Cardiovascular disease (CVD) contributes to high morbidity and mortality rates around the world. Coronary artery disease (CAD), hypertrophic cardiomyopathy (HCM), and idiopathic dilated cardiomyopathy (IDCM) are among CVD phenotypes which are affected by genetic and environmental factors. In addition to primary risk factors, single nucleotide polymorphisms (SNPs) in inflammatory cytokines like resistin gene (RETN) and tumor necrosis factor-alpha (TNF-alpha) are considered to influence the pathogenesis of CVD. Resistin is a relatively novel inflammatory marker, whereas TNF-alpha gene polymorphism has been widely investigated in patients with CVD among different ethnic populations with conflicting results. In the present study the RETN SNPs at -420 C>G (rs1862513) and +299 G>A (rs3745367), and the TNF-alpha gene SNPs at -308 G>A (rs1800629) and +238 G>A (rs361525) were investigated to determine the association of the cytokines’ mutant genotypes with the pathogenesis of CAD, HCM and IDCM in a Pakistani population. Blood samples were obtained from families (n = 40 families) with CAD history, sporadic CVD cases (n = 718), and healthy control subjects (n = 720) randomly selected from the regions of CVD cases. Biochemical analysis of lipids and high sensitivity C-reactive protein (hs-CRP) was carried out spectrophotometrically, while serum resistin levels were determined by enzyme-linked immunosorbent assay (ELISA). RETN and TNF-alpha genotyping was performed by polymerase chain reaction (PCR) and DNA sequencing or restriction fragment length polymorphism (RFLP). The evaluation of the RETN -420 C>G and +299 G>A polymorphism in a case- control study from forty complex Pakistani families with CAD history revealed that the said SNPs were significantly associated with the pathophysiology of CAD (P < 0.0001 for both SNPs). Heritability of the susceptible/variant alleles was investigated from parent–offspring trios in these families by using the transmission disequilibrium test (TDT) analysis. Data showed preferential transmission of the disease susceptible alleles from parent to affected off-spring (P < 0.0001 for both SNPs). Elevated resistin and hs-CRP levels were observed from familial CAD cases vs. unaffected subjects of the families (P < 0.0001 for both markers). The present study revealed that the RETN−420 C>G and +299 G>A variant genotypes were significantly associated with Resistin and Tumor Necrosis Factor-Alpha Gene Polymorphism and the Risk for Cardiovascular Disease in a Pakistani Population high concentrations of lipid biomarkers, resistin, and hs-CRP in familial cases of CAD (P < 0.05 for each variable). The TNF gene polymorphism at -308 and -238 was investigated in sporadic CAD cases, and healthy subjects of the study population. The findings demonstrated a significant link between the TNF-308A variant allele and CAD, whereas the -238 SNP was not associated with the disease. Further, RETN SNP at -420 was investigated in patients with HCM. The results demonstrated an association between the RETN -420 C>G polymorphism and cardiac hypertrophy in the study population (P < 0.0001). Logistic regression analysis revealed a significant association of the serum resistin levels (P < 0.0001) and the RETN -420 C>G polymorphism (P = 0.001) with the disease. Data from this investigation was published as a pioneer report on the association of the RETN -420 C>G polymorphism with HCM. The current study also demonstrated a link between the RETN -420 C>G (P < 0.0001) and +299 G>A (P = 0.0007) polymorphism and IDCM cases vs. healthy controls of the study population. The RETN -420G and +299A haplotype was more prevalent in the patient vs. control group (P < 0.0001). The results suggest that the RETN -420 C>G and +299 G>A polymorphism may have a role in the pathogenesis of IDCM. The current research leads to conclusion that the RETN SNPs at -420 and +299 are associated with familial cases of CAD in Pakistani families with the disease history. It was observed that the disease-susceptible alleles from parents to affected off-springs were transmitted more frequently in a family trios study. Regarding the TNF-alpha, it was observed that the -308 SNP was associated with the pathogenesis of CAD in the study population, whereas the variant genotype at -238 showed no link with the disease. Furthermore, this study demonstrated that the RETN -420 C>G polymorphism is associated with HCM in the study population; this was a pioneer finding in relation to the disease. Another interesting data from this study revealed that the RETN -420 C>G and +299 G>A polymorphism is associated with pathology of IDCM in the study population; the said SNPs have not been investigated among other populations prior to this study. This study concludes that the RETN and TNF- alpha gene polymorphisms are significantly associated with the pathogenesis of CAD and cardiomyopathy in the study population. Resistin and Tumor Necrosis Factor-Alpha Gene Polymorphism and the Risk for Cardiovascular Disease in a Pakistani Population XVII Abstract Some data from the present study has been published in the following papers: Hussain S, Bibi S, Javed Q (2011). Heritability of genetic variants of resistin gene in patients with coronary artery disease: a family-based study. Clinical Biochemistry 44: 618-622. Hussain S, Asghar M, Javed Q (2010). Resistin gene promoter region polymorphism and the risk of hypertrophic cardiomyopathy in patients. Translational Research 155: 142-147.
اے ربِ رحیم و کریم۔۔۔! اِن اللہ علی کلِ شیئٍ قدیر! میں خانہ بدوش ، سیلانی ، آوارہ! تیری زمیں پر۔۔۔تیرے موسموں کے ساتھ محوِ سفر ہوں تو کریم۔۔۔سبز موسم کا لباس پہن کر! تو رحیم۔۔۔خوشبو کی طرح روح میں اُتر کر! میرے تڑپتے سسکتے دل کو۔۔۔! اپنی آغوش میں لے کر۔۔۔اپنے ہاتھوں سے سہلاتا ہے دشتِ بیاباں میں دل فریب آہو بلا کر ! ستاروں کی سرگوشیوں میں! نرم ٹھنڈی ریت پر سلا کر! میرے خیالوں کے، حوالوں کی بدکتی ناقہ کو وحشتوں سے نجات دلاتا ہے میرے تڑپتے سسکتے دل کو! اپنی آغوش میں لے کر ، اپنے ہاتھوں سے سہلاتا ہے تو ہی خالق۔۔۔ تو ہی مالک۔۔۔! تیری کائنات میں اسرار جبرائیل ؑ کے ثبوت موجود ہیں نیاز الہام اور قلب نامہ بری کے! چراغ نور کی روشنی میں مظہر خلیلؑ کے ثبوت موجود ہیں تو مجھے بزم رقص سے۔۔۔! کوہ قبیس کی طرف لسان شعور کے لہجے میں بلاتا ہے مسافتوں کے مارے دل کو! اپنی آغوش میں لے کر، اپنے ہاتھوں سے سہلاتا ہے تیری وجہ سے لوح و قلم کو بھی ۔۔۔اپنے ہونے کا یقین ہے تو ہی ’’وھو علی کل شی ئٍ قدیر۔۔۔وھو علی بِکل شی ئٍ علیم‘‘ ہے صبح و شام میرے ارادوں کو۔۔۔تو اپنی پہچان کرواتا ہے مسافتوں کے مارے دل کو! اپنی آغوش میں لے کر ۔۔۔اپنے ہاتھوں سے سہلاتا ہے
After reading the whole books and find out the interpretation, there were various sayings, the meanings and interpretations of the verses of Quran. The reader does not have the capability to select correct and incorrect. He does not know what to do about the various interpretations. At first the people of Mecca knew the status of Revelation; they do not need to explain that revelation, because it was their native language while the Prophet (S.A.W) explains it in detail. After the earlier periods, it was necessary to adapt some rules to know the correct sayings, that rules were already include the Quran itself, in the Sunnah, in the Quranic Sciences, in the books of fundamentals of Jurisprudence, and in the books of Quranic Sciences. Later on, however, wrote the books as contemporary independent science as such as book of Husain Al Ḥarbī named (قواعد الترجيح عند المفسرين) and book written by Khalid Al Sabbath named (قواعد التفسير جمعاً ودراسةً). These rules of preference are most important as with the help of these rules, the books of interpretation can be clarified from incorrect sayings. These rules are various, including, related to Quranic text, Sunnah, the views of Companions, the evidence, or related to the linguistics of Arabs. The preference proves the strength of a saying or strengthens an aspect than others through rules of preference. One of the objectives of this research is that the rules of preference can distinguish between correct and incorrect interpretation. The researcher recommended attention to these rules of preference and to study it as a separate subject to get full benefit from the books of interpretation.
The presented research work in this dissertation comprises of synthesis, characterization, antimicrobial, hemolytic and enzyme inhibition studies of some new acetamides/sulfides bearing substituted-1,3,4-Oxadiazole and morpholine moieties. The acetamide, 1,3,4-oxadiazole and morpholine moieties are important functionalities because of their broad range of known pharmacological activities. Synthetic approaches (scheme-1-11) were utilized to synthesize poly-functional compounds. In first scheme, twenty three 5-substituted-1,3,4-Oxadiazol-2-thiols were synthesized by converting multifarious organic acids consecutively into the corresponding esters and hydrazides. Further the intermolecular cyclization of various carbohydrazides with carbon disulfide and potassium hydroxide yielded subsequent 5- substituted-1,3,4-Oxadiazol-2-thiols. Moreover, the reaction of different 5- substituted-1,3,4-Oxadiazol-2-thiols (scheme-2 & 3) with electrophiles, 2-bromo-N- [4-(4-morpholinyl)phenyl]acetamide and 2-bromo-N-[2-(4-morpholinyl)phenyl] acetamide yielded thirteen, N-[4-(4-morpholinyl)phenyl]-2-[(5-aryl/aralkyl-1,3,4- Oxadiazol-2-yl)thio]acetamides and fourteen N-[2-(4-morpholinyl)phenyl]-2-[(5- aryl/aralkyl-1,3,4-oxadiazol-2-yl)thio]acetamides respectively in the presence of N,N- dimethylformamide and sodium hydride. Sixteen novel benzyl sulfides (scheme-4) bearing 1,3,4-oxadiazole moiety and sulfo- morpholine functionality were synthesized (bromomethyl)phenyl)sulfonyl)morpholine with by the different reaction of 4-(4- 5-substituted-1,3,4- Oxadiazole-2-thiols. Nucleophilic substitution reaction of free thiol group in 1,3,4- Oxadiazoles with 4-(2-chloroethyl)morpholine hydrochloride yielded thirteen, 4-[2- [[5-aryl/aralkyl-1,3,4-Oxadiazol-2-yl]thio]ethyl]morpholine derivatives (scheme-5) in the presence of acetone and potassium carbonate . A series of nineteen electrophiles (scheme-5), N-substituted-2-bromoacetamides was developed by the reaction of different substituted/unsubstituted aryl/aralkyl/alkyl amines with 2-bromoacetyl bromide by using DCM or basic aqueous medium as solvent. Seventy one (71) acetamides were synthesized by the reaction of 5-(2-chloro/3- chloro/4-chloro/4-nitrophenyl/phenyl)-1,3,4-Oxadiazol-2-thiols with different electrophiles by simple stirring in the presence of DMF solvent and NaH base at the room temperature. The structures of all the synthesized compounds were characterized by using IR, 1H- NMR and mass spectral data. In addition, 13C-NMR technique was also used in some cases to support the structural analysis. A rational mass fragmentation pattern of some of the compounds is also proposed. Some of the 1H-NMR, 13 C-NMR and EIMS spectra of synthesized compounds are also presented for the obvious perceptive of signals. The synthesized compounds were evaluated for antibacterial, antifungal, hemolytic and enzyme inhibition activities. Some of compounds were found to be active and showed interesting results in different studies declared above. The biological activity data in comparison of each scheme with the reference standard drugs is presented in biological activity section.