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Background Citrullinated proteins formed by peptidyl arginine deiminases (PADIs) deimination of arginine residues in proteins are of particular interest in arthritis pathogenesis. Polymorphisms on the PADI-4 gene lead to the malfunctioning of PADIs leading to the onset of arthritis. Objective The present study was conducted to determine the polymorphisms on the PADI-4 gene and their association with rheumatoid arthritis (RA) as well as Osteoarthritis (OA). Methodology To achieve the above-mentioned objective a case-control study was conducted. Blood samples were collected from RA, OA, and control subjects. DNA was extracted from each blood sample by modified organic method and was quantified as well as qualified by DNA gel electrophoresis and Nanodrop. Patients were tested for rs874881, rs11203366, rs11203367, rs2240336, rs2240337, rs2240339, rs1748033 and rs2240340 polymorphic sites by amplifying targeted regions through PCR with site-specific primers. Genotyping was performed by Restriction Fragment Length Polymorphism and direct sequencing method. Mutations were identified by analyzing sequences on BioEdit software. Allelic, genetic, and multiple site analysis were performed by SHEsis and PLINK software. Change in the amino acid sequence was identified by MEGA 6.0 software. Results Polymorphisms were identified on all targeted polymorphic sites except rs2240337 in both RA and OA individuals. In addition, two novel mutations were also identified in exon 4 identified i-e SCV000804840: c.218T > C and SCV000807675: c.241G > T. All the SNPs except rs11203366 were found to be significantly associated with RA at an allelic level whereas all SNP’s have been significant risk factors in the onset of OA. At genotypic level rs874881, rs11203366, rs2240339, SCV000804840 and SCV000807675 were significantly associated to RA development whereas rs874881, rs11203366, rs11203367, rs2240339, SCV000804840 and SCV000807675 were genetic risk factors in OA onset. Haplotype analysis indicated that GACCACGCC and GACCACGCT were highly significant in disease development. Polymorphisms identified altered the functioning of PADIs by altering their amino acid sequence. Conclusion In conclusion, it was found that PADI-4 gene polymorphism was not only involved in the onset of RA but was also found to be a significant risk factor in OA onset.

A number of novel 7-chloro-4-aminoquinoline derivatives have been efficiently synthesized by nucleophilic aromatic substitution reaction of 4,7-dichloroquinoline with α,ω-diaminoalkanes of variable carbon-chain length. Treatment of the intermediates with substituted aromatic/heteroaromatic aldehydes has led to the corresponding Schiff bases. Structures of the products have been elucidated from FTIR, 1H, and 13C NMR, and mass spectra. Antimicrobial tests of the compounds have indicated that the most active ones displayed MIC values in the range of 1.5 to 12.5 µg/mL, however they displayed no antifungal activity. According to the accumulated data, length of the carbon-chain linker and electronic properties of the compounds are decisive for their biological activity. Molecular docking studies have supported the above relationships.

The Hedgehog (Hh) pathway has emerged as a potential target for effectual hepatic repair based on convincing clinical and preclinical evidence that proves its significance in regulating hepatic damage. The purpose of this study is to probe the effect of quercetin on liver fibrosis through the modulation of the Hh pathway. Healthy male Wistar rats were divided into four groups (n = 10). The control group was treated with saline, rats in the remaining three groups received twice a week intoxication with intraperitoneal injections of thioacetamide (200 mg/kg) for the induction of hepatic fibrosis for 6 weeks. After 28 days of quercetin and silymarin treatment, histological changes, serum biochemical index, antioxidant enzyme activity, key mediators of Hh pathway and inflammation were analyzed. Serological analysis showed statistically improved cholesterol, H.D.L-Cholesterol, and L.D.L-Cholesterol in the treatment groups. Superoxide dismutase and glutathione levels were found to be increased after the treatment with quercetin and silymarin. mRNA expression of important mediators of the Hh signaling, and inflammation including Shh, Ihh, Ptch-1, Smo, Hhip, Gli-3, TNF-α, NFκ-β, and Socs-3 were significantly downregulated after the use of quercetin and silymarin. Quercetin also minimized the thioacetamide-induced histopathological changes, as confirmed by a lower degree of hepatic lobule degeneration, the intralobular occurrence of inflammatory cells, and a lower degree of hepatocytic necrosis. Sudan Black B staining showed remarked lipids improvements in the treatment groups. Taken together, these findings demonstrate that quercetin could ameliorate hepatic fibrosis by antagonizing the hedgehog pathway and also suggest the hedgehog pathway as a potential therapeutic target for the treatment of liver fibrosis.

Isatin and substituted isatin derivatives possess a broad spectrum of biological activities. These moieties also have a wide scope for substitution, particularly at positions N-1 and C-3. Therefore, the study focused at synthesizing some novel isatin/substituted isatin Schiff’s bases and screening them for anti-cancer activity against MCF-7 cell lines. All the compounds were synthesized by conventional methods in a two-step synthesis. Mannich bases of isatin were synthesized by reacting secondary amines and 37% formalin, which were then reacted with primary aromatic amines in the presence of glacial acetic acid to yield the title compounds. All the compounds were characterized by physical, chromatographic and spectroscopic methods. The synthesized analogues showed good activity against MCF-7 cell lines when compared to the standard drug, Doxorubicin. At a concentration of 10µg/ml, the analogues IDF 3B, IDF 3G, IDF 3H and IDF 3I showed percentage cell viability of 35.46227 ± 12.92, 34.37412 ± 5.39, 35.81035 ± 5.25, 36.19748 ± 3.27 respectively compared to percentage cell viability of 22.36828 ± 2.35 for the standard. The obtained data indicated that the analogues were effective against breast cancer, and therefore the isatin moiety could serve as the lead to the development of new anti-breast cancer agents.

Hepatocellular carcinoma (HCC), a leading cause of cancer related deaths is predominantly driven by chronic inflammatory responses. Due to asymptomatic nature and lack of early patient biopsies, precise involvement of inflammation in hepatic injury initiation remains unidentified. Aim of the study was to elucidate the regulation patterns of inflammatory signalling from initiation of hepatic injury to development of HCC. HCC mice model was established using DEN followed by repeated doses of CCl

Citrullinated proteins formed by peptidyl arginine deiminases (PADIs) deimination of arginine residues in proteins are of particular interest in arthritis pathogenesis. Polymorphisms on theThe present study was conducted to determine the polymorphisms on theTo achieve the above-mentioned objective a case-control study was conducted. Blood samples were collected from RA, OA, and control subjects. DNA was extracted from each blood sample by modified organic method and was quantified as well as qualified by DNA gel electrophoresis and Nanodrop. Patients were tested for rs874881, rs11203366, rs11203367, rs2240336, rs2240337, rs2240339, rs1748033 and rs2240340 polymorphic sites by amplifying targeted regions through PCR with site-specific primers. Genotyping was performed by Restriction Fragment Length Polymorphism and direct sequencing method. Mutations were identified by analyzing sequences on BioEdit software. Allelic, genetic, and multiple site analysis were performed by SHEsis and PLINK software. Change in the amino acid sequence was identified by MEGA 6.0 software.Polymorphisms were identified on all targeted polymorphic sites except rs2240337 in both RA and OA individuals. In addition, two novel mutations were also identified in exon 4 identified i-e SCV000804840: c.218T C and SCV000807675: c.241G T. All the SNPs except rs11203366 were found to be significantly associated with RA at an allelic level whereas all SNP's have been significant risk factors in the onset of OA. At genotypic level rs874881, rs11203366, rs2240339, SCV000804840 and SCV000807675 were significantly associated to RA development whereas rs874881, rs11203366, rs11203367, rs2240339, SCV000804840 and SCV000807675 were genetic risk factors in OA onset. Haplotype analysis indicated that GACCACGCC and GACCACGCT were highly significant in disease development. Polymorphisms identified altered the functioning of PADIs by altering their amino acid sequence.In conclusion, it was found that

Rat sarcoma gene (RAS) holds great importance in pathogenesis of acute myeloid leukemia (AML). The activated mutations in Neuroblastoma rat sarcoma viral oncogene homolog (NRAS) and Kirsten rat sarcoma viral oncogene homolog (KRAS) confers proliferative and survival signals, deliberating numerous effects on overall survival and progression free survival in AML patients. In this study thirty one (31) blood samples of adult newly diagnosed AML patients were collected to identify possible incidence of mutations through amplification of KRAS (exon 1 and 2) and NRAS gene (exon 1 and 2) using polymerase chain reaction (PCR). Amplicons were then subjected to sequencing and were analyzed through Geneious Prime 2019. Five of thirty one (16.12%) patients had altered sites in either NRAS or KRAS. The NRAS mutations were observed in three AML patients (N = 3, 9.67%). A novel missense mutation NRAS-I36R (239 T > G) representing a substitution of single nucleotide basepair found in NRAS exon 1 while exon 2 was detected with heterozygous mutation NRAS-E63X (318G > T) and insertion (A), resulting in frameshift of the amino acid sequence and insertion of two nucleotide basepairs (TA) in two of the patients. KRAS mutations (N = 2, 6.45%) were found in exon 1 whereas no mutations in KRAS exon 2 were detected in our patient cohort. Mutation in KRAS Exon 1, KRAS-D30N (280G > A) was observed in two patients and one of them also had a novel heterozygous mutation KRAS-L16N (240G > C). In addition there was no statistically significant association of mutRAS gene of AML patients with several prognostic markers including age, gender, karyotyping, CD34 positivity, cytogenetic abnormalities, total leukocyte count, white blood cell count and French-American-British (FAB) classification. However, the presence of mutRAS gene were strongly associated (p = 0.001) with increased percentage of bone marrow blasts. The prevalence of mutations in correlation with clinical and hematological parameter is useful for risk stratification in AML patients.

“Markhor” (Capra falconeri) name is derived from two Persian and Pashto words, “Mar” means ‘snake’ and “khor” means ‘eater’. It is a large wild goar, habitant of mountains and high altitude rainy forest of Western and Central Asia. It is national animal of Pakistan and also termed as the ‘screw-horned goat’ or ‘Shakhawat’. The male Markhor are usually loners while females live in herds of 9. They are diurnal and excellent climbers and jump on rocky, mountains. After chewing the cud, they form a foamy substance in their drool which is used by the native people for extracting poison of the snake. Male Markhor lives in forest during the hot weathers, while female Markhor climb the highest peaks. However, they descend down to the area of relatively lower altitudes in cold season to avoid the extreme weather conditions. They forage for around 8-12 hours a day and then rest during the mid-day to chew their cud. Markhor are normally kept with other 83:wild goats. They are captivated in zoo and wildlife parks for conservation purpose. Markhor have an average life span of 10 to 13 years. They are susceptible of being eaten, when threatened, they give an alarm that is similar to that of a domestic goat bleating. It is listed as an endangered species on ‘The International Union for Conservation of Nature (IUCN) Red List since 2015. During the last fifteen years (2006-2020), hundreds of markhor have been killed in Chitral gol national park (CGNP), Pakistan [1]. Direct predation and disturbance of natural environment to these animals have compromised conservation of markhor in Pakistan.

Vitamin D is an anti-inflammatory molecule and has a role in prevention of arthritis development. Biologically active form 1, 25(OH)2D3 of vitamin D can only exert its action after binding its definite vitamin D receptor encoded by VDR gene. VDR gene polymorphism leads to dysfunctioning of 1, 25(OH)2D3 ultimately disease onset. The purpose of current study was to evaluate the effect of vitamin D level and VDR gene polymorphism on rheumatoid arthritis and osteoarthritis. Blood samples were collected from case and control after taking written consent. Serum was separated and vitamin D level as determined from each sample by ELISA. DNA was extracted from each blood sample and amplified by using gene specific primers. Genotyping was performed by Sangers sequencing and PCR-RFLP technique. It was found that vitamin D level was not significantly different among patients and controls. The rs10735810, rs1544410, rs7975232, and rs731236 were associated with the onset of arthritis at both allelic and genotypic level (p < 0.01). Nucleotide change on rs10735810 site leads to change of tryptophan with arginine. The frequencies of haplotype CGAT, CGGA, CGGT, CTAA, CTAT, TGAA, TGAT, TGGA, and TTGA were higher in patients and act as risk factors of RA onset, whereas haplotypes CGAT, CGAT, CGGT, CTGA, TGAT, TGGA, TTAA, and TTGA were associated with OA onset. In conclusion, serum vitamin D level may be normal among arthritis patients but polymorphism on VDR gene restricts vitamin D to perform its anti-inflammatory function by altering the 1, 25(OH)2 D3 binding sites.

The diversity in the biological response of 4-thiazolidinones has attracted the attention of many researchers to explore this framework for its potential. It is, therefore, of prime importance that the study of this topic and the development of new synthetic strategies should be based on the most recent knowledge, emerging from the latest research. This review is an endeavor to highlight the progress in the chemistry and biological activity of the 4-thiazolidinones, predominantly after 2006. The last section of the review encompasses the various patents granted on 4-thiazolidinone analogs/derivatives with World Intellectual Proprietary Organization (WIPO) and United State Patent Trademark Office (USPTO), particularly in the duration of the year 2000 to the year 2012.

The diversity in the biological response of 4-thiazolidinones has attracted the attention of many researchers to explore this framework for its potential. It is, therefore, of prime importance that the study of this topic and the development of new synthetic strategies should be based on the most recent knowledge, emerging from the latest research. This review is an endeavor to highlight the progress in the chemistry and biological activity of the 4-thiazolidinones, predominantly after 2006. The last section of the review encompasses the various patents granted on 4-thiazolidinone analogs/derivatives with World Intellectual Proprietary Organization (WIPO) and United State Patent Trademark Office (USPTO), particularly in the duration of the year 2000 to the year 2012.