Variation of modulation and expression of biomarkers associated with inflammation in bariatric surgery patients: A systematic review and meta-analysis.

BACKGROUND: Bariatric surgery is an effective intervention that causes a series of metabolic changes related to inflammatory processes; however, the variation of biomarkers related to these processes is not entirely understood. Our objective was to investigate the variation of modulation and expression of biomarkers associated with inflammation in patients who underwent bariatric surgery. METHODS: We searched the MEDLINE (via PubMed), EMBASE (via Elsevier), Cochrane Central Register of Controlled Trials, Latin American and Caribbean Literature on Health Sciences (via virtual health library), Cumulative Index to Nursing and Allied Health Literature (via EBSCO), Web of Science core collection, and Scopus (via Elsevier) databases, and the gray literature was examined from inception to January 2022. Three pairs of reviewers performed data screening, extraction, and quality assessment independently. Meta-analysis with random effects models was used for general, subgroup, and sensitivity analyses. The I2 statistic was used to assess heterogeneity between studies. RESULTS: In total, 96 articles were included in this systematic review; of these, 87 studies met the criteria for the meta-analysis, involving 3,533 participants. Five biomarkers were included in the meta-analysis (tumor necrosis factor alpha; interleukin 6; leptin; interleukin 1 beta, and lipopolysaccharides). Only leptin showed a significant decrease in the first month after surgery (mean difference -20.71; [95% confidence interval: -28.10 to -13.32, P < .0001; I2 = 66.7%), with moderate heterogeneity. The 12 months after surgery showed a significant decrease in tumor necrosis factor alpha (mean difference -0.89; [95% confidence interval: -1.37 to -0.42], P = .0002; I2 = 94.7%), interleukin 6 (mean difference -1.62; [95% confidence interval: -1.95 to -1.29], P < .0001; I2 = 94.9%), leptin (mean difference -28.63; [95% confidence interval: -34.02 to -23.25], P < .0001; I2 = 92.7%), and interleukin 1 beta (mean difference -2.46; [95% confidence interval: -4.23 to -0.68], P = .006; I2 = 98.3%), all with high heterogeneity. The type of surgery did not show significant differences for the biomarkers at the first month and 12 months, and the results have not changed with high-quality studies. In the 12-month measurement, variations in tumor necrosis factor alpha and leptin were associated with body mass index. CONCLUSION: The findings of this meta-analysis suggest that Roux-en-Y gastric bypass and sleeve gastrectomy bariatric surgeries are associated with a significant reduction in leptin at 1 month after bariatric surgical intervention and tumor necrosis factor alpha, leptin, and interleukin 1 beta after 12 months.

Structure-based discovery of thiosemicarbazones as SARS-CoV-2 main protease inhibitors.

Aim: Discovery of novel SARS-CoV-2 main protease (Mpro) inhibitors using a structure-based drug discovery strategy. Materials & methods: Virtual screening employing covalent and noncovalent docking was performed to discover Mpro inhibitors, which were subsequently evaluated in biochemical and cellular assays. Results: 91 virtual hits were selected for biochemical assays, and four were confirmed as reversible inhibitors of SARS CoV-2 Mpro with IC50 values of 0.4-3 µM. They were also shown to inhibit SARS-CoV-1 Mpro and human cathepsin L. Molecular dynamics simulations indicated the stability of the Mpro inhibitor complexes and the interaction of ligands at the subsites. Conclusion: This approach led to the discovery of novel thiosemicarbazones as potent SARS-CoV-2 Mpro inhibitors.

Leishmanicidal and cytotoxic activities and 4D-QSAR of 2-arylidene indan-1,3-diones.

The indan-1,3-dione and its derivatives are important building blocks in organic synthesis and present important biological activities. Herein, the leishmanicidal and cytotoxicity evaluation of 16 2-arylidene indan-1,3-diones is described. The compounds were evaluated against the leukemia cell lines HL60 and Nalm6, and the most effective ones were 2-(4-nitrobenzylidene)-1H-indene-1,3(2H)-dione (4) and 4-[(1,3-dioxo-1H-inden-2(3H)-ylidene)methyl]benzonitrile (10), presenting IC50 values of around 30 µmol/L against Nalm6. The leishmanicidal activity was assessed on Leishmania amazonensis, with derivative 4 (IC50 = 16.6 µmol/L) being the most active. A four-dimensional quantitative structure-activity analysis (4D-QSAR) was applied to the indandione derivatives, through partial least-squares regression. The statistics presented by the regression models built with the selected field descriptors of Coulomb (C) and Lennard-Jones (L) nature, considering the activities against L. amazonensis, HL60, and Nalm6 leukemia cells, were, respectively, R2 = 0.88, 0.92, and 0.98; Q2 = 0.83, 0.88, and 0.97. The presence of positive Coulomb descriptors near the carbonyl groups indicates that these polar groups are related to the activities. Besides, the presence of positive Lennard-Jones descriptors close to substituents R3 or R1 indicates that bulky nonpolar substituents in these positions tend to increase the activities. This study provides useful insights into the mode of action of indandione derivatives for each biological activity involved.

Pencil it in: pencil drawn electrochemical sensing platforms.

Inspired by recent reports concerning the utilisation of hand drawn pencil macroelectrodes (PDEs), we report the fabrication, characterisation (physicochemical and electrochemical) and implementation (electrochemical sensing) of various PDEs drawn upon a flexible polyester substrate. Electrochemical characterisation reveals that there are no quantifiable electrochemical responses upon utilising these PDEs with an electroactive analyte that requires an electrochemical oxidation step first, therefore the PDEs have been examined towards the electroactive redox probes hexaammineruthenium(iii) chloride, potassium ferricyanide and ammonium iron(ii) sulfate. For the first time, characterisation of the number of drawn pencil layers and the grade of pencil are examined; these parameters are commonly overlooked when utilising PDEs. It is demonstrated that a PDE drawn ten times with a 6B pencil presented the most advantageous electrochemical platform, in terms of electrochemical reversibility and peak height/analytical signal. In consideration of the aforementioned limitation, analytes requiring an electrochemical reduction as the first process were solely analysed. We demonstrate the beneficial electroanalytical capabilities of these PDEs towards p-benzoquinone and the simultaneous detection of heavy metals, namely lead(ii) and cadmium(ii), all of which are explored for the first time utilising PDEs. Initially, the detection limits of this system were higher than desired for electroanalytical platforms, however upon implementation of the PDEs in a back-to-back configuration (in which two PDEs are placed back-to-back sharing a single connection to the potentiostat), the detection limits for lead(ii) and cadmium(ii) correspond to 10 µg L(-1) and 98 µg L(-1) respectively within model aqueous (0.1 M HCl) solutions.

Metallic modified (bismuth, antimony, tin and combinations thereof) film carbon electrodes.

In this paper in situ bismuth, antimony, tin modified electrodes and combinations thereof are explored towards the model target analytes cadmium(II) and lead(II), chosen since they are the most widely studied, to explore the role of the underlying electrode substrate with respect to boron-doped diamond, glassy carbon, and screen-printed graphite electrodes. It is found that differing electrochemical responses are observed, dependent upon the underlying electrode substrate. The electrochemical response using the available range of metallic modifications is only ever observed when the underlying electrode substrate exhibits relatively slow electron transfer properties; in the case of fast electron transfer properties, no significant advantages are evident. Furthermore these bismuth modified systems which commonly employ a pH 4 acetate buffer, reported to ensure the bismuth(III) stability upon the electrode surface can create create a problem when sensing at low concentrations of heavy metals due to its high background current. It is demonstrated that a simple change of pH can allow the detection of the target analytes (cadmium(II) and lead(II)) at levels below that set by the World Health Organisation (WHO) using bare graphite screen-printed electrodes.

DNA methylation analysis of SOCS1, SOCS3, and LINE-1 in microdissected gingival tissue.

OBJECTIVES: DNA methylation plays a critical role in the regulation of the transcription of the suppressors of cytokine signaling (SOCS) 1 and SOCS3, which are modulators in the inflammation. We hypothesized that the methylation status of SOCS1, SOCS3, and long interspersed nuclear element (LINE)-1 in gingival tissues previously inflamed would be similar to that found in gingival tissues without clinical inflammation in the period studied. MATERIALS AND METHODS: Laser capture microdissection was performed to isolate epithelial and connective gingival tissues. The groups were comprised by ten patients without history of periodontitis and absence of clinical signs of inflammation in the gingiva during the study (healthy group) and ten patients with history of periodontitis, presenting inflammation in the gingival tissue at the first examination of the study (controlled chronic periodontitis group). The gingival biopsies from the controlled chronic periodontitis group were collected after controlling the inflammation. DNA methylation patterns were analyzed using methylation-specific high-resolution melting and combined bisulfite restriction analysis. RESULTS: DNA methylation levels for SOCS1 and SOCS3 did not differ between groups or tissues; likewise, no differences were observed in total LINE-1 methylation or at specific loci. CONCLUSION: At 3 months following control of inflammation in gingival tissues, the methylation profile of SOCS1, SOCS3, and LINE-1 is similar between connective and epithelial tissues from patients that were previously affected or not by chronic inflammation. CLINICAL RELEVANCE: Clinical results of a successful treatment are observed after inflammation control and the molecular findings illustrate local and general methylation patterns in recovering tissues toward health conditions and might help to understand events that are occurring in oral cells.

Screen-printed back-to-back electroanalytical sensors: heavy metal ion sensing.

Screen-printed back-to-back microband electroanalytical sensors are applied to the quantification of lead(II) ions for the first time. In this configuration the electrodes are positioned back-to-back with a common electrical connection to the two working electrodes with the counter and reference electrodes for each connected in the same manner as a normal "traditional" screen-printed sensor. Proof-of-concept is demonstrated for the electroanalytical sensing of lead(II) ions utilising square-wave anodic stripping voltammetry where an increase in the electroanalytical sensitivity is observed by a factor of 5 with the back-to-back microband configuration at a fixed lead(II) ion concentration of 5 µg L(-1) utilising a deposition potential and time of -1.2 V and 30 seconds respectively, compared to a conventional (single) microband electrode. The back-to-back microband configuration allows for the sensing of lead(II) ions with a linear range from 5 to 110 µg L(-1) with a limit of detection (based on 3σ) corresponding to 3.7 µg L(-1). The back-to-back microband configuration is demonstrated to quantify the levels of lead(II) ions within drinking water corresponding to a level of 2.8 (±0.3) µg L(-1). Independent validation was performed using ICP-OES with the levels of lead(II) ions found to correspond to 2.5 (±0.1) µg L(-1); the excellent agreement between the two methods validates the electroanalytical procedure for the quantification of lead(II) ions in drinking water. This back-to-back configuration exhibits an excellent validated analytical performance for the determination of lead(II) ions within drinking water at World Health Organisation levels (limited to 10 µg L(-1) within drinking water).

MMP3 and TIMP1 variants contribute to chronic periodontitis and may be implicated in disease progression.

AIM: Matrix metalloproteinases (MMPs) play a key role in the tissue destruction characteristic of chronic periodontitis. The purpose of this study was to investigate the association of MMP and TIMP polymorphisms with chronic periodontitis in two populations. MATERIAL AND METHODS: A total of 34 polymorphisms spanning 12 MMP and 2 TIMP genes were genotyped in 401 individuals from Brazil (99 cases with chronic periodontitis and 302 controls), and 274 individuals from the US (70 cases and 204 controls). Individuals were considered cases if presenting at least three teeth exhibiting sites of clinical attachment loss ≥ 5 mm in two different quadrants. Controls were characterized by absence of clinical attachment loss and no sites with probing depth >3 mm. MMP3 and TIMP1 mRNA expression was evaluated in healthy and diseased periodontal tissues. RESULTS: TIMP1 showed association with chronic periodontitis in the Brazilian population (for rs5906435, p = 0.0004), whereas MMP3 showed association in the US population (for rs679620, p = 0.0003; and rs650108, p = 0.002) and in the Brazilian population (for rs639752, p = 0.005). MMP3 and TIMP1 mRNA expression was significantly higher in diseased tissues when compared to control tissues. CONCLUSIONS: Our results further support a role for variations in MMP3 in chronic periodontitis and report a novel association with TIMP1. These genes may be considered additional candidate genes for chronic periodontitis.

Association of matrix metalloproteinase gene polymorphism with temporomandibular joint degeneration.

Temporomandibular joint (TMJ) degeneration is a frequent cause of orofacial pain. Matrix metalloproteinases (MMPs) degrade extracellular matrix components and play an important role in TMJ degeneration. We investigated the frequency of the MMP1 1G/2G polymorphism (rs1799750), the MMP3 5A/6A polymorphism (rs3025058), and the MMP9 C/T polymorphism (rs3918242) in individuals with TMJ degeneration, in order to analyze the association of polymorphisms in these genes with TMJ degeneration. The population studied comprised 117 healthy controls and 115 individuals diagnosed with TMJ degeneration upon examination of magnetic resonance imaging (MRI) and computed tomography (CT) images. Genotypes were determined using PCR restriction fragment length polymorphism (RFLP). Logistic regression analyses revealed an association between the MMP1 2G/2G genotype and degeneration; in contrast, there was no association between either the MMP3 or the MMP9 genotype and degeneration. Our results may indicate a role for the MMP1 polymorphism in TMJ degeneration.

Interleukin-8 gene promoter polymorphism (rs4073) may contribute to chronic periodontitis.

BACKGROUND: The proinflammatory chemokine interleukin (IL)-8 is important in the regulation of the inflammatory response. Analyses of the single nucleotide polymorphism (SNP) reference sequence (rs) 4073 showed that the A allele upregulated IL-8 levels after stimulation with lipopolysaccharides. We investigated the association of the SNP rs4073 with chronic periodontitis. METHODS: Genotyping was performed by a standard polymerase chain reaction-restriction fragment length polymorphism assay in 289 genomic DNA samples of healthy control subjects and patients with chronic periodontitis; analyses were adjusted by multivariate logistic regression modeling. A real-time polymerase chain reaction performance was used to detect levels of the IL-8 mRNA. RESULTS: The analysis pointed to a statistically significant association of chronic periodontitis with the heterozygous TA genotype (P = 0.001); the results showed an increase in the frequency of the A allele in the diseased group (36% in the control group versus 48% in the periodontitis group). The higher levels of the IL-8 mRNA were found in the periodontitis group, mainly in individuals who presented the TA genotype (P = 0.03). CONCLUSION: The SNP rs4073 was associated with chronic periodontitis in non-smoker Brazilian subjects because the frequency of the A allele was higher in the disease group than in the control group, and the TA genotype was associated with increased levels of IL-8 mRNA transcripts.

The use of a gold disc microelectrode for the determination of copper in human sweat.

A novel approach of using a gold disc microelectrode to analyze sweat samples for copper ions by anodic square wave stripping voltammetry (SW stripping voltammetry) is described. Sweat was collected from the lower back of four subjects after physical exercise and the sample volume required for the determinations was 100 µL. Under the optimized conditions, the calibration plot was linear over the range 1-100 µmol L(-1) Cu(II) with a limit of detection of 0.25 µmol L(-1). The precision was evaluated by carrying out five replicate measurements in a 1 µmol L(-1) Cu(II) solution and the standard deviation was found to be 1.5%. Measurements were performed by inserting the microelectrode into sweat drops and Cu(II) concentrations in the analyzed samples ranged from 0.9 to 28 µmol L(-1). Values obtained by the proposed voltammetric method agreed well with those found using graphite furnace atomic absorption spectroscopy (GFAAS).

DNA methylation status of the IL8 gene promoter in aggressive periodontitis.

BACKGROUND: Studies evaluating the methylation status of cytokine genes may have relevance for inflammatory diseases in which the expression of some cytokines is altered, such as periodontitis. This study observes the DNA methylation status in the interleukin-8 (IL8) gene promoter in cells of the oral epithelium of subjects affected by generalized aggressive periodontitis (AgP) and compares it to those of control subjects. METHODS: Genomic DNA from epithelial oral cells of 37 generalized AgP patients and 37 controls were purified and modified by sodium bisulphite. Modified DNA was submitted by methylation-specific polymerase chain reaction, electrophoresed on 10% polyacrylamide gels, and stained. RESULTS: Subjects who presented generalized AgP have a higher frequency of hypomethylation of the IL8 gene promoter in oral epithelium cells than that of controls (86.5% in the generalized AgP group versus 62% in the control group; P = 0.016; chi(2) test). CONCLUSIONS: A marked hypomethylated status is found in the oral epithelial cells of subjects presenting with generalized AgP, compared to controls, in the promoter region of the IL8 gene. This hypomethylated status may reflect a generalized condition of oral epithelial cells, including gingival epithelium, because gingival epithelial cells were also collected during mouthwash use.

2-hydroxyethyl methacrylate as an inhibitor of matrix metalloproteinase-2.

This study evaluated the effect of different concentrations of 2-hydroxyethyl methacrylate (HEMA) on the inhibition of matrix metalloproteinase-2 (MMP-2) in vitro. Mouse gingival explants were cultured overnight in Dulbecco's modified Eagle's minimal essential medium, following which the expression of secreted enzymes was analyzed by gelatin zymography and the effects of different amounts of HEMA on enzyme activity were investigated. The gelatinolytic proteinases present in the conditioned media were characterized as being matrix metalloproteinases (MMPs) by means of specific chemical inhibition. The MMPs present in the conditioned media were identified, using immunoprecipitation, as MMP-2. Three major bands were detected in the zymographic assays and were characterized, according to their respective molecular weights, into the following forms of MMP-2: zymogene (72 kDa), intermediate (66 kDa), and active (62 kDa). All forms of MMP-2 were inhibited by HEMA in a dose-dependent manner, implying that MMP-2 may be inhibited by HEMA in vivo.

Osseointegrated implant failure associated with MMP-1 promotor polymorphisms (-1607 and -519).

PURPOSE: Two polymorphisms in the promoter region of human MMP-1 gene, an insertion of a guanine at position -1607 and A-519G substitution, have been shown to increase the transcriptional activity of these matrix metalloproteinases (MMPs). The objective of this study was to investigate the possible relationship between these polymorphisms and early implant failure. MATERIALS AND METHODS: A sample of 104 nonsmokers was divided into 2 groups: a test group comprising 44 patients with 1 or more early failed implants and a control group consisting of 60 individuals with 1 or more healthy implants. Genomic DNA from oral mucosa was amplified by polymerase chain reaction and analyzed by restriction endonucleases. The significance of the differences in observed frequencies of polymorphisms were assessed by chi2 tests. RESULTS: The G-1607GG polymorphism with the genotype G/G was observed at a frequency of 62% in the control group, while in the test group this genotype was noted in 34% of the individuals (P = .011). The allele G was found at a frequency of 75% in control group and 61.66% in the test group (P = .05). No significant differences were seen in the genotypes and allele frequencies in the A-519G polymorphism among the groups (P = .064 and P = .124, respectively). The distribution of the haplotypes arranged as alleles and genotypes showed a significant difference between control and test groups (P = .031 and P = .002, respectively). CONCLUSION: On the basis of this study of 60 patients who experienced no implant failure and 44 patients who experienced implant failure, the results suggest that G-1607GG polymorphism in MMP-1 gene is associated with early implant failure, while A-519G polymorphism in MMP-1 gene does not show a significant relationship with implant loss. This study also suggests that haplotypes G-1607GG and A-519G of MMP-1 may be associated with the osseointegration process.

Genetic polymorphism of matrix metalloproteinase (MMP)-9 does not affect plasma MMP-9 activity in healthy subjects.

BACKGROUND: Plasma MMP-9 levels have been shown to predict cardiovascular risk, and a functional substitution C to T at position -1562 in the promoter region of the MMP-9 gene has been associated with the severity of cardiovascular diseases. We examined the association between the C(-1562)T polymorphism and MMP-9 activity in healthy subjects. METHODS: We studied 200 healthy male white volunteers (age range: 20-55 y) who were nonsmokers and were not taking medicines. Genomic DNA was extracted and genotypes for the C(-1562)T polymorphism were determined by PCR and restriction fragment length digestion. Plasma was assayed for pro-MMP-9 and MMP-9 activities by gelatin zymography. RESULTS: The frequency of the alleles "C" and "T" were 90% and 10%, respectively. Because of the relatively low frequency of the TT genotype, we combined both TT and CT genotypes together (CT+TT group) and compared with the CC genotype group. We found no differences in pro-MM9 and MMP-9 activity levels among the genotype groups (both P>0.05). CONCLUSIONS: While the present study indicates lack of effect for the C(-1562)T polymorphism on MMP-9 activity in plasma, it is possible that the C(-1562)T polymorphism contributes to an increased cardiovascular risk under conditions of induced MMP-9 expression.