Targeting Akt/NF-κB/p53 Pathway and Apoptosis Inducing Potential of 1,2-Benzenedicarboxylic Acid, Bis (2-Methyl Propyl) Ester Isolated from Onosma bracteata Wall. against Human Osteosarcoma (MG-63) Cells.

Onosma bracteata Wall. is an important medicinal and immunity-enhancing herbs. This plant is commonly used in the preparation of traditional Ayurvedic drugs to treat numerous diseases. Inspired by the medicinal properties of this plant, the present study aimed to investigate the antiproliferative potential and the primary molecular mechanisms of the apoptotic induction against human osteosarcoma (MG-63) cells. Among all the fractions isolated from O. bracteata, ethyl acetate fraction (Obea) showed good antioxidant activity in superoxide radical scavenging assay and lipid peroxidation assay with an EC50 value of 95.12 and 80.67 µg/mL, respectively. Silica gel column chromatography of ethyl acetate (Obea) fraction of O. bracteata yielded a pure compound, which was characterized by NMR, FTIR, and HR-MS analysis and was identified as 1,2-benzene dicarboxylic acid, bis (2-methyl propyl) ester (BDCe fraction). BDCe fraction was evaluated for the antiproliferative potential against human osteosarcoma MG-63, human neuroblastoma IMR-32, and human lung carcinoma A549 cell lines by MTT assay and exhibited GI50 values of 37.53 µM, 56.05 µM, and 47.12 µM, respectively. In MG-63 cells, the BDCe fraction increased the level of ROS and simultaneously decreased the mitochondria membrane potential (MMP) potential by arresting cells at the G0/G1 phase, suggesting the initiation of apoptosis. Western blotting analysis revealed the upregulation of p53, caspase3, and caspase9 while the expressions of p-NF-κB, p-Akt and Bcl-xl were decreased. RT-qPCR studies also showed upregulation in the expression of p53 and caspase3 and downregulation in the expression of CDK2, Bcl-2 and Cyclin E genes. Molecular docking analysis displayed the interaction between BDCe fraction with p53 (-151.13 kcal/mol) and CDK1 (-133.96 kcal/mol). The results of the present work suggest that the BDCe fraction has chemopreventive properties against osteosarcoma (MG-63) cells through the induction of cell cycle arrest and apoptosis via Akt/NF-κB/p53 pathways. This study contributes to the understanding of the utilization of BDCe fraction in osteosarcoma treatment.

Neuroprotective effects of hydro-alcoholic extract of Eclipta alba against 1-methyl-4-phenylpyridinium-induced in vitro and in vivo models of Parkinson's disease.

Pathogenesis of Parkinson's disease (PD) specifically involves the degeneration of dopaminergic neurons in the substantia nigra region, which mainly begun with the overwhelmed oxidative stress and neuroinflammation. Considering the antioxidant and other pharmacological properties, Eclipta alba needs to be exploited for its possible neuroprotective efficacy against PD and other neurological disorders. Therefore, the current study was conducted to exemplify the remedial effects of hydro-alcoholic extract of E. alba (EA-MEx) against MPP+-elicited in vitro and in vivo PD models. SH-SY5Y, a neuroblastoma cell culture and male Wistar rats were used to impersonate the hallmarks of PD. Qualitative and quantitative analyses of EA-MEx revealed the presence of quercetin, ellagic acid, catechin, kaempferol, and epicatechin at varying concentrations. EA-MEx was found to deliver considerable protection against MPP+-induced oxidative damages in SH-SY5Y cells. Furthermore, in vivo study also supported the neuroprotective efficacy of EA-MEx, with significant mitigation of behavioral deficits induced by intrastriatal injection of MPP+. Furthermore, the disturbed levels of cellular antioxidant machinery have been significantly improved with the pre-treatment of EA-MEx. Mechanistically, the expression of α-synuclein, tyrosine hydroxylase, and mortalin were also found to be improved with the prior treatment of EA-MEx. Hence, the study suggests Eclipta alba as a suitable candidate for the development of better neuropathological therapeutics.

Correction to: Synthesis, spectroscopic characterization and in vitro anticancer activity of new platinum(II) complexes with some thione ligands in the presence of triethylphosphine.

Due to an unfortunate turn of events, the main affiliation of Dr. Saleh Altuwaijri was omitted from the above mentioned three articles. The complete affiliations are published below and should be treated as definitive.

Isolation of Phytochemicals from Bauhinia variegata L. Bark and Their In Vitro Antioxidant and Cytotoxic Potential.

Plants have been the basis of traditional medicine since the dawn of civilizations. Different plant parts possess various phytochemicals, playing important roles in preventing and curing diseases. Scientists, through extensive experimental studies, are playing an important part in establishing the use of phytochemicals in medicine. However, there are still a large number of medicinal plants which need to be studied for their phytochemical profile. In this study, the objective was to isolate phytochemicals from bark of Bauhinia variegata L. and to study them for their antioxidant and cytotoxic activities. The bark was extracted with methanol, followed by column chromatography and thus isolating kaempferol, stigmasterol, protocatechuic acid-methyl ester (PCA-ME) and protocatechuic acid (PCA). 2,2-azinobis-3-ethyl-benzothiazoline-6-sulfonic acid (ABTS) and 2, 2'-diphenyl-1-picrylhydrazyl radical (DPPH) radical scavenging assays were utilized for assessment of antioxidant activity, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) dye reduction assay was used to determine cytotoxic activity against C-6 glioma rat brain, MCF-7 breast cancer, and HCT-15 colon cancer cell lines. The compounds were found to have significant antioxidant and cytotoxic activity. Since there is a considerable increase in characterizing novel chemical compounds from plant parts, the present study might be helpful for chemotaxonomic determinations, for understanding of medicinal properties as well as for the quality assessment of herbal supplements containing B. variegata bark, thus establishing its use in traditional medicine.

Synthesis, spectroscopic characterization and in vitro anticancer activity of new platinum(II) complexes with some thione ligands in the presence of triethylphosphine.

Seven new platinum(II) complexes (1-7) of triethylphosphine (Et3P) and thiones (L) with general formula, cis-[Pt(Et3P)2(L)2]Cl2 were prepared and characterized by elemental analysis, FTIR and NMR (1H, 13C & 31P) measurements. The analytical and spectroscopic data suggested the formation of the desired complexes. The complexes were tested for in vitro cytotoxicity against four cell lines: Hela (human cervical adenocarcinoma), MCF-7 (human breast carcinoma), A549 (human lung carcinoma), and HTC15 (human colon carcinoma). The anticancer activity values of compounds 1-6 are much better than cisplatin and carboplatin as indicated by their IC50 values.

To compare the efficacy of tamsulosin and alfuzosin as medical expulsive therapy for ureteric stones.

AIMS AND OBJECTIVES: This study aims to evaluate the efficacy of tamsulosin and alfuzosin for the distal ureteral stone. This study assessed the spontaneous passage and expulsion of the stone. MATERIALS AND METHODS: The study was conducted in the Department of Surgery at Maharishi Markandeshwar Institute of Medical Sciences and Research, Mullana, Ambala, from May 2013 to May 2014. A total number of 136 patients diagnosed as distal ureteric stone (US) of size <10 mm were included in this study. It was divided into two groups (I and II) out of which 36 cases were excluded. Group I received tablet tamsulosin 0.4 mg/day, and Group II received alfuzosin 10 mg/day. The efficacy of tamsulosin and alfuzosin as an adjunctive medical therapy was determined. RESULTS: Both the drugs can be safely used for the distal USs. The stone expulsion rate was seen in 36 patients (72.0%) in Group I, and in 34 patients (68.0%) in Group II (P = 0.545). The passage of stones noticed by 32 patients in each Groups I and II (P = 1.000). The mean number of pain attacks was 2.91 ± 1.01 for Group I, and 1.8 ± 0.83 for Group II (P < 0.001 and P < 0.001). Thus, we propagate the use of alfuzosin significantly lower number of pain attacks. The drug-related side-effects were postural hypertension (four in Group I and one in Group II) and retrograde ejaculation (eight in Group I, and one in Group II). Thus, the difference was statistically significant in terms of retrograde ejaculation but insignificant for postural hypotension. CONCLUSION: There is no difference between both medications in term of efficacy (passing stones) for the management of distal ureteral stones. Both medications are safe and effective. In addition, alfuzosin was better tolerated than tamsulosin as it has fewer side effects.

Bacopa monnieri extracts prevent hydrogen peroxide-induced oxidative damage in a cellular model of neuroblastoma IMR32 cells.

Neurodegenerative diseases are the consequences of imbalance between the production of oxidative stress and its nullification by cellular defense mechanisms. Hydrogen peroxide (H2O2), a precursor of deleterious reactive oxygen species, elicits oxidative stress, resulting in severe brain injuries. Bacopa monnieri is well known for its nerve relaxing and memory enhancing properties. The present study was designed to evaluate the protective effects of extracts from Bacopa monnieri against H2O2 induced oxidative stress using a cellular model, neuroblastoma IMR32 cell line. The protective potential of methanolic, ethanolic, and water extracts of B. monnieri (BM-MEx, BM-EEx, and BM-WEx) was evaluated using MTT assay. Although, all the B. monnieri extracts were found to protect cells against H2O2-mediated stress but BM-MEx showed significantly greater protection. UPLC analysis of BM-MEx revealed various polyphenols, including quercetin, catechin, umbelliferone, and caffeic acid predominance. Further, BM-MEx was found to possess considerable greater neuroprotective potential in comparison to the standard polyphenols such as quercetin, catechin, umbelliferone, and caffeic acid. The levels of antioxidant enzymes were significantly elevated after the pretreatment of BM-MEx and quercetin. The expression levels of oxidative stress markers, such as NF200, HSP70, and mortalin, were significantly alleviated after the pretreatment of BM-MEx as shown by immunofluorescence and RT-PCR. In conclusion, the present study demonstrated the protective effects of BM-MEx, suggesting that it could be a candidate for the development of neuropathological therapeutics.

Scaffolds of hydroxyl apatite nanoparticles disseminated in 1, 6-diisocyanatohexane-extended poly(1, 4-butylene succinate)/poly(methyl methacrylate) for bone tissue engineering.

Poly(1, 4-butyl succinate) extended 1, 6-diisocyanatohexane (PBSu-DCH) polymers and Polymethylmethacrylate (PMMA) scaffolds decorated with nano hydroxyl apatite have been prepared and characterized for regeneration of bone in cranio-maxillofacial region. Synthesized scaffolds revealed good response in bone regeneration and excellent cell viability in comparison to commercial available glass plate, which lead to better proliferation of MG-63 cell lines. Additionally, they demonstrate high porosity and excellent water retention ability. Moreover, controlled degradation (in pH=7.4) and sustained drug release in pH (4.5 and 7.4) are advantages of these scaffolds to serve as delivery vehicles for therapeutic drugs. Samples also provide the protection against Escherichia coli and Methicillin Resistant Staphylococcus aureus microorganisms which can be helpful for quick recovery of the patient. In-vitro inflammatory response has been assessed via adsorption of human plasma/serum proteins on the surface of the scaffolds. Results suggest that prepared scaffolds have good bone regeneration ability and provide friendly environment for the cell growth with the additional advantage of protection of the surrounding tissues from microbial infection. With all these features, it is speculated that these scaffolds will have wide utility in the area of tissue engineering and regenerative medicine.

Evaluation and comparison of postoperative levels of serum bilirubin, serum transaminases and alkaline phosphatase in laparoscopic cholecystectomy versus open cholecystectomy.

BACKGROUND: Laparoscopic cholecystectomy (LC) requires the creation of a pneumoperitoneum via insufflations of carbon dioxide; resulting in increased partial pressure of carbon dioxide (CO2) and intraperitoneal pressure which leads to the changes in pulmonary function and hemodynamic measurements. Hypercarbia leads to visceral organ ischemia including liver and venous stasis/thromboembolism or both due to impaired flow. The present study has been undertaken to see the changes in liver function tests (LFTs) after laparoscopic/open cholecystectomy (OC), the incidences of such change, their relation to age, sex, duration of surgery and to know the clinical significances of such disturbances. AIMS AND OBJECTIVES: To compare and correlate the serum level of bilirubin, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) in patients who underwent LC to those who underwent OC. MATERIALS AND METHODS: The present study was conducted in the Department of Surgery at MMIMSR, MM University, Mullana, Ambala. A total number of 200 patients diagnosed as cholelithiasis were included in the study from May 2012 to May 2014. These cases were randomly divided into two groups (A and B) consisting of 100 cases each. LC was performed in group A patients and OC was done in group B patients. Three blood samples were taken: (I) pre-operatively; (II) after 24 hours of surgery; and (III) after 72 hours of surgery for comparison of the enzyme level alterations. RESULTS: In LC patients, there were rise in the levels of serum bilirubin, AST and ALT after 24 hrs of surgery from the preoperative value and then again fall was noted (near to normal value) after 72 hrs of surgery except in that of ALP. ALP levels showed slight fall after 24 hrs of surgery and then slight rise after 72 hrs which was within the normal limit. Whereas in OC patients, there were slight variations in the liver enzymes (which were within the normal range). CONCLUSIONS: Transient elevation of serum bilirubin, AST and ALT occurs after LC or after OC. The alteration in the liver enzymes can be attributed to CO2 pneumoperitoneum, surgical manipulations, diathermy, patient position, and arterial injury may also other factors. These changes return to normal in 3-4 days after procedure and they have no clinical consequences in patients with normal hepatic function but they may still cause worry to the surgeon regarding the integrity of biliary tree.

Leveraging population admixture to characterize the heritability of complex traits.

Despite recent progress on estimating the heritability explained by genotyped SNPs (h(2)g), a large gap between h(2)g and estimates of total narrow-sense heritability (h(2)) remains. Explanations for this gap include rare variants or upward bias in family-based estimates of h(2) due to shared environment or epistasis. We estimate h(2) from unrelated individuals in admixed populations by first estimating the heritability explained by local ancestry (h(2)γ). We show that h(2)γ = 2FSTCθ(1 - θ)h(2), where FSTC measures frequency differences between populations at causal loci and θ is the genome-wide ancestry proportion. Our approach is not susceptible to biases caused by epistasis or shared environment. We applied this approach to the analysis of 13 phenotypes in 21,497 African-American individuals from 3 cohorts. For height and body mass index (BMI), we obtained h(2) estimates of 0.55 ± 0.09 and 0.23 ± 0.06, respectively, which are larger than estimates of h(2)g in these and other data but smaller than family-based estimates of h(2).

Role of glass structure in defining the chemical dissolution behavior, bioactivity and antioxidant properties of zinc and strontium co-doped alkali-free phosphosilicate glasses.

We investigated the structure-property relationships in a series of alkali-free phosphosilicate glass compositions co-doped with Zn(2+) and Sr(2+). The emphasis was laid on understanding the structural role of Sr(2+) and Zn(2+) co-doping on the chemical dissolution behavior of glasses and its impact on their in vitro bioactivity. The structure of glasses was studied using molecular dynamics simulations in combination with solid state nuclear magnetic resonance spectroscopy. The relevant structural properties are then linked to the observed degradation behavior, in vitro bioactivity, osteoblast proliferation and oxidative stress levels. The apatite-forming ability of glasses has been investigated by X-ray diffraction, infrared spectroscopy and scanning electron microscopy-energy-dispersive spectroscopy after immersion of glass powders/bulk in simulated body fluid (SBF) for time durations varying between 1h and 14 days, while their chemical degradation has been studied in Tris-HCl in accordance with ISO 10993-14. All the glasses exhibit hydroxyapatite formation on their surface within 1-3h of their immersion in SBF. The cellular responses were observed in vitro on bulk glass samples using human osteosarcoma MG63 cell line. The dose-dependent cytoprotective effect of glasses with respect to the concentration of zinc and strontium released from the glasses is also discussed.

Some new [(thione)2Au(diamine)]Cl3 complexes: synthesis, spectroscopic characterization, computational and in vitro cytotoxic studies.

Recent advances in oncology are focused on developing new complexes of gold(III) with various ligands that show augmented anti-proliferative potential and reduced toxicity as compared to cis-platin. In this study, new Au(III) complexes of the type [(thione)2Au(diamine)]Cl3 are reported, where thione=1,3-imidazolidine-2-thione (Imt), 1,3-Diazinane-2-thione (Diaz) and diamine=1,2-diaminoethane (en), 1,3-diaminopropane (pn) or 1,4-diaminobutane (bn). The solid state IR as well as (13)C and (15)N NMR data indicate that Au(III) center is bonded via sulfur of thiocarbonyl SC site of the thiones and also chelated by the diamines from the trans side of coordinated thiones. Spectroscopic data are evaluated by comparisons with calculated data from the built and optimized structure by GAUSSIAN 09 at the RB3LYP level with LanL2DZ bases set. These new Au(III) complexes based on mixed thione and diamine ligands are very similar to the square planar structure of tetracoordinate [Au(en)2]Cl3complex. In this study, cytotoxicity data for these gold(III) complexes against C6 glioma cell lines are also reported, and the results indicate some complexes have cytotoxicity comparable to cis-platin.

Cytoprotective effect of methanolic extract of Nardostachys jatamansi against hydrogen peroxide induced oxidative damage in C6 glioma cells.

Oxidative stress has been implicated as an important factor in the process of neurodegeneration and hydrogen peroxide (H2O2) is one of the most important precursors of reactive oxygen species (ROS), responsible for many neurodegenerative diseases. This study used extracts from Nardostachys jatamansi rhizomes, known for nerve relaxing properties in Ayurvedic medicine, to ascertain their protective role in H2O2-induced oxidative stress in C6 glioma cells. The protective effect of methanolic, ethanolic and water extracts of N. jatamansi (NJ-MEx, NJ-EEx and NJ-WEx respectively) was determined by MTT assay. NJ-MEx significantly protected against H2O2 cytotoxicity when cells were pretreated for 24 h. The level of antioxidant enzymes, catalase, superoxide dismutase (Cu-ZnSOD), glutathione peroxidase (GPx), and a direct scavenger of free radicals, glutathione (GSH), significantly increased following pre-treatment with NJ-MEx. Lipid peroxidation (LPx) significantly decreased in NJ-MEx-pretreated cultures. The expression of a C6 differentiation marker, GFAP (glial fibrillary acidic protein), stress markers HSP70 (heat shock protein) and mortalin (also called glucose regulated protein 75, Grp75) significantly decreased when cells were pre-treated with NJ-MEx before being subjected to H2O2 treatment as shown by immunofluorescence, western blotting and RT-PCR results. The present study suggests that NJ-MEx could serve as a potential treatment and/or preventive measure against neurodegenerative diseases.

Quantifying missing heritability at known GWAS loci.

Recent work has shown that much of the missing heritability of complex traits can be resolved by estimates of heritability explained by all genotyped SNPs. However, it is currently unknown how much heritability is missing due to poor tagging or additional causal variants at known GWAS loci. Here, we use variance components to quantify the heritability explained by all SNPs at known GWAS loci in nine diseases from WTCCC1 and WTCCC2. After accounting for expectation, we observed all SNPs at known GWAS loci to explain 1.29 x more heritability than GWAS-associated SNPs on average (P=3.3 x 10⁻5). For some diseases, this increase was individually significant: 2.07 x for Multiple Sclerosis (MS) (P=6.5 x 10⁻9) and 1.48 x for Crohn's Disease (CD) (P = 1.3 x 10⁻³); all analyses of autoimmune diseases excluded the well-studied MHC region. Additionally, we found that GWAS loci from other related traits also explained significant heritability. The union of all autoimmune disease loci explained 7.15 x more MS heritability than known MS SNPs (P < 1.0 x 10⁻¹6 and 2.20 x more CD heritability than known CD SNPs (P = 6.1 x 10⁻9), with an analogous increase for all autoimmune diseases analyzed. We also observed significant increases in an analysis of > 20,000 Rheumatoid Arthritis (RA) samples typed on ImmunoChip, with 2.37 x more heritability from all SNPs at GWAS loci (P = 2.3 x 10⁻6) and 5.33 x more heritability from all autoimmune disease loci (P < 1 x 10⁻¹6 compared to known RA SNPs (including those identified in this cohort). Our methods adjust for LD between SNPs, which can bias standard estimates of heritability from SNPs even if all causal variants are typed. By comparing adjusted estimates, we hypothesize that the genome-wide distribution of causal variants is enriched for low-frequency alleles, but that causal variants at known GWAS loci are skewed towards common alleles. These findings have important ramifications for fine-mapping study design and our understanding of complex disease architecture.

Intrathecal Drug Delivery (ITDD) systems for cancer pain.

Intrathecal drug delivery is an effective pain management option for patients with chronic and cancer pain. The delivery of drugs into the intrathecal space provides superior analgesia with smaller doses of analgesics to minimize side effects while significantly improving quality of life. This article aims to provide a general overview of the use of intrathecal drug delivery to manage pain, dosing recommendations, potential risks and complications, and growing trends in the field.

Tracheal granulation as a cause of unrecognized airway narrowing.

Tracheostomy is one of the most common elective surgical procedures performed in critically ill patients. The most frequent late complication after tracheostomy is the development of granulation tissue, a complication that may cause airway occlusion or result in airway stenosis. We report the successful management of a patient with tracheal granulation presenting as an unrecognised cause of difficulty breathing.

Genome-wide comparison of African-ancestry populations from CARe and other cohorts reveals signals of natural selection.

The study of recent natural selection in human populations has important applications to human history and medicine. Positive natural selection drives the increase in beneficial alleles and plays a role in explaining diversity across human populations. By discovering traits subject to positive selection, we can better understand the population level response to environmental pressures including infectious disease. Our study examines unusual population differentiation between three large data sets to detect natural selection. The populations examined, African Americans, Nigerians, and Gambians, are genetically close to one another (F(ST) < 0.01 for all pairs), allowing us to detect selection even with moderate changes in allele frequency. We also develop a tree-based method to pinpoint the population in which selection occurred, incorporating information across populations. Our genome-wide significant results corroborate loci previously reported to be under selection in Africans including HBB and CD36. At the HLA locus on chromosome 6, results suggest the existence of multiple, independent targets of population-specific selective pressure. In addition, we report a genome-wide significant (p = 1.36 × 10(-11)) signal of selection in the prostate stem cell antigen (PSCA) gene. The most significantly differentiated marker in our analysis, rs2920283, is highly differentiated in both Africa and East Asia and has prior genome-wide significant associations to bladder and gastric cancers.