Plasma membrane Ca2+ pump isoform 4 function in cell migration and cancer metastasis.

The Ca2+ ion is a universal second messenger involved in many vital physiological functions including cell migration and development. To fulfil these tasks the cytosolic Ca2+ concentration is tightly controlled, and this involves an intricate functional balance between a variety of channels and pumps of the Ca2+ signalling machinery. Among these proteins, plasma membrane Ca2+ ATPases (PMCAs) represent the major high-affinity Ca2+ extrusion systems in the cell membrane that are effective in maintaining free Ca2+ concentration at exceedingly low cytosolic levels, which is essential for normal cell function. An imbalance in Ca2+ signalling can have pathogenic consequences including cancer and metastasis. Recent studies have highlighted the role of PMCAs in cancer progression and have shown that a particular variant, PMCA4b, is downregulated in certain cancer types, causing delayed attenuation of the Ca2+ signal. It has also been shown that loss of PMCA4b leads to increased migration and metastasis of melanoma and gastric cancer cells. In contrast, an increased PMCA4 expression has been reported in pancreatic ductal adenocarcinoma that coincided with increased cell migration and shorter patient survival, suggesting distinct roles of PMCA4b in various tumour types and/or different stages of tumour development. The recently discovered interaction of PMCAs with basigin, an extracellular matrix metalloproteinase inducer, may provide further insights into our understanding of the specific roles of PMCA4b in tumour progression and cancer metastasis.

Clinical characteristics, outcomes, and seasonality of acute respiratory infection associated with single and codetected rhinovirus species among hospitalized children in Amman, Jordan.

Rhinovirus (RV)-specific surveillance studies in the Middle East are limited. Therefore, we aimed to study the clinical characteristics, outcomes, and seasonality of RV-associated acute respiratory infection among hospitalized young children in Jordan. We conducted a prospective viral surveillance study and enrolled children <2 years old admitted to a large public hospital in Amman, Jordan (2010-2013). Demographic and clinical data were collected by structured interviews and chart abstractions. Nasal and/or throat swabs were collected and tested for a panel of respiratory viruses, and RV genotyping and speciation was performed. At least one virus was detected in 2641/3168 children (83.4%). RV was the second most common virus detected (n = 1238; 46.9%) and was codetected with another respiratory virus in 730 cases (59.0%). Children with RV codetection were more likely than those with RV-only detection to have respiratory distress but had similar outcomes. RV-A accounted for about half of RV-positive cases (54.7%), while children with RV-C had a higher frequency of wheezing and reactive airway disease. RV was detected year-round and peaked during winter. In conclusion, though children with RV codetection had worse clinical findings, neither codetection nor species affected most clinical outcomes.

Correction to: The antiangiogenic activities of ethanolic crude extracts of four Salvia species.

CORRECTION: After the publication [1] it came to the attention of the authors that one of the co-authors was incorrectly included as Hamza Somrain. The correct spelling is as follows: Hamzeh Sumrein.

APOE Gene polymorphism among Jordanian Alzheimer`s patients with relation to lipid profile.

OBJECTIVE: To investigate the frequencies of the apolipoprotein E (APOE) alleles and genotypes and study their relationship with the lipid profile in Jordanian patients with late-onset Alzheimer`s disease (AD). METHODS: This case-control study was carried out on 71 Jordanian individuals: 38 patients with late-onset AD (age >/=65 years) and 33 age-matched healthy controls. All participants were recruited from senior homes and Jordan University Hospital, Amman, Jordan between January 2010 and December 2013. Each sample was examined for APOE`s 3 major isoforms (e2, e3, e4) using the polymerase chain reaction technique (PCR) followed by the sequencing technique. In addition, samples were screened for lipid profiles (total cholesterol (TC), high-density lipoprotein (HDL), lower-density lipoprotein (LDL), and triglyceride (TG) levels. RESULTS: The e3/e4 genotype and e4 allele prevalence were higher in AD patients compared to healthy controls (26.3% vs. 3.0%, p=0.03 and 15.8% vs. 4.5%, p=0.03; respectively). In the AD group, the e2 carriers showed the lowest levels of total and LDL cholesterol, and the e4 carriers showed the highest levels of total and LDL cholesterol, although the difference was not statistically significant (p>0.05). CONCLUSION: APOE-e4 frequency was almost 4 times higher in the AD group compared to the control group, and this difference was statistically significant. A trend that was observed in the AD group regarding the lipid profile and e2 and e4 carriers requires further investigation using a larger sample size.

An intronic single-nucleotide polymorphism (rs13217795) in FOXO3 is associated with asthma and allergic rhinitis: a case-case-control study.

BACKGROUND: Asthma and allergic rhinitis are respiratory diseases with a significant global burden. Forkhead box O3 (FOXO3) is a gene involved in the etiology of a number of respiratory diseases. The objective of this study is to assess the association of rs13217795, an intronic FOXO3 single-nucleotide polymorphism, with asthma and allergic rhinitis. METHODS: In this case-case-control genetic association study, genotyping was conducted using the PCR-RFLP method. Genotype-based associations were investigated under the general, recessive, and dominant models of disease penetrance using binomial logistic regression; and, allele-based associations were tested using Pearson's chi-squared test. RESULTS: The final study population consisted of 94 controls, 124 asthmatics, and 110 allergic rhinitis patients. The general and recessive models of disease penetrance were statistically significant for both case-control comparisons. Under the general model, the odds of the asthma phenotype were 1.46 (0.64 to 3.34) and 3.42 (1.37 to 8.57) times higher in heterozygotes and derived allele homozygotes, respectively, compared to ancestral allele homozygotes. The corresponding odds ratios for the allergic rhinitis phenotype were 1.05 (0.46 to 2.40) and 2.35 (0.96 to 5.73), respectively. The dominant model of disease penetrance was not statistically significant. The minor allele in all study groups was the ancestral allele, with a frequency of 0.49 in controls. There was no deviation from Hardy-Weinberg equilibrium in controls. Both case-control allele-based associations were statistically significant. CONCLUSIONS: Herein we present the first report of the association between rs13217795 and allergic rhinitis, and the first independent verification of the association between rs13217795 and asthma. Marker selection in future genetic association studies of asthma and allergic rhinitis should include functional polymorphisms in linkage disequilibrium with rs13217795.

Cisplatin Provokes Peripheral Nociception and Neuronal Features of Therapy-Induced Senescence and Calcium Dysregulation in Rats.

Therapy-Induced Senescence (TIS) is a form of senescence that is typically described in malignant cells in response to the exposure of cancer chemotherapy or radiation but can also be precipitated in non-malignant cells. TIS has been shown to contribute to the development of several cancer therapy-related adverse effects; however, evidence on its role in mediating chemotherapy-induced neurotoxicity, such as Chemotherapy-induced Peripheral Neuropathy (CIPN), is limited. We here show that cisplatin treatment over two cycles (cumulative dose of 23 mg/kg) provoked mechanical allodynia and thermal hyperalgesia in Sprague-Dawley rats. Isolation of dorsal root ganglia (DRG) from the cisplatin-treated rats demonstrated robust SA-ß-gal upregulation at both day 8 (after the first cycle) and day 18 (after the second cycle), decreased lmnb1 expression, increased expression of cdkn1a and cdkn2a, and of several factors of the Senescence-associated Secretory Phenotype (SASP) (Il6, Il1b, and mmp9). Moreover, single-cell calcium imaging of cultured DRGs revealed a significant increase in terms of the magnitude of KCl-evoked calcium responses in cisplatin-treated rats compared to vehicle-treated rats. No significant change was observed in terms of the magnitude of capsaicin-evoked calcium responses in cisplatin-treated rats compared to vehicle-treated rats but with decreased area under the curve of the responses in cisplatin-treated rats. Further evidence to support the contribution of TIS to therapy adverse effects is required but should encourage the use of senescence-modulating agents (senotherapeutics) as novel palliative approaches to mitigate chemotherapy-induced neurotoxicity.

The antiangiogenic activities of ethanolic crude extracts of four Salvia species.

BACKGROUND: Angiogenesis is one of cancer hallmarks that are required for both cancer progression and metastasis. In this study we examined the antiangiogenic properties of the ethanolic crude extracts of four Salvia species grown in Jordan. METHODS: The direct antiangiogenic activity was evaluated using various models: ex vivo rat aortic ring assay, in vitro assessment of HUVEC proliferation and migration, and in vivo CAM assay, while we used the changes in the expression of HIF-1α and VEGF in breast cancer cells (MCF 7) as an indicative for the indirect antiangiogenic activity. RESULTS: All four crude extracts showed a potential antiangiogenic activity in the rat aortic assay, however two species were found to be cytotoxic against Fibroblast cell line (PLF); the finding that caused the exclusion of these two extracts from further studies. Of the two remaining extracts, S. triloba showed very promising direct and indirect antiangiogenic activities. S. triloba inhibited the HUVEC proliferation with an IC50 of 90 µg/mL and HUVEC migration by 82% at 150 µg/mL. Furthermore, the in vivo CAM assay also illustrated the high impact of S. triloba against the newly formed vessel in the chicken embryonic membrane. Interestingly, the S. triloba inhibited the expression of VEGF at the mRNA and protein and the HIF-1α mRNA in the MCF 7 breast cancer cells under both normoxic and hypoxic conditions. CONCLUSIONS: Taken together, all these findings of the direct and indirect angiogenic investigations nominated S. triloba as a highly potent antiangiogenic plant that may have chemotherapeutic and/or chemoprevention potentials.

Allele and genotype frequencies of the polymorphic cytochrome P450 genes (CYP1A1, CYP3A4, CYP3A5, CYP2C9 and CYP2C19) in the Jordanian population.

Drug metabolizing enzymes participate in the neutralizing of xenobiotics and biotransformation of drugs. Human cytochrome P450, particularly CYP1A1, CYP2C9, CYP2C19, CYP3A4 and CYP3A5, play an important role in drug metabolism. The genes encoding the CYP enzymes are polymorphic, and extensive data have shown that certain alleles confer reduced enzymatic function. The goal of this study was to determine the frequencies of important allelic variants of CYP1A1, CYP2C9, CYP2C19, CYP3A4 and CYP3A5 in the Jordanian population and compare them with the frequency in other ethnic groups. Genotyping of CYP1A1(m1 and m2), CYP2C9 (2 and 3), CYP2C19 (2 and 3), CYP3A4 5, CYP3A5 (3 and 6), was carried out on Jordanian subjects. Different variants allele were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). CYP1A1 allele frequencies in 290 subjects were 0.764 for CYP1A1 1, 0.165 for CYP1A1 2A and 0.071 for CYP1A1 2C. CYP2C9 allele frequencies in 263 subjects were 0.797 for CYP2C9 1, 0.135 for CYP2C9 2 and 0.068 for CYP2C9 3. For CYP2C19, the frequencies of the wild type (CYP2C19 1) and the nonfunctional (2 and 3) alleles were 0.877, 0.123 and 0, respectively. Five subjects (3.16 %) were homozygous for 2/2. Regarding CYP3A4 1B, only 12 subjects out of 173 subjects (6.9 %) were heterozygote with none were mutant for this polymorphism. With respect to CYP3A5, 229 were analyzed, frequencies of CYP3A5 1, 3 and 6 were 0.071, 0.925 and 0.0022, respectively. Comparing our data with that obtained in several Caucasian, African-American and Asian populations, Jordanians are most similar to Caucasians with regard to allelic frequencies of the tested variants of CYP1A1, CYP2C9, CYP2C19, CYP3A4 and CYP3A5.

Screening the antiangiogenic activity of medicinal plants grown and sold in Jordan.

Angiogenesis is essential for the growth, invasion, and metastasis of most solid tumors and has become a valuable pharmacological target for cancer prevention and treatment. This study was performed to assess the antiangiogenic activity of 31 medicinal plants grown and sold in Jordan. The antiangiogenic activity was assessed using the rat aortic ring assay. Out of 31 extracts, 15 extracts showed more than 50 % inhibition of the blood vessels outgrowth from the primary tissue explants (p = 0.000). Three of these 15 extracts showed a potential cytotoxic effect on normal fibroblast cells. Four extracts shared antiangiogenic and antiproliferative activity towards MCF7 breast cancer cell lines. Eight extracts demonstrated selective antiangiogenic activity. This is the first report demonstrating the potential antiangiogenic activity of Artemisia judaica, Aloysia citriodora, Salvia egyptiaca, and Calendula arvensis. Some extracts with antiangiogenic activity exhibited selectivity against the endothelial cells proliferation, demonstrating a direct inhibitory activity against the key step in tumor angiogenesis.

Synthesis, and antitumor activity of some N1-(coumarin-7-yl) amidrazones and related congeners.

A series of new N1-(coumarin-7-yl)amidrazones incorporating N-piperazines and related congeners were synthesized by reacting the hydrazonoyl chloride derived from 7-amino-4-methylcoumarin with the appropriate piperazines. The chemical structures of the newly prepared compounds were supported by elemental analyses, ¹H-NMR, ¹³C-NMR, and ESI-HRMS spectral data. The antitumor activity of the newly synthesized compounds was evaluated. Among all the compounds tested, 7-{2-[1-(4-(1-benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)piperazin-1-yl)-2-oxopropylidene]hydrazinyl}-4-methyl-2H-chromen-2-one (3n) was the most potent against MCF-7 and K562 cells, with IC50 values of 20.2 and 9.3 µM, respectively.

Synthesis and biological activity of some 3-(4-(substituted)-piperazin-1-yl)cinnolines.

A new series of 6-substituted-4-methyl-3-(4-arylpiperazin-1-yl)cinnolines 8-10 were synthesized as potential antifungal agents via intramolecular cyclization of the respective 1-(2-arylhydrazono)-1-(4-arylpiperazin-1-yl)propan-2-ones 5-7, mediated by polyphosphoric acid (PPA). The amidrazones themselves were synthesized via direct interaction of the appropriate hydrazonoyl chlorides 4a-d with the corresponding N-substituted piperazine in the presence of triethylamine. The structures of the new prepared compounds were confirmed by elemental analyses, (1)H-NMR, (13)C-NMR, and ESI-HRMS spectral data. The antitumor, antibacterial, and antifungal activity of the newly synthesized compounds was evaluated.

Association between Gasdermin A, Gasdermin B Polymorphisms and Allergic Rhinitis Amongst Jordanians.

BACKGROUND: Gasdermin A (GSDMA) and Gasdermin B (GSDMB) have been associated with childhood and to a lesser extent with adult asthma in many populations. In this study, we investigate whether there is an association between GSDMA (rs7212938, T/G) and GSDMB (rs7216389, T/C) at locus 17q21.2 and risk of Allergic Rhinitis among Jordanians. Also, we aimed to determine if there is an association between such polymorphisms and the IgE level. METHODS: The study included 112 rhinitis patients and 111 Healthy controls. Gasdermin A (GSDMA) (rs7212938, T/G) and Gasdermin B (rs7216389, T/C) polymorphisms were genotyped using the PCRRFLP method. RESULTS: On the genotype level, three analysis models were applied namely co-dominant, dominant and recessive genotypes. GSDMB CC genotype was found to have a significant protective effect against allergic Rhinitis (< 0.05). cc genotype was also significantly associated with higher IgE level among the studied population. CONCLUSION: The GSDMB CC of homozygous minor genotype showed a protective effect against Allergic rhinitis. It also was found to be significantly associated with lower IgE level among the studied population. No association was found between GSDMA with the risk of allergic Rhinitis.

The Plasma Membrane Ca2+ Pump PMCA4b Regulates Melanoma Cell Migration through Remodeling of the Actin Cytoskeleton.

We demonstrated that the plasma membrane Ca2+ ATPase PMCA4b inhibits migration and metastatic activity of BRAF mutant melanoma cells. Actin dynamics are essential for cells to move, invade and metastasize, therefore, we hypothesized that PMCA4b affected cell migration through remodeling of the actin cytoskeleton. We found that expression of PMCA4b in A375 BRAF mutant melanoma cells induced a profound change in cell shape, cell culture morphology, and displayed a polarized migratory character. Along with these changes the cells became more rounded with increased cell-cell connections, lamellipodia and stress fiber formation. Silencing PMCA4b in MCF-7 breast cancer cells had a similar effect, resulting in a dramatic loss of stress fibers. In addition, the PMCA4b expressing A375 cells maintained front-to-rear Ca2+ concentration gradient with the actin severing protein cofilin localizing to the lamellipodia, and preserved the integrity of the actin cytoskeleton from a destructive Ca2+ overload. We showed that both PMCA4b activity and trafficking were essential for the observed morphology and motility changes. In conclusion, our data suggest that PMCA4b plays a critical role in adopting front-to-rear polarity in a normally spindle-shaped cell type through F-actin rearrangement resulting in a less aggressive melanoma cell phenotype.

P38 MAPK Promotes Migration and Metastatic Activity of BRAF Mutant Melanoma Cells by Inducing Degradation of PMCA4b.

Metastatic melanoma is the most aggressive type of skin cancer. Previously, we identified the plasma membrane Ca2+ pump isoform 4b (PMCA4b or ATP2B4) as a putative metastasis suppressor in BRAF mutant melanoma cells. Metastasis suppressors are often downregulated in cancer, therefore, it is important to identify the pathways involved in their degradation. Here, we studied the role of p38 MAPK in PMCA4b degradation and its effect on melanoma metastasis. We found that activation of p38 MAPK induces internalization and subsequent degradation of PMCA4b through the endo/lysosomal system that contributes to the low PMCA4b steady-state protein level of BRAF mutant melanoma cells. Moreover, BRAF wild type cell models including a doxycycline-inducible HEK cell system revealed that p38 MAPK is a universal modulator of PMCA4b endocytosis. Inhibition of the p38 MAPK pathway markedly reduced migration, colony formation and metastatic activity of BRAF mutant cells in vitro partially through an increase in PMCA4b and a decrease in ß4 integrin abundance. In conclusion, our data suggest that the p38 MAPK pathway plays a key role in PMCA4b degradation and inhibition of this pathway-by increasing the stability of PMCA4b-may provide a potential therapeutic target for inhibition of melanoma progression and metastasis.

Co-encapsulation of thymoquinone with docetaxel enhances the encapsulation efficiency into PEGylated liposomes and the chemosensitivity of MCF7 breast cancer cells to docetaxel.

Combinatorial therapeutic strategies to eradicate tumors can be superior to a single therapeutic modality. Docetaxel (DT) has been approved for the treatment of local or metastasized breast cancer alone or in combination with other chemotherapeutic agents. Thymoquinone (TQ) originated from the seeds of Nigella Sativa plant has been reported to possess in vitro and in vivo antitumor activity against variety of tumors. In the current study, we have investigated the synergistic anticancer efficacy of a novel combination of DT and TQ on MCF7 breast cancer cell line using MTT cell viability assay. Moreover, this study describes for the first time the co-encapsulation of DT and TQ into PEGylated liposomes. The results showed that the combination of DT and TQ resulted in significant synergistic cytotoxicity compared to DT and TQ alone. Moreover, DT and TQ have been successfully co-encapsulated into PEGylated liposomes with higher encapsulation efficiency compared to DT and TQ alone. In conclusion, DT and TQ combination poses a synergistic effect and may aid in decreasing the required doses of DT. Also, the co-encapsulation of DT and TQ into PEGylated liposomes can provide a promising DT and TQ delivery system into cancer cells.

Cross-sectional correlates of paraoxonase 1 and soluble intercellular adhesion molecule-1 in metabolic syndrome patients with and without diabetes.

BACKGROUND: Paraoxonase 1 (PON1) and soluble intercellular adhesion molecule-1(sICAM-1) are intricately involved in metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) pathophysiology. This study aimed to investigate PON1 and sICAM-1 plasma levels in addition to correlating them with adiposity, atherogenicity and hematological indices in T2DM and MetS. METHODS: This cross-sectional study composed of 28 healthy lean subjects (control), 29 normoglycemic MetS subjects and 30 MetS-Pre/T2DM. RESULTS: The sICAM-1 levels (ng/ml) were markedly higher in the pre/diabetic MetS group (828 ± 250.37 versus controls' 608.62 ± 184; p < 0.05). Conversely, PON1 levels (mlU/ml) were markedly lower in the pre/diabetic MetS group [252,700 (163,950, 362,800) versus controls' 394,900 (212,550, 469,350); p < 0.05]. sICAM-1 correlated directly with all adiposity indices [conicity index (CI), waist circumference (WC), waist-hip ratio (WHR) waist-to-height (WHtR) ratio, hip circumference (HC) and body adiposity index (BAI)] in addition to the atherogenicity index of plasma (AIP). PON1 correlated negatively and significantly with CI, WC, WHR, WHtR and HC but directly with lymphocyte. Significantly, a reciprocal sICAM-1-PON1 relationship was observed in the total population (r = -0.262, p = 0.015). CONCLUSION: Utility of sICAM-1 and PON1 as surrogate prognostic biomarkers and putative therapeutic targets in the management of diabetes and MetS is strongly suggested.

Glycated LDL-C and glycated HDL-C in association with adiposity, blood and atherogenicity indices in metabolic syndrome patients with and without prediabetes.

BACKGROUND: The aim of the study was to compare and correlate glycated high-density lipoprotein (GHDL-C) and glycated low-density lipoprotein (GLDL-C) plasma levels with adiposity indices [weight/hip ratio (WHR) and body adiposity index (BAI)], lipid ratios and hematological indices [platelet/lymphocyte ratio (PLR), monocyte/lymphocyte ratio (MLR)]. METHODS: This was a cross-sectional study of 30 nondiabetic metabolic syndrome (MetS) patients, 30 prediabetic or type 2 diabetes mellitus (T2DM) patients and 30 normoglycemic controls. RESULTS: Remarkably both GHDL-C and GLDL-C levels lacked any intergroup statistically significant discrepancy in either MetS or MetS-pre/T2DM versus control (p > 0.05). Unlike GLDL-C/LDL-C ratios for either MetS groups; there were highly significant intergroup differences in the means of GHDL-C/HDL-C ratios when comparing both nondiabetic MetS and MetS-pre/T2DM groups versus controls (p = 0.001). In MetS patients; GHDL-C and GLDL-C proportionally correlated with WHR (p < 0.05). Also, MetS GHDL-C correlated inversely with MLR and monocytes (p < 0.05). In MetS-pre/T2DM; GLDL-C directly correlated with BAI, platelet count and PLR (p < 0.05). CONCLUSION: GLDL-C and GHDL-C are dysfunctional glucolipotoxicity lipoproteins and may present putatively surrogate biomarkers for prediction/prevention of metabolic disturbances.

Cross-sectional correlates of myeloperoxidase and alpha-1-acid glycoprotein with adiposity, atherogenic and hematological indices in metabolic syndrome patients with or without diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) are associated with obesity, which triggers the release of inflammatory substances. Myeloperoxidase (MPO), a peroxidase enzyme, and alpha-1-acid glycoprotein (AGP), an acute-phase protein, are known to be released in patients with inflammatory conditions and cardiovascular disease (CVD). METHODS: In this study, we investigated the correlation between MPO and AGP levels in pre/diabetic and MetS patients by conducting a cross-sectional study at The University of Jordan Hospital (UoJH) at the diabetes and endocrinology outpatient clinics. A total of 237 patients were recruited and assessed for eligibility. Of these, 149 patients were excluded, and 88 patients were assigned as: 29 patients in a healthy lean normoglycemic control group; 29 patients in a nondiabetic MetS group; and 30 patients in a prediabetic/newly diagnosed T2DM MetS group. RESULTS: MPO levels were only significantly higher in the nondiabetic MetS group compared with the control group (p = 0.026). AGP levels were significantly higher in both nondiabetic MetS and MetS-prediabetic/T2DM groups versus control (p = 0.007 and p = 0.015, respectively). Both biomarkers lacked inter-MetS-group discrepancy. CONCLUSIONS: Our results demonstrate an association between MPO and AGP with obesity and hyperglycemia, alongside their correlation with several adiposity, hematology and atherogenicity indices. Our findings reinforce the use of MPO and AGP as potentially putative and surrogate predictive/prognostic tools for MetS and its related disorders.

Increased malondialdehyde vs. reduced sirtuin 1 in relation with adiposity, atherogenicity and hematological indices in metabolic syndrome patients with and without prediabetes.

BACKGROUND: Sirtuin 1 (SIRT 1) and malondialdehyde (MDA) were implicated in metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) pathophysiology. AIMS AND METHODS: This cross-sectional study aimed to investigate both SIRT 1 and MDA in 30 lean healthy control, 31 normoglycemic MetS subjects and 30 MetS-Pre/T2DM drug naïve. C orrelation studies were established for both biomarkers with adiposity indices [conicity index (CI), waist circumference (WC), weight-to-height (WHtR) ratio, weight-to-hip (WHR) ratio, hip circumference (HC), and body adiposity index (BAI)], hematological indices [red cell distribution width (RDW), mean platelet volume (MPV), platelet-to-lymphcyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR)] and atherogenicity indices (atherogenicity index of plasma (AIP = log10TG/HDL-C ratio), TC/HDL-C and LDL-C/HDL-C ratios]. RESULTS: SIRT1 levels (ng/mL) were markedly lower in both MetS groups (2.12 ±â€¯0.06 and 2.32 ±â€¯0.19, respectively, vs. controls 4.73 ±â€¯0.15; P < 0.05). Conversely, a gradual increase in MDA levels (µM) was attained (MetS 72 ±â€¯3.3 and MetS pre-T2DM 81 ±â€¯6.1 vs. controls 62 ±â€¯3.5; P > 0.05). A significant inverse MDA-SIRT1 relationship was observed (P = 0.006). SIRT1 correlated inversely with all the studied adiposity (WC: P < 0.001, HC: P < 0.001, WHR: P < 0.001, C-index: P < 0.001, BAI: P < 0.001) and atherogenicity indices (AIP: P < 0.001, TC/HDL-C: P < 0.001, LDL-C/HDL-C: P < 0.001) as well as MPV (P < 0.01). Whereas MDA directly with WHtR, CI and BAI (WC: P < 0.01, HC: P < 0.05, BMI: P < 001, WHtR: P < 0.001, C-index: P < 0.005, BAI: P < 0.01). CONCLUSION: The substantial variations and correlations emphasize a potential molecular role of SIRT1 and MDA in the pathophysiology of MetS and pre/T2DM.

Melatonin and cryptochrome 2 in metabolic syndrome patients with or without diabetes: a cross-sectional study.

Background Metabolic syndrome (MetS) is a cluster of metabolic risk factors which increases the chances for future cardiovascular diseases, as well as diabetes. The underlying causes of MetS include overweight and obesity, physical inactivity and genetic factors. Our intension here was to focus in this study on the importance of the chronobiology, represented by melatonin (MT) and cryptochrome 2 (CRY2), in developing MetS and type 2 diabetes mellitus (T2DM). Thus, we aimed to compare MT and CRY2 plasma levels and correlate both biomarkers with adiposity, atherogenicity and hematological indices in MetS and T2DM cohorts. Methods In a cross-sectional study, 28 normoglycemic lean subjects (controls), 29 normoglycemic MetS subjects and 30 MetS (pre-diabetic/diabetic) were recruited. Results MT (pg/mL) was elevated significantly in MetS arm p-value < 0.05, whereas CRY2 levels (ng/mL) were markedly higher in both MetS groups (non-diabetic and pre-diabetic/diabetic) (all with p-value < 0.001). A reciprocal MT-CRY2 relationship was observed in the MetS (non-diabetic) group (p-value = 0.003). Of note in the total study population, both MT and CRY2 proportionally correlated with each of the following: atherogenicity index of plasma (AIP), waist circumference (WC) and systolic blood pressure (SBP) (all with p-value < 0.05) for MT and CRY2, respectively). Whereas MT correlated inversely with high-density lipoprotein-cholesterol (HDL-C) (p-value < 0.05). Additionally, CRY2 correlated directly with each of the following: diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoprotein (LDL-C), hip circumference (HC), body adiposity index (BAI), weight-to-height (WHtR) ratio, mean platelet volume (MPV) and platelet/lymphocyte ratio (PLR) (p-value < 0.05). Conclusion These findings substantiate that both metabolic risk biomarkers can be prognostic tools and pharmacotherapeutic targets to slowdown the accelerated nature of T2DM.