation, and energy expenditure.

The molecular mechanisms involved in the development of obesity and related complications remain unclear. Here, we report that obese mice and human subjects have increased activity of neutrophil elastase (NE) and decreased serum levels of the NE inhibitor α1-antitrypsin (A1AT, SerpinA1). NE null (Ela2(-/-)) mice and A1AT transgenic mice were resistant to high-fat diet (HFD)-induced body weight gain, insulin resistance, inflammation, and fatty liver. NE inhibitor GW311616A reversed insulin resistance and body weight gain in HFD-fed mice. Ela2(-/-) mice also augmented circulating high molecular weight (HMW) adiponectin levels, phosphorylation of AMP-activated protein kinase (AMPK), and fatty acid oxidation (FAO) in the liver and brown adipose tissue (BAT) and uncoupling protein (UCP1) levels in the BAT. These data suggest that the A1AT-NE system regulates AMPK signaling, FAO, and energy expenditure. The imbalance between A1AT and NE contributes to the development of obesity and related inflammation, insulin resistance, and liver steatosis.

Is surgical exploration necessary in bilateral anorchia?

OBJECTIVE: To review the current management of boys with bilateral anorchia and assess whether surgical exploration is necessary when endocrine investigation indicates absent testicular function. PATIENTS AND METHODS: The medical records of 11 boys being managed for bilateral anorchia were reviewed in relation to clinical presentation, pituitary-gonadal function, surgical and histological findings. RESULTS: All boys had absence of testicular function based on undetectable levels of serum anti-Müllerian hormone, elevated basal or peak follicle-stimulating hormone and luteinising hormone levels and no testosterone response to human chorionic gonadotrophin stimulation. All boys underwent abdominal exploration, ten of whom showed no macroscopic signs of testis tissue, confirmed histologically in seven. Histology was not available in the remaining three boys. Abnormally small intra-abdominal testes were found bilaterally in one boy. These were sited in the scrotum at orchidopexy but had subsequently atrophied. Endocrine tests confirmed absent testicular function. CONCLUSION: Based on the high degree of concordance between the surgical and histological findings and the results of the endocrine tests, it is suggested that surgery is unnecessary in bilateral anorchia when endocrine tests confirm the absence of functioning testicular tissue.

Preparation and Characterization of Porous Gold and its Application as a Platform for Immobilization of Acetylcholine Esterase.

We report a method for fabrication of free-standing porous gold material with high surface area, and well-defined, tunable pore morphology. Porous gold is formed via a simple procedure which involves an acidic treatment of a commercially available complex white-gold alloy. We used SEM and AFM techniques to characterize the surface morphology, size and shape of the meso-pores as well as the surface roughness of the prepared porous gold samples. Formation of self-assembled monolayers of a flavin sulfide on the gold surface was used to estimate the total surface area of porous gold material. The monolayers were found to be electrochemically active by cyclic and square-wave voltammetry. It was found that 24 hour HNO(3) treatment gave a 12,400 times surface enlargement and resulted in a surface area of 14.2 m(2)/g, whereas 72 hour HNO(3) treatment resulted in a 6900 times surface enlargement and a surface area of 8.7 m(2)/g. In addition, the enzyme acetylcholine esterase was immobilized on the different porous gold surfaces in order to demonstrate biocompatibility of the porous gold material. Kinetic parameters and the amount of the immobilized acetylcholine esterase were determined.

In-vitro and in-vivo anti-cancer activity of a novel gemcitabine-cardiolipin conjugate.

Our objectives were to study the biological activity of a novel gemcitabine-cardiolipin conjugate (NEO6002) and compare that with gemcitabine. Cytotoxicity in vitro was determined against several gemcitabine-sensitive parental and gemcitabine-resistant cancer cell lines using the sulforhodamine B assay. The in vivo toxicity was examined by changes in body weight and hematologic indices of conventional mice. Immunodeficient SCID mice bearing P388 and BxPC-3 tumor xenografts were used to evaluate the in-vivo therapeutic efficacy. Both NEO6002 and gemcitabine showed pro-apoptotic and cytotoxic effects against all gemcitabine-sensitive cell lines tested. Unlike gemcitabine, the cytotoxicity of NEO6002 was independent of nucleoside transporter (NT) inhibitors, indicating a different internalization route of NEO6002. The conjugate demonstrated a favorable activity not only in ARAC-8C, a NT-deficient gemcitabine-resistant human leukemia cell line, but also in several other gemcitabine-resistant cell lines. At the in-vivo level, a comparative toxicity study showed a significant body weight loss and a decrease in white blood cell counts in gemcitabine-treated mice, whereas the influence of NEO6002 was mild. Treatment of NEO6002 at 27 micromol/kg increased the median survival of CD2F1 mice bearing P388 cells by up to 73%, while at the same doses and schedule of gemcitabine resulted in toxic deaths of all treated mice. At a dose of 18 micromol/kg, NEO6002 inhibited the growth of BxPC-3 xenografts by 52%, while only 32% of tumor inhibition was achieved with gemcitabine. We conclude that NEO6002 may be an effective chemotherapeutic agent with improved tolerability and can potentially circumvent NT-deficient, gemcitabine-resistant tumors.

Synthesis and biological evaluation of gemcitabine-lipid conjugate (NEO6002).

A novel gemcitabine-lipid conjugate 5 was synthesized and tested for its in vivo efficacy and toxicity. Compound 5 was tested in BxPC-3 human pancreatic tumor model in SCID mice and exhibited promising activity and lower toxicity when compared with Gemzar.

Open laparoscopic access for primary trocar using modified Hasson's technique.

OBJECTIVE: To describe the safety and efficacy of open laparoscopic access for the primary trocar using modified Hasson's technique for laparoscopic surgery in children. METHODS: All 100 laparoscopic procedures performed at King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia between January 1999 and April 2001 using modified Hasson's technique were prospectively evaluated. They were aged from 3 months to 12 years. RESULTS: One hundred children who had open laparoscopic access during the study period had diagnosis of acute appendicitis (n=57), impalpable undescended testes (n=29), gallstones (n=5), varicocele (n=3) and others (n=6). Three children had minor operative complications (2 cases of pre-peritoneal placement of trocar, which were recognized immediately and the other had omental bleeding). Two children had post-operative complications related to primary access (one port infection and other port site hematoma). Access to the abdominal cavity was generally secured in 3-12 minutes (average 4+/-2). Clinic follow-up ranged from 3-14 months. CONCLUSION: Open laparoscopic access using modified Hasson's technique was associated with no major or life-threatening complications. Minor operative (3%) and post-operative (2%) complications occurred in the first 100 cases. Modified Hasson's technique for the primary trocar for accessing the abdominal cavity is a safe and effective method, and is recommended for all laparoscopic procedures in children.

Copper, zinc and magnesium levels in type-1 diabetes mellitus.

OBJECTIVE: Alterations in plasma concentrations of several trace elements have been reported to occur in type-1 diabetes mellitus. These micronutrients are suspected to have a role in pathogenesis and progression of the disease. METHODS: In a comparative analysis, the plasma concentration of copper, zinc and magnesium was estimated in 37 patients with type-1 diabetes mellitus and 25 healthy non-diabetic subjects at Sher-i-Kashmir Institute of Medical Sciences, Srinagar, Kashmir, India. Trace elements were estimated using a GBC 902 double beam atomic absorption spectrophotometer. RESULTS: Mean plasma concentrations of copper and magnesium were comparable between diabetic patients and control subjects. Plasma zinc levels were significantly higher (P=0.022) in diabetic patients (17.78 0.6 micromol/L) as compared to controls (15.80 0.75 micromol/L). Glycemic control and presence of microalbuminuria did not influence the plasma levels of copper, zinc and magnesium. CONCLUSION: Plasma zinc levels are significantly higher in type-1 diabetes mellitus patients, while plasma copper and magnesium levels are not significantly altered. No effect of sex, glycemic control or presence of microalbuminuria could be demonstrated on plasma concentration of trace elements in type-1 diabetes mellitus patients.