DNA damage and ALAD polymorphism in high blood lead (Pb) levels of pregnant women attending a tertiary care teaching hospital.

Background: Pregnant women are particularly vulnerable to lead toxicity due to increased absorption and decreased elimination of lead from their bodies. The δ-aminolevulinic acid dehydratase (ALAD) gene plays a crucial role in lead metabolism, and its polymorphisms have been implicated in modifying the susceptibility to lead toxicity. Methods: A cross-sectional study was conducted involving 90 pregnant women and blood samples were collected to measure blood lead levels (BLL) and assessed DNA damage using the comet assay. ALAD polymorphisms were genotyped using PCR-RFLP analysis with MspI restriction enzyme. Statistical analysis, including chi-square tests, logistic regression, and correlation analysis, was performed to determine associations between ALAD polymorphisms, BLL, and DNA damage. Results: From 90 pregnant women the participants, 16 had high BLL (≥5 µg/dL), while the remaining 74 had normal levels (<5 µg/dL). The ALAD 1-2 genotype was found to be significantly associated with high BLL (p < 0.001). Pregnant women with the ALAD 1-2 genotype exhibited higher levels of DNA damage compared to those with other genotypes (p < 0.001). Furthermore, a positive correlation was observed between the transfer of lead concentration from mother to infant and DNA damage severity (r = 0.511, p < 0.001). Conclusions: The combination of comet assay and polymorphism analysis offers a comprehensive approach to understanding the impact of lead exposure during pregnancy. These findings underscore the urgent need for effective regulatory measures to reduce lead exposure in the environment and mitigate its adverse effects of lead on maternal and child health.

Blood lead levels in pregnant women and their newborn infants at an Indian teaching hospital.

Background and Aim: With the growth of the world's economy and industrialization, lead (Pb) contamination in the environment has become a major issue on a global scale. Lead is typically linked to unfavorable pregnancy outcomes such as stillbirth, low birth weight preterm, and spontaneous abortion. In this study, we evaluated the blood lead levels of pregnant women and their birth outcomes attending an Indian tertiary care teaching hospital, those who were not exposed to any lead-associated industry or shops. Methods: A descriptive study was undertaken to evaluate blood lead estimation in pregnant women and umbilical blood lead levels in a community hospital. Blood samples from 104 mothers during the 1st trimester, 90 mothers during 3rd trimester, and from the umbilical cord were collected. Self-administered questionnaires were used to collect information on demographics, medical history, and concerns linked to pregnancy. Following acid digestion, the levels of lead in whole blood were determined by an atomic absorption spectrometer. The DNA damage in high blood lead-concentrated pregnant women was evaluated by comet assay methods. Results: Among 194 blood samples of pregnant women, 31 (15.98%) samples revealed ≥5 µg/dL blood lead levels. High lead concentration (≥5 µg/dL) in 1st trimester pregnant women, end of 3rd trimester and cord blood were detected 20.19%, 11.11% and 1.11% respectively. The mean blood lead levels in 1st trimester, 3rd trimester, and cord blood were 3.88 ± 3.19, 2.66 ± 1.82, and 1.53 ± 1.06 mg/dL, respectively. The blood lead concentrations were significantly higher in the 1st trimester of pregnancy than in the 3rd trimester of pregnancy (P < 0.0017). A positive correlation between maternal and infant blood lead levels was revealed (P < 0.0001). When the comet assay was used to assess the genotoxic consequences of elevated blood lead levels during pregnancy, higher amounts of DNA damage were found in the samples (P < 0.01). Conclusion: In this descriptive study, there was a significant amount of lead transferred from mother to baby through the placenta. All mothers were not exposed to lead-associated industry and most were housewives. This article may be viewed as an eye-opener for understanding the blood lead concentration during pregnancy to avoid abnormal birth outcomes. To minimize exposure to environmental lead, all possible measures should be undertaken.

Unraveling the interaction between lead and calcium in occupationally exposed males: an exploratory observation study.

OBJECTIVE: The systemic illnesses associated with chronic lead exposure are partially explained by the interaction between lead and calcium metabolism. Lead exposure is posited to alter calcium levels either by altering calcium homeostasis markers or altering bone remodeling. The present study investigated the interaction between blood lead levels and calcium homeostasis markers and bone remodeling markers among lead-smelting plant workers. METHOD: Adult male workers employed at the lead-smelting plant were clinically investigated as part of their regular occupational health assessment program. Additionally, control participants without occupational lead exposure, employed in administrative and white-collar jobs were invited to participate in the study. Sociodemographic and occupational details were collected by pre-standardized semi-structured questionnaires from all consenting participants, followed by clinical examination and blood collection. Blood lead levels were estimated using microwave-assisted acid digestion and the inductively coupled plasma mass spectrometry technique. Serum calcium and total protein and alkaline phosphatase levels were estimated as per standard biochemical techniques. 25-hydroxy vitamin-D3, calcitriol, and osteocalcin were estimated using the enzyme-linked immunosorbent assay. In addition to comparative analysis for comparing the two groups, independent linear regression models were explored to investigate the associations between serum calcium and blood lead and osteocalcin levels. RESULT: A total of 189 lead-exposed men employed at the lead-smelting plant and 25 male control participants consented to participate. The two groups were similar in age, diet, and body mass index. Occupationally exposed individuals exhibited significantly lower serum calcium and higher bone remodeling markers (osteocalcin and alkaline phosphatase) as compared to controls. However, the serum 25-hydroxy vitamin-D3 and calcitriol levels were not significantly different between the two groups. Lastly, the serum lead and osteocalcin were weakly but significantly associated with serum calcium levels after controlling for variations in total protein, diet, 25-hydroxy vitamin-D3, calcitriol, and alkaline phosphatase in the study participants. CONCLUSION: Current observations reinforce the adverse role of lead exposure on calcium metabolism. Although lead exposure is posited to affect calcium metabolism by multiple pathways, current study observations favor the bone remodeling pathway. The observations recommend periodic screening for calcium and bone health among lead-exposed adults.

Association Between Blood Lead Levels and Thyroid Function: An Updated Systematic Review and Meta-Analysis.

Chronic Lead (Pb) exposure is associated with disrupting certain endocrine levels and is referred to as an endocrine disruptor. Thyroid hormones, involved in regulating numerous physiological functions, are reported with conflicting associations with chronic Pb exposure. This study broadly evaluated the association between long-term lead exposure and thyroid function parameters. In this systematic review, the observational studies documenting the changes in thyroid function parameters between the chronically Pb-exposed and controls were systematically identified from PubMed-Medline, Scopus, and Embase digital databases from the beginning to March 31, 2022. The protocol was previously registered with PROSPERO (ID: CRD42022315520) and executed following PRISMA 2020 guidelines. The random-effects model was used to analyze the mean differences in thyroid function parameters between groups. The classical I2 statistic was applied to assess heterogeneity, while the Newcastle Ottawa Scale was used to assess the risk of various biases. Where data allowed, sub-group, sensitivity, and meta-regression analyses were carried out. The current systematic review included fifteen observational studies. The Pb-exposed have a higher mean blood Pb level [i.e. 28.07 (95% CI 21.43-34.72) µg/dl], significantly higher free T3 [(i.e. 0.48 pg/dl (95% CI 0.05-0.95)] and trend of higher T3. T4, FT4, and TSH levels than controls with high heterogeneity (I2 > 85%). Considering the important role of thyroid hormone in multiple biological functions, the present findings emphasize the requisite for high-quality studies to investigate the association between levels of thyroid function parameters among individuals known for cumulative exposure to Pb. Supplementary Information: The online version contains supplementary material available at 10.1007/s12291-023-01113-8.

Development and validation of Graphite Furnace Atomic Absorption Spectrometry method and its application for clinical evaluation of blood lead levels among occupationally exposed lead smelting plant workers.

The growing interest in estimating the blood lead levels, for early detection of lead exposure, warranted a need for a validated analytical method for trace levels estimation of lead. The present study aimed to develop an analytical method for detecting trace amounts to elevated levels of lead in human blood using the Graphite Furnace Atomic Absorption Spectrometry technique and its application in evaluating blood lead levels among occupationally exposed individuals. The method validation was performed with standard test parameters including linearity, recovery, precision, method detection limit, and limit of quantification. The validation results for each performance parameter were in agreement with acceptable criteria as per standard guidelines. The correlation was observed as optimum linear (R2 = 0.998) between absorbance and lead concentration range from 0 to 10 µg/dL. The recoveries for spiked samples ranged between 95 and 105%. The calculated value for the method detection limit was 0.16 µg/dL and the limit of quantification was 0.51 µg/dL. The precision for all spiked concentrations was below 10% of the relative standard deviation. Evaluation of lead exposure among occupationally exposed individuals revealed the study population had found average blood lead level (42.80 ± 12.47 µg/dL), which was above the upper acceptable limit suggested by Occupational Safety and Health Administration, USA. The majority of system-specific symptoms were observed among study groups having mean blood lead levels above 40 µg/dL. However, sociodemographic status and employment factors were found possible determinants of the prevalence of high blood lead levels.

A Comparative Health Assessment of Occupationally Lead Exposed Individuals with Blood Lead Levels Range across Upper Acceptable Limit.

Context: Lead (Pb) smelting workers are exposed to high lead levels and its adverse health effects. Despite no biological role, regulatory bodies regard blood lead levels (BLL) ≤40 µg/dL as upper acceptable limit in occupationally lead exposed population. Objective: To explore the differences in general health status of individuals with BLL ≤40 µg/dL and >40 µg/dL. Methods: All workers (n = 803) of age >18 years employed in a Pb smelting plant were interviewed with a semi-structured questionnaire to obtain sociodemographics, occupational details, followed by detailed clinical examination. 5 ml of venous blood was collected and BLLs were determined as per standard NIOSH method using GF-AAS technic. A complete general health status was performed including hemoglobin and blood pressure (BP). Results: About 47.7% of the participants exhibited high BLL (>40 µg/dL), while the rest 52.3% were identified to have ≤40 µg/dL. Both groups were grossly similar in the majority of demographic and occupational parameters. Interestingly, both groups had substantially higher fraction of workers with elevated BP. Conclusions: Lead exposed workers with BLL ≤40 µg/dL are at equal risk of health hazards as those with BLL >40 µg/dL. There is a need to revisit the current guidelines on the BLL for workers to protect from the hazards of chronic lead exposure.

Association between blood lead levels and markers of calcium homeostasis: a systematic review and meta-analysis.

Chronic Pb exposure associated systemic illness are partly posited to involve calcium homeostasis. Present systematic review aims to comprehensively evaluate the association between chronic lead exposure and markers of calcium homeostasis. Observational studies documenting the changes in calcium homeostasis markers (i.e. serum calcium, parathyroid hormone, vitamin D & calcitonin) between occupationally Pb exposed group and control group were systematically searched from pubmed-Medline, Scopus, and Embase digital databases since inception to September 24, 2021. The protocol was earlier registered at PROSPERO (ID: CRD42020199503) and executed adhering to PRISMA 2020 guidelines. Mean differences of calcium homeostasis markers between the groups were analysed using random-effects model. Conventional I2 statistics was employed to assess heterogeneity, while the risk for various biases were assessed using Newcastle Ottawa Scale. Sub-group, sensitivity and meta-regression analyses were performed where data permitted. Eleven studies including 837 Pb exposed and 739 controls were part of the present study. Pb exposed group exhibited higher mean blood lead level [i.e. 36.13 (with 95% CI 25.88-46.38) µg/dl] significantly lower serum calcium (i.e. - 0.72 mg/dl with 95% CI - 0.36 to - 1.07) and trend of higher parathyroid levels and lower vitamin D levels than controls. Heterogeneity was high (I2 > 90%) among the studies. Considering the cardinal role of calcium in multiple biological functions, present observations emphasis the need for periodic evaluation of calcium levels and its markers among those with known cumulative Pb exposure.

Evaluation and in vivo efficacy study of pyrano[3,2-c]quinoline analogues as TNF-α inhibitors.

A series of pyrano[3,2 c]quinoline was evaluated for its in vivo efficacy as TNF-α inhibitor using LPS, phosphodiesterase (PDE)-4, and CIA assays in different mice/rat models. The synthesis was performed using one-pot multicomponent condensation between 2,4-dihydroxy-1-methylquinoline, malononitrile, and diverse un(substituted) aromatic aldehydes. In vivo efficacy of the title compounds was evaluated using LPS assay in BALB/c mice, PDE4 inhibition in ketamine-xylazine-induced anesthetize SD rats, and CIA assay was performed in DBA/1J mice as per the standard literature protocols. The outcome of the study revealed that compound 4v was found to be most promising candidate of the series. It was efficacious with 48.8 ± 13.0% inhibition of TNF-α release at 100 mg/kg p.o., in the LPS assay in Balb/c mice model. It was effective in PDE4 assay in ketamine-xylazine-induced anesthetize SD rats with duration of 38.3 ± 4.5 min for reversal of anesthetic effect and also showed significant inhibition of PDE4 in salbutamol treated U937 cell assay. It was also abolished TNF-α induced phosphorylation and degradation of IκBα. Ultimately, its effect on CIA-related bone and cartilage damage was found statistically similar to Enbrel.

Evaluation of Pyrano[3,2 C] Quinoline Analogues as Anticancer Agents.

BACKGROUND: Quinoline analogues exhibited diversified biological activities depending on the structure type. A number of natural products with pyrano[3,2-c]quinolone structural motifs and patented chromenes were reported as promising cytotoxic agents. OBJECTIVE: The present study is aimed to evaluate a new series of pyrano[3,2-c]quinoline scaffolds derived from the fusion of bioactive quinolone pharmacophore with structurally diverse aryl substituted chromene for its cytotoxicity. METHODS: A library of pyrano[3,2-c]quinoline analogues was prepared from one-pot multi component synthesis using various aromatic aldehydes, malononitrile and 2,4-dihydroxy-1-methylquinoline. The new synthetics were primarily screened for its cytotoxicity (IC50) against different human cancer cell lines in vitro. The promising synthetics were further evaluated in vitro for their potency against different kinase activity. The promising compounds were finally tested for their in vivo efficacy in SCID type mice HCT-116 tumor model. RESULTS: The screening results revealed that compounds 4c, 4f, 4i and 4j showed promising activity in in vitro study. However, compound 4c was found to be the most potent candidate with 23% tumor growth inhibition in HCT-116 tumor mice model. CONCLUSION: The structure activity relationship suggested that 3-substitution on the aryl ring at C4 position of the pyrano[3,2 c]quinolone moiety seems to have an important position for cytotoxicity activity. However, 3- chloro substitution at C4 aryl ring showed a significant alteration of the bioactive conformer of the parent scaffold and outcome with compound 4c as the most potent candidate of the series.

Synthesis and Biological Screening of Pyrano[3,2-c]quinoline Analogues as Anti-inflammatory and Anticancer Agents.

A series of pyrano[3,2-c]quinoline based structural analogues was synthesized using one-pot multicomponent condensation between 2,4-dihydroxy-1-methylquinoline, malononitrile, and diverse un(substituted) aromatic aldehydes. The synthesized compounds were evaluated for their anti-inflammatory and cytotoxicity activity. Initially, all the compounds were evaluated for the percent inhibition of cytokine release, and cytotoxicity activity and 50% inhibitory concentrations (IC50) were also determined. Based on the primary results, it was further studied for their ability to inhibit TNF-α production in the human peripheral blood mononuclear cells (hPBMC) assay. The screening results revealed that compound 4c, 4f, 4i, and 4j were found most active candidates of the series against both anti-inflammatory and anticancer activity. The structure-activity relationship is discussed and suggested that 3-substitution on the aryl ring at C4 position of the pyrano[3,2-c]quinolone structural motif seems to be an important position for both TNF-α and IL-6 inhibition and anticancer activity as well. However, structural diversity with electron withdrawing, electron donating, sterically hindered, and heteroaryl substitution sincerely affected both the inflammation and anticancer activities.

Evaluation of structurally diverse benzoazepines clubbed with coumarins as Mycobacterium tuberculosis agents.

Tuberculosis caused by Mycobacterium tuberculosis remains a leading cause of mortality worldwide into 21st century. In continuation with our anti-tuberculosis research programme, in this work, we have prepared molecularly diverse coumarins clubbed with benzothiazepines as well as its aza-analogues-benzodiazepines by molecular hybridization. The resulting compounds were screened for their M. tuberculosis activity against H(37) Rv strains using microplate alamar blue assay. Among the designed diversity, the compounds 5k, 5n and 5o were found significantly active in primary anti-tuberculosis assay at minimum inhibitory concentration <6.25 µm. Moreover, the IC(50) values of 5k and 5o in level-2 screening were observed as >10 µg/mL and 3.63 µg/mL, respectively. Design and synthesis of more focused library and its three-dimensional quantitative structure activity relationship analysis are underway.

Synthesis and biological evaluation of 4-styrylcoumarin derivatives as inhibitors of TNF-α and IL-6 with anti-tubercular activity.

A series of 4-styrylcoumarin have been synthesized by Knoevenagel condensation between substituted 4-methylcoumarin-3-carbonitrile and different heterocyclic or aromatic aldehydes. 4-Methylcoumarin-3-carbonitrile has been synthesized by the base catalyzed reaction between substituted 2-hydroxyacetophenone and ethyl cyanoacetate. The structures of the newly synthesized compounds were confirmed by (1)H NMR, IR and mass spectral analysis. All the compounds were evaluated for their anti-inflammatory activity (against TNF-α and IL-6) and anti-tubercular activity. Compounds 6a, 6h and 6j exhibited promising activity against IL-6 with 72-87% inhibition and compound 6v showed potent activity against TNF-α with 73% inhibition at 10 µM concentration. Whereas compounds 6n, 6o, 6r and 6u showed very good anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain at <6.25 µM.

Screening for in vitro antimycobacterial activity and three-dimensional quantitative structure-activity relationship (3D-QSAR) study of 4-(arylamino)coumarin derivatives.

The resurgence of tuberculosis and the emergence of multidrug-resistant strains of Mycobacteria necessitate the search for new classes of antimycobacterial agents. We have synthesized a small library of 50 analogues of 4-(arylamino)coumarins with various aromatic amines at the C(4) - position of the coumarin scaffold. The compounds were evaluated for antimycobacterial activity against Mycobacterium tuberculosis H(37) Rv with rifampicin as the standard. Of the molecules synthesized, compound 9 was found to be most potent with a minimum inhibitory concentration >6.25 µg/mL for 100% inhibition. In an effort to develop new and more effective molecules in this series, the relationship between structure and activity was investigated by comparative molecular field analysis. Various models were generated using comparative molecular field analysis alone and comparative molecular field analysis plus a hydropathy field (HINT). In all, eight models were generated with atom-fit and field-fit alignment strategies. The comparative molecular field analysis models (Models 3a and 4a) based on field-fit alignment were the best with statistically good correlation coefficients (r²) and cross-validated q². The values of r²(pred) for the validation set were 0.469 and 0.516. Based on the comparative molecular field analysis contours, some insights into the structure-activity relationship of the compounds could be gained.

Synthesis, in vitro antitubercular activity and 3D-QSAR study of 1,4-dihydropyridines.

In continuation of our research program on new antitubercular agents, this article is a report of the synthesis of 97 various symmetrical, unsymmetrical, and N-substituted 1,4-dihydropyridines. The synthesized molecules were tested for their activity against M. tuberculosis H (37)Rv strain with rifampin as the standard drug. The percentage inhibition was found in the range 3-93%. In an effort to understand the relationship between structure and activity, 3D-QSAR studies were also carried out on a subset that is representative of the molecules synthesized. For the generation of the QSAR models, a training set of 35 diverse molecules representing the synthesized molecules was utilized. The molecules were aligned using the atom-fit technique. The CoMFA and CoMSIA models generated on the molecules aligned by the atom-fit method show a correlation coefficient (r (2)) of 0.98 and 0.95 with cross-validated r (2)(q (2)) of 0.56 and 0.62, respectively. The 3D-QSAR models were externally validated against a test set of 19 molecules (aligned previously with the training set) for which the predictive r(2)(r(r)(pred)) is recorded as 0.74 and 0.69 for the CoMFA and CoMSIA models, respectively. The models were checked for chance correlation through y-scrambling. The QSAR models revealed the importance of the conformational flexibility of the substituents in antitubercular activity.

Synthesis of 1-(2,6-dichlorophenyl)-3-methylene-1,3-dihydro-indol-2-one derivatives and in vitro anticancer evaluation against SW620 colon cancer cell line.

A small library of 2-indolinone derivatives with the 2,6-dichlorophenyl ring at the N(1) position and with varying substitutions including aryl groups at the 3-position were synthesized, and their structures were confirmed by spectral analysis. All molecules were screened for their in vitro cytotoxic activity on SW620 colon cancer cell lines. Among the designed series compounds 4c, 4f and 4j were found to be active at concentrations of 2-15 microg/ml. Some 3D-QSAR models were also built to understand the structure-activity relationship.

1,5-Benzothiazepine, a versatile pharmacophore: a review.

1,5-Benzothiazepine and 1,5-benzodiazipine are the two main seven-membered heterocyclic ring systems reported for their cardiac and psychotherapeutic activities. Successful introduction of diltiazem and clentiazem for angina pectoris, hypertension, arrhythmias and other related cardiac disorders proved potential of 1,5-benzothiazepine moiety. Subsequently 1,5-benzodiazepines were highlighted as important biologically active scaffolds. Also, discovery of thiazesim and quetiapine fumarate as psychotropic agents attracted much attention worldwide. The current review article focuses on pharmacological profile associated with 1,5-benzodiazepines. This article mainly covers structural modifications done for various targets along with the brief description of the targets.

Synthesis, anti-tubercular activity and 3D-QSAR study of coumarin-4-acetic acid benzylidene hydrazides.

A set of 25 coumarin-4-acetic acid benzylidene hydrazides were synthesized and characterized by NMR, IR and mass spectroscopic techniques. The compounds were evaluated for their anti-tubercular activity against Mycobacterium tuberculosis H(37)Rv strain using the BACTEC 460 system to determine percentage inhibition. To understand the relationship between structure and activity, a 3D-QSAR analysis has been carried out by Comparative Molecular Field Analysis (CoMFA). Several statistically significant CoMFA models were generated. The CoMFA model generated with database alignment was the best in terms of overall statistics. The CoMFA contours provide a good insight into the structure activity relationships of the compounds reported herein.