Synthesis, Kinetics and Computational Explorations of 4-Phenylpiperazine Bearing N-(Aryl)-3-substituted-benzamides as Auspicious Tyrosinase Inhibitors.

In the aimed research study, a new series of N-(aryl)-3-[(4-phenyl-1-piperazinyl)methyl]benzamides was synthesized, which was envisaged as tyrosinase inhibitor. The structures of these newly designed molecules were verified by IR, 1H-NMR, 13C-NMR, EI-MS and CHN analysis data. These molecules were screened against tyrosinase and their inhibitory activity explored that these 3-substituted-benzamides exhibit good to excellent potential, comparative to the standard. The Kinetics mechanism was investigated through Lineweaver-Burk plots which depicted that molecules inhibited this enzyme in a competitive mode. Moreover, molecular docking was also performed to determine the binding interaction of all synthesized molecules (ligands) with the active site of tyrosinase enzyme and the results showed that most of the ligands exhibited efficient binding energy values. Therefore, it is anticipated that these molecules might serve as auspicious therapeutic scaffolds for treatment of the tyrosinase associated skin disorders.

Structure-based designing and synthesis of 2-phenylchromone derivatives as potent tyrosinase inhibitors: In vitro and in silico studies.

The present study describes the discovery of novel inhibitors of mushroom tyrosinase enzyme. For that purpose, a series of varyingly substituted 2-phenylchromone analogues 1-28 were synthesized and characterized in detail by various spectroscopic techniques (UV-Vis, FTIR, 1H NMR, 13C NMR) and mass spectrometry. All the derivatives (1-28) were screened in vitro for their inhibitory potential against mushroom tyrosinase enzyme. Interestingly, all the synthetic compounds displayed good to excellent inhibitory activity with IC50 values ranging from 0.093 ± 0.003 µg/ml to 23.58 ± 0.94 µg/ml for brominated 3-hydroxy-2-phenylchromones and 0.22 ± 0.017 µg/ml to 22.22 ± 1.1 µg/ml for brominated 2-phenylchromones against tyrosinase in comparison to the standard kojic acid (IC50 = 1.79 ± 0.64 µg/ml). Remarkably, the bromine atoms attached on ring A attribute to increases the inhibitory potential of 2-phenylchromone moiety and anti-tyrosinase assay demonstrated that compound 10 (IC50 = 0.093 ± 0.003 µg/ml) was found almost nineteenfold, 11 (IC50 = 0.126 ± 0.015 µg/ml) fourteenfold and 26 (IC50 = 0.22 ± 0.017 µg/ml) about eightfold more active than the positive control. Notably, among the already literature reported tyrosinase inhibitors, these analogues have been found the most active inhibitors of mushroom tyrosinase with the lowest possible IC50 values. To design and develop novel tyrosinase inhibitors using 2-phenylchromone as a structural motif in the future, a limited structure-activity relationship was established. Moreover, in silico studies were carried out to rationalize the binding mode of interactions of all the targeted compounds (1-28) with the active site of enzymes. The experimental and theoretical results are in parallel with one another. In addition, molecular description was performed with the drug-likeness and bioactivity scores. Computational analysis predicted that few compounds are in a linear correlation with Lipinski's RO5 indicating superb drug-likeness and bioactivity score for drug targets.

Interplay of N acetyl cysteine and melatonin in regulating oxidative stress-induced cardiac hypertrophic factors and microRNAs.

Early and specific diagnosis of oxidative stress linked diseases as cardiac heart diseases remains a major dilemma for researchers and clinicians. MicroRNAs may serve as a better tool for specific early diagnostics and propose their utilization in future molecular medicines. We aimed to measure the microRNAs expressions in oxidative stress linked cardiac hypertrophic condition induced through stimulants as Endothelin and Isoproterenol. Cardiac hypertrophic animal models were confirmed by BNP, GATA4 expression, histological assays, and increased cell surface area. High oxidative stress (ROS level) and decreased antioxidant activities were assessed in hypertrophied groups. Enhanced expression of miR-152, miR-212/132 while decreased miR-142-3p expression was observed in hypertrophic condition. Similar pattern of these microRNAs was detected in HL-1 cells treated with H2O2. Upon administration of antioxidants, the miRNAs expression pattern altered from that of the cardiac hypertrophied model. Present investigation suggests that oxidative stress generated during the cardiac pathology may directly or indirectly regulate anti-hypertrophy pathway elements through microRNAs including antioxidant enzymes, which need further investigation. The down-regulation of free radical scavengers make it easier for the oxidative stress to play a key role in disease progression.

Role of resistin genetic variations in knee osteoarthritis pathogenesis, a cross sectional study.

Osteoarthritis (OA) is a serious health concern globally and is recognized by degradation of articular cartilage, bone remodeling and synovial inflammation. Resistin is an adipokine that shown to be involved in inflammatory process associated with OA. Aim of the current study was to estimate the link of resistin gene polymorphisms (- 420 C>G, + 299 G>A) with genetic susceptibility of knee OA in a Pakistani population. 280 patients and 308 age and sex matched controls were recruited in this case-control study. Genotype and allele frequencies were evaluated by Polymerase chain reaction-Restriction Fragment Length Polymorphism. Resistin concentration was measured by immunoassay. A significant difference in allele and genotype frequency was observed for both study groups. Resistin - 420 mutant genotype was associated with an increased susceptibility to OA (p = 0.001). Similarly, resistin + 299 GA + AA genotypes showed a relation with an elevated risk of knee OA compared to GG genotype (p = 0.01). Moreover, the mutant alleles frequency was significantly high in patient group as compared to healthy individuals for both loci (p < 0.01). Resistin - 420/+ 299 alleles haplotype analysis demonstrated that mutant alleles were more prevalent in OA affected individuals compared to healthy subjects (p < 0.05). The serum resistin levels were not remarkably different in patient vs. control group (p = 0.9). Further, the circulating resistin level was not found to be influenced by - 420G and + 299A alleles and non significant differences were observed in resistin concentration in mutant vs. wild type genotypes for both SNPs (p > 0.05). Our data suggest an association between investigated resistin genetic variants and knee OA susceptibility in our population. This is the first report to show association between investigated single nucleotide polymorphisms and OA among any population.

Interplay of mitochondria apoptosis regulatory factors and microRNAs in valvular heart disease.

Valvular heart disease (VHD) is an active process involving a wide range of pathological changes. The major complications of VHD are stenosis and regurgitation, which are macroscopic phenomena, induced in part through cellular changes. Altered expression of mitochondria associated genes causes membrane potential depolarization, leading to the increased levels of apoptosis observed in cardiac dysfunction. Objective of this study is to find molecular medicine candidates that can control expression of the key mitochondria apoptosis regulatory genes. Present study aims to assess the way microRNA are involved in regulating mitochondrial apoptosis regulatory genes and observation of their expression in the heart valve dysfunction. Apoptotic genes PUMA and DRP1 were found to be highly expressed, whereas anti-apoptotic gene ARC was down regulated. The expression level of GATA-4 transcription factor was also reduced in cardiac valve tissues. MicroRNAs miR-15a and miR-29a were repressed, while miR-214 was up regulated. Furthermore, study showed that PUMA, DRP1 and ARC expression might be attenuated by their respective miRNAs. Our results indicate that mitochondria regulatory genes might be controlled by miR-15a, miR-29a and miR-214, in VHD patients. Present study may provide platform for future research regarding potential therapeutic role of miRNAs in CVDs.

Gender differences in normal left ventricle of adult FVB/N mice due to variation in interleukins and natriuretic peptides expression levels.

This study examined the sex differences for physical, morphological, histological, mRNA, and protein expression levels changes for interleukins and natriuretic peptides in left ventricle (LV) of two groups of adult FVB/N mice; males (WM) and females (WF). LV morphological, histological, reverse transcription and quantitative real-time PCR (RT-PCR), and immunohistochemical (IHC) alterations were determined in FVB/N mice at 34-35 weeks on gender basis. Confirming the gender dimorphism, FVB/N males (WM) illustrated a significant reduction in ANP and IL1-A levels as well as significantly increased body weight (BW (gm)), tibia length (TL (mm)), heart weight (HW (mg)), heart weight-to-body weight (HW/BW (mg/gm)) ratio, heart weight-to-tibia length (HW/TL (mg/mm)) ratio, left ventricle weight (LV (mg)), left ventricle-to-body weight (LV/BW (mg/gm)) ratio, and left ventricle-to-tibia length (LV/TL (mg/mm)) ratio, left ventricular (LV) cardiomyocyte diameter, high BNP, NPRA, IL-1B, and IL1R1 expression in comparison with FVB/N females (WF). Gender differences in relation to left ventricle (LV) may be due to differences in the interleukins and natriuretic peptides levels as an outcome of sex related hormones.

Transcriptional changes associated with resistance to inhibitors of epidermal growth factor receptor revealed using metaanalysis.

BACKGROUND: EGFR is important in maintaining metabolic homeostasis in healthy cells, but in tumors it activates downstream signaling pathways, causing proliferation, angiogenesis, invasion and metastasis. Consequently, EGFR is targeted in cancers using reversible, irreversible or antibody inhibitors. Unfortunately, tumors develop inhibitor resistance by mutations or overexpressing EGFR, or its ligand, or activating secondary, EGFR-independent pathways. METHODS: Here we present a global metaanalysis comparing transcriptional profiles from matched pairs of EGFR inhibitor-sensitive vs. -resistant cell lines, using 15 datasets comprising 274 microarrays. We also analyzed separately pairs of cell lines derived using reversible, irreversible or antibody inhibitors. RESULTS: The metaanalysis identifies commonalities in cell lines resistant to EGFR inhibitors: in sensitive cell lines, the ontological categories involving the ErbB receptors pathways, cell adhesion and lipid metabolism are overexpressed; however, resistance to EGFR inhibitors is associated with overexpression of genes for ErbB receptors-independent oncogenic pathways, regulation of cell motility, energy metabolism, immunity especially inflammatory cytokines biosynthesis, cell cycle and responses to exogenous and endogenous stimuli. Specifically in Gefitinib-resistant cell lines, the immunity-associated genes are overexpressed, whereas in Erlotinib-resistant ones so are the mitochondrial genes and processes. Unexpectedly, lines selected using EGFR-targeting antibodies overexpress different gene ontologies from ones selected using kinase inhibitors. Specifically, they have reduced expression of genes for proliferation, chemotaxis, immunity and angiogenesis. CONCLUSIONS: This metaanalysis suggests that 'combination therapies' can improve cancer treatment outcomes. Potentially, use of mitochondrial blockers with Erlotinib, immunity blockers with Gefitinib, tyrosine kinase inhibitors with antibody inhibitors, may have better chance of avoiding development of resistance.

The tumor necrosis factor-α -238G/A and IL-6 -572G/C gene polymorphisms and the risk of idiopathic dilated cardiomyopathy: a meta-analysis of 25 studies including 9493 cases and 13,971 controls.

BACKGROUND: Inflammation plays an imperative role in the etiology of cardiovascular diseases (CVD). The role of cytokines in the development and progression of idiopathic dilated cardiomyopathy (IDCM) is still uncertain. The current study was conducted to evaluate the association of tumor necrosis factor-α (TNF-α) -238G/A and IL-6 -572G/C gene polymorphism with IDCM in a Pakistani population. METHODS: IDCM cases (n=250) and healthy controls (n=300) were genotyped using PCR-RFLP. RESULTS: The variant genotypes of both the loci showed significant differences between patients and controls (p<0.05). However, -238G/A polymorphism did not show association with the disease in the presence of covariates. We also conducted a meta-analysis of both the loci with regards to CVD in accordance with the Prisma checklist. No significant relation of the TNF-α -238G/A polymorphism with CVD was found; however, this single nucleotide polymorphism (SNP) showed an association with the disease in the Asian population after subgroup analysis (p=0.01). Whereas, the IL-6 -572G/C polymorphism showed that the variant genotype (GC+CC) was associated with higher risk of CVD in contrast to the GG genotype. Furthermore, subgroup meta-analysis demonstrated a significant association of the -572 polymorphism with CVD in Asians, but no association was observed among Western populations with this SNP. CONCLUSIONS: Our findings support an association between the IL-6 -572G/C polymorphism and IDCM risk. The role of the TNF-α -238G/A polymorphism in IDCM is still unclear. Further studies are warranted to determine the serum cytokine levels in relation to the cytokines' SNP in diverse ethnic groups to ascertain the molecular basis of the disease pathology.

Loss-of-function mutations of ILDR1 cause autosomal-recessive hearing impairment DFNB42.

By using homozygosity mapping in a consanguineous Pakistani family, we detected linkage of nonsyndromic hearing loss to a 7.6 Mb region on chromosome 3q13.31-q21.1 within the previously reported DFNB42 locus. Subsequent candidate gene sequencing identified a homozygous nonsense mutation (c.1135G>T [p.Glu379X]) in ILDR1 as the cause of hearing impairment. By analyzing additional consanguineous families with homozygosity at this locus, we detected ILDR1 mutations in the affected individuals of 10 more families from Pakistan and Iran. The identified ILDR1 variants include missense, nonsense, frameshift, and splice-site mutations as well as a start codon mutation in the family that originally defined the DFNB42 locus. ILDR1 encodes the evolutionarily conserved immunoglobulin-like domain containing receptor 1, a putative transmembrane receptor of unknown function. In situ hybridization detected expression of Ildr1, the murine ortholog, early in development in the vestibule and in hair cells and supporting cells of the cochlea. Expression in hair cell- and supporting cell-containing neurosensory organs is conserved in the zebrafish, in which the ildr1 ortholog is prominently expressed in the developing ear and neuromasts of the lateral line. These data identify loss-of-function mutations of ILDR1, a gene with a conserved expression pattern pointing to a conserved function in hearing in vertebrates, as underlying nonsyndromic prelingual sensorineural hearing impairment.

Real-World Challenges of Managing Diffuse Large B-Cell Lymphoma in a Developing Country.

PURPOSE: To highlight challenges and cancer care disparities in patients of diffuse large B-cell lymphoma management in resource-constrained settings. MATERIALS AND METHODS: This multicenter retrospective study included 738 patients from 12 public and private sector hematology-oncology centers across Pakistan. Patients were divided into limited-resource and enhanced-resource settings as per national diffuse large B-cell lymphoma (DLBCL) guidelines. RESULTS: The median age at diagnosis was 47 years (range, 14-89). Male:female ratio was 2.5:1. Majority of the patients (69.3%) were treated in limited-resource settings. Computed tomography was used as a staging modality in 442 (60%) patients. Limited-stage DLBCL was present in 13.5% of patients, while 86.3% had advanced-stage disease at diagnosis. First-line regimens included rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in 56% and cyclophosphamide, doxorubicin, vincristine, prednisone in 34% of patients, while 10% of patients received palliative regimens upfront. Of evaluable data, complete remission was documented in 299 (74.4%) patients, 39 (9.8%) had partial response and 63 (13.5%) had progressive disease. Disease-free survival (DFS) and overall survival (OS) status were not available for 345 (46.8%) patients at the time of data collection. Overall study cohort had a median follow-up of 2.2 years with a median OS of 3.6 years (95% CI, 3.1 to 4.1), median DFS of 3.1 years (95% CI, 2.6 to 3.6), and a 5-year OS of 40% and DFS of 36%. CONCLUSION: Patients from low- and middle-income countries present at an earlier age and have more advanced disease. Patients were frequently lost to follow-up, and record keeping was inadequate more so in patients treated in limited-resource settings. There is a need to establish a national lymphoma registry, improve record keeping, and standardize treatments to ensure improvement in treatment outcomes.

Association of interleukin-6 gene promoter polymorphism with coronary artery disease in Pakistani families.

Interleukin-6 (IL-6) is a well-known inflammatory cytokine and suggested to be involved in the development of coronary artery disease (CAD). IL-6 gene expression has been investigated with controversy in CAD patients. This study investigates the association of the IL-6 gene expression with CAD, the molecular basis for the regulation of interleukin-6 expression in a Pakistani population. Our data show that the serum IL-6 levels were increased in patients with CAD compared with healthy controls and that the IL-6 gene polymorphism at -174 was more prevalent in CAD cases. There was a statistically significant association between the IL-6 gene polymorphism and CAD, which may be associated with an increased risk for the disease. Moreover, circulating IL-6 and hs-CRP levels were significantly higher in patients with CC genotype (P < 0.0001 and P < 0.0001, resp.). In a binary logistic-regression model, an independent association was found between CAD and increased serum IL-6 and hs-CRP levels and -174G>C polymorphism. This is the first report on the IL-6 expression and the IL-6 gene polymorphism in patients with CAD from Pakistan, and hence it highlights a novel risk factor for the disease.

Tumor necrosis factor-alpha gene promoter region polymorphism and the risk of coronary heart disease.

BACKGROUND: Tumor necrosis factor-alpha (TNF- α ) gene polymorphisms have been implicated in the manifestation of atherosclerosis. Controversy exists regarding the link between the cytokine's variant genotype and CHD among different ethnic groups. There have been fewer studies on the TNF- α gene -1031T>C and -863C>A polymorphisms in relation to CHD. Therefore, the current study was designed to investigate the association of the TNF- α gene -1031T>C and -863C>A polymorphisms with CHD in a Pakistani population. METHODS: Patients with CHD (n = 310) and healthy individuals (n = 310) were enrolled in this study. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: A significant difference was observed in the -863C>A polymorphism between patients with CHD and control subjects (P < 0.0001). CHD risk was positively associated with the variant allele -863A (P < 0.0001) in the study subjects. There was no significant link between the -1031T>C polymorphism and CHD risk in the study population. Haplotypes A-T and A-C of the TNF-alpha gene loci at -863 and -1031 showed higher frequency in the patient group compared with controls (P < 0.05). CONCLUSION: The TNF- α -863C>A gene polymorphism was associated with the pathogenesis of CHD while the -1031T>C polymorphism did not show any link with the disease in a Pakistani population.

Therapeutic potential of tumour necrosis factor-alpha antagonists in patients with chronic heart failure.

OBJECTIVES: Elevated levels of tumour necrosis factor alpha (TNF-alpha) are associated with the development of heart failure. TNF-alpha antagonists, etanercept (ETA) and infliximab (INF) have been used for treating different clinical conditions. Anti-TNF-alpha therapy did not show favourable results in patients with chronic heart failure (CHF). This review analyses the reasons for anti-TNF-alpha therapy failure in CHF patients; potential approaches for improved clinical outcome are also addressed. DESIGN AND METHODS: Data analysis from clinical trials of CHF patients treated with ETA and INF. RESULTS: In heart failure patients, ETA and INF therapy did not lead to improved clinical outcomes and high doses of INF were associated with worsening of cardiac events. This contrasts with the observation that these agents are associated with reduced cardiac events when used in patients with inflammatory diseases such as rheumatoid arthritis (RA). CONCLUSIONS: Treatment of CHF patients with TNF-alpha antagonists did not show encouraging results. There is a need for the development of better treatment strategies for CHF. Perhaps, tailored anti-TNF-alpha therapy in relation to the TNF-alpha genotype of CHF patients and targeting of the cytokine gene expression via signalling pathway inhibitors may have useful clinical implications.

Regulation of cell cycle and differentiation markers by pathogenic, non-pathogenic and opportunistic skin bacteria.

Skin is the first line of defense against the physical, chemical and the biological environment. It is an ideal organ for studying molecular responses to biological infections through a variety of skin cells that specialize in immune responses. Comparative analysis of skin response to pathogenic, non-pathogenic, and commensal bacteria would help in the identification of disease specific pathways for drug targets. In this study, we investigated human breast reduction skin responses to Cutibacterium acnes (C. acnes), Staphylococcus aureus (S. aureus), Staphylococcus epidermidis (S. epidermidis), and TLR1/2 agonist using Affymetrix microarray chips. The Pam3CSK4 solution and bacterial cultures were prepared and inoculated in steel rings, that were placed on the acetone treated epidermis in a petri dish. After 24 h incubation, 8 mm punch biopsies were taken from the center of the ring, and RNA was extracted. The genome-wide expression was then analyzed using Affymetrix HG-133A gene chip microarray. We found that the C. acnes and S. aureus boosted the production of extracellular matrix components and attenuated the expression of differentiation markers. The above responses were mediated through the TLR2 pathway. Skin also responded to S. aureus and C. acnes by inducing the genes of the cell cycle machinery; this response was not TLR2-dependent. S. aureus induced, whereas C. acnes suppressed the genes associated with apoptosis; this was also not TLR2-dependent. Moreover, S. epidermis apparently did not lead to changes in gene expression. We conclude that the breast reduction skin is a very useful model to study the global gene expression in response to bacterial treatments.

Cephalosporin as Potent Urease and Tyrosinase Inhibitor: Exploration through Enzyme Inhibition, Kinetic Mechanism, and Molecular Docking Studies.

In present study, eleven cephalosporin drugs were selected to explore their new medically important enzyme targets with inherited safety advantage. To this end, selected drugs with active ingredient, cefpodoxime proxetil, ceftazidime, cefepime, ceftriaxone sodium, cefaclor, cefotaxime sodium, cefixime trihydrate, cephalexin, cefadroxil, cephradine, and cefuroxime, were evaluated and found to have significant activity against urease (IC50 = 0.06 ± 0.004 to 0.37 ± 0.046 mM) and tyrosinase (IC50 = 0.01 ± 0.0005 to 0.12 ± 0.017 mM) enzymes. Urease activity was lower than standard thiourea; however, tyrosinase activity of all drugs outperforms (ranging 6 to 18 times) the positive control: hydroquinone (IC50 = 0.18 ± 0.02 mM). Moreover, the kinetic analysis of the most active drugs, ceftriaxone sodium and cefotaxime sodium, revealed that they bind irreversibly with both the enzymes; however, their mode of action was competitive for urease and mixed-type, preferentially competitive for tyrosinase enzyme. Like in vitro activity, ceftriaxone sodium and cefotaxime sodium docking analysis showed their considerable binding affinity and significant interactions with both urease and tyrosinase enzymes sufficient for downstream signaling responsible for observed enzyme inhibition in vitro, purposing them as potent candidates to control enzyme-rooted obstructions in future.

Preparation of Spice Extracts: Evaluation of Their Phytochemical, Antioxidant, Antityrosinase, and Anti-α-Glucosidase Properties Exploring Their Mechanism of Enzyme Inhibition with Antibrowning and Antidiabetic Studies In Vivo.

Tyrosinase and α-glucosidase enzymes are known as promising target candidates for inhibitors to control unwanted pigmentation and type II diabetics mellitus. Therefore, twenty extracts as enzyme inhibitors were prepared from edible spices: nutmeg, mace, star anise, fenugreek, and coriander aiming to explore their antioxidant, antibrowning, and antidiabetic potential. Results confirmed that all extracts showed potent antioxidant activity ranging from IC50 = 0.14 ± 0.03 to 3.69 ± 0.37 µg/mL. In addition, all extracts exhibited excellent antityrosinase (IC50 = 1.16 ± 0.06 to 71.32 ± 4.63 µg/mL) and anti-α-glucosidase (IC504.76 ± 0.71 to 42.57 ± 2.13 µg/mL) activities outperforming the corresponding standards, hydroquinone, and acarbose, respectively. Among all extracts, star anise ethyl acetate (Star anise ETAC) was found most potent inhibitor for both tyrosinase and α-glucosidase enzymes and was further studied to explore the mechanism of enzyme inhibition. Kinetic analysis revealed its irreversible but mixed-type tyrosinase inhibition with preferentially competitive mode of action. However, it binds reversibly with α-glucosidase through competitive mode of action. Further, star anise ETAC extract showed concentration dependent and posttreatment time-dependent antibrowning effect on potato slices and antidiabetic effect on diabetic rabbits in vivo proposing it promising candidate for tyrosinase-rooted antibrowning and α-glucosidase-associated diabetes management for future studies.

Association of TNF-α polymorphisms (-857, -863 and -1031), TNF-α serum level and lipid profile with acne vulgaris.

BACKGROUND: Acne is an inflammatory condition principally affected by genetic and dietary factors. Investigation into functional polymorphisms of TNF-α gene and their association with acne vulgaris will be helpful in exploring genetic influence on skin immune mediated inflammatory events. In the present study, we analyzed association of TNF-α gene polymorphisms, its expression levels and lipid profiles in a large cohort of acne patients and controls. METHODS: We used PCR-RFLP to study association of TNF-α polymorphisms at -857C/T, -863C/A and -1031 T/C sites with acne vulgaris. Lipid profiles were measured using enzymatic end-point method. The serum levels of TNF-α and apolipoprotein a were measured using ELISA. NIH, LDlink was used to investigate patterns of linkage disequilibrium across south Asian reference genome (Punjabi from Lahore Pakistan). RESULTS: We found that TNF-α -863 polymorphism is strongly associated with acne in overall population as well as in gender and severity based groups of acne patients. Polymorphisms at -863 and -1031 position were in linkage disequilibrium. Importantly, TNF-α serum level was significantly increased in acne patients with severe disease symptoms. Furthermore, levels of total cholesterol (TC) and triglycerides (TG) were significantly increased, whereas high density lipoprotein cholesterol (HDL-C) level was significantly decreased in acne patients. The levels of apolipoprotein a varied widely in studied populations and no significant difference was found in the analyzed groups. CONCLUSION: In conclusion, we found that TNF-α expression increases in acne patients affected by TNF-α polymorphisms, and that the lipid profile is specifically disrupted in acne patients.

Current Trends of Cardiovascular Risk Determinants in Pakistan.

We carried out a case control study to determine the prevalence of various cardiovascular risk factors in a Pakistani population. A total of 835 patients (555 males and 280 females) and 794 control subjects (486 males and 308 females) were recruited in this study. Patients with documented history of coronary artery disease (CAD) were included. We assessed major risk factors such as age, body mass index (BMI), hypertension and dyslipidemia, using pre-specified definitions. A comparative analysis of the biochemical and clinical parameters was carried out between controls and patients using student's t test. We observed that the cardiovascular disease (CVD) risk factors were more prominent in the patient group as compared to the controls (P < 0.05). In the whole studied population females had increased levels of total cholesterol (TC) (P = 0.01), triglyceride (TG) (P = 0.02), and very low density lipoprotein cholesterol (vLDL-C) (P = 0.02) as compared to males. Among patients group all the risk factors were significantly higher and more prevalent in females when compared with male patients (P < 0.05). The study population was also analyzed according to the smoking status and BMI to study the effect of these risk factors independently. The smokers and study subjects with raised BMI had significantly raised blood pressure and cholesterol levels. The role of age as a risk factor was also investigated in the current study. The persons with age ≤45 years had the highest levels of lipid profile including TC, TG, low density lipoprotein cholesterol (LDL-C), vLDL-C and high density lipoprotein cholesterol (HDL-C) among the three (≤45, 46-55, ≥56 years) groups (P < 0.05). In conclusion, the present study demonstrates an increased propensity of CVD risk factors at a younger age with female preponderance. Moreover, hypertension and dyslipidemia are the most prominent of the risk factors.