Synthesis and evaluation of pyridine-3-carboxamide analogs as effective agents against bacterial wilt in tomatoes.

This study focused on developing novel pyridine-3-carboxamide analogs to treat bacterial wilt in tomatoes caused by Ralstonia solanacearum. The analogs were synthesized through a multistep process and their structures confirmed using spectroscopy. Molecular docking studies identified the most potent analog from the series. A specific analog, compound 4a, was found to significantly enhance disease resistance in tomato plants infected with R. solanacearum. The structure-activity relationship analysis showed the positions and types of substituents on the aromatic rings of compounds 4a-i strongly influenced their biological activity. Compound 4a, with a chloro group at the para position on ring C and hydroxyl group at the ortho position on ring A, was exceptionally effective against R. solanacearum. When used to treat seeds, the analogs displayed remarkable efficacy, especially compound 4a which had specific activity against bacterial wilt pathogens. Compound 4a also promoted vegetative and reproductive growth of tomato plants, increasing seed germination and seedling vigor. In plants mechanically infected with bacteria, compound 4a substantially reduced the percentage of infection, pathogen quantity in young tissue, and disease progression. The analogs were highly potent due to their amide linkage. Molecular docking identified the best compounds with strong binding affinities. Overall, the strategic design and synthesis of these pyridine-3-carboxamide analogs offers an effective approach to targeting and controlling R. solanacearum and bacterial wilt in tomatoes.

Computational analysis of bevacizumab binding with protein receptors for its potential anticancer activity.

Breast cancer poses a significant global challenge, prompting researchers to explore novel approaches for potential treatments. In this study, we investigated the binding free energy (ΔG) of bevacizumab, an anti-cancer therapy targeting angiogenesis through the inhibition of vascular endothelial growth factor (VEGF), with various proto-oncogenes including CDK4, EGFR, frizzled, IGFR, OmoMYC, and KIT. Our in-silico investigation revealed that hydrogen bonding is pivotal in inducing conformational changes within the DNA structure, impeding its replication and preventing cell death. Molecular docking results revealed the presence of crucial hydrogen bonds and supported the formation of stable bevacizumab complexes. The molecular docking scores for the tested complexes were CDK4 (Score = -7.2 kcal/mol), EGFR (Score = -8.5 kcal/mol), frizzled (Score = -6.9 kcal/mol), IGFR (Score = -7.8 kcal/mol), KIT (Score = -6.5 kcal/mol), and MYC (Score = -8.3 kcal/mol). The binding mode demonstrated vital hydrogen bonds correlated with the observed energy gap. Notably, the calculated binding free energies of the tested compounds are as follows: CDK4 (ΔG = 24275.195 ± 6411.293 kJ/mol), EGFR (ΔG = 363273.625 ± 8731.466 kJ/mol), frizzled (ΔG = 181751.990 ± 28438.515 kJ/mol), IGFR (ΔG = 162414.725 ± 10728.367 kJ/mol), KIT (ΔG = 40162.585 ± 4331.017 kJ/mol), and MYC (ΔG = 434783.463 ± 53989.676 kJ/mol). Furthermore, through extensive 100 ns MD simulations, we observed the formation of a stable bevacizumab complex structure. The simulations confirmed the stability of the bevacizumab complex with the proto-oncogenes. The results of this study highlight the potential of bevacizumab complex as a promising candidate for anticancer treatment. The identification of hydrogen bonding, along with the calculated binding free energies and molecular docking scores, provides valuable insights into the molecular interactions and stability of the bevacizumab complexes. These findings and the extensive MD simulations open new avenues for future research and development of bevacizumab as a targeted therapy for breast cancer and other related malignancies.Communicated by Ramaswamy H. Sarma.

Computational investigation of the impact of potential AT2R polymorphism on small molecule binding.

For more than a century, the renin-angiotensin system (RAS) has been acknowledged for playing a crucial part in the physiological control of arterial pressure, as well as sodium and fluid balance. It is now generally acknowledged that one of the receptor of RAS system i.e. angiotensin type 2 receptor (AT2R) functions as a repair system during pathophysiologic circumstances and performs a significant protective role. Efforts have been made previously to design suitable agonist and antagonist molecules to potentially modulate AT2R. One of the agonists and antagonists, named C21 and EMA401, has been studied in a number of pathological conditions. Additionally, a wide panel of single nucleotide polymorphisms (SNPs) has been reported for AT2R, which might potentially affect the efficacy of these molecules. Therefore, computational investigations have been carried out to analyze all the SNPs (1151) reported in NCBI to find potential SNPs affecting the active site of AT2R, as this domain is still unexplored. Structures of these polymorphic forms were modeled, and in silico drug interaction studies with C21 and EMA401 were carried out. The two mutants (rs868939201 and rs1042852794) that significantly affect the binding affinity as that of the wild type were subjected to molecular dynamics simulations. Our analysis of native and mutant AT2R and their complexes with C21 and EMA401 indicated that the occurrence of these mutations affects the conformation of the protein and has affected the binding of these ligand molecules. The study's findings will aid in the development of better, more versatile medications in the near future, and also in vitro and in vivo studies might be planned in accordance with recent findings.Communicated by Ramaswamy H. Sarma.

Origin of Antibiotics and Antibiotic Resistance, and Their Impacts on Drug Development: A Narrative Review.

Antibiotics have revolutionized medicine, saving countless lives since their discovery in the early 20th century. However, the origin of antibiotics is now overshadowed by the alarming rise in antibiotic resistance. This global crisis stems from the relentless adaptability of microorganisms, driven by misuse and overuse of antibiotics. This article explores the origin of antibiotics and the subsequent emergence of antibiotic resistance. It delves into the mechanisms employed by bacteria to develop resistance, highlighting the dire consequences of drug resistance, including compromised patient care, increased mortality rates, and escalating healthcare costs. The article elucidates the latest strategies against drug-resistant microorganisms, encompassing innovative approaches such as phage therapy, CRISPR-Cas9 technology, and the exploration of natural compounds. Moreover, it examines the profound impact of antibiotic resistance on drug development, rendering the pursuit of new antibiotics economically challenging. The limitations and challenges in developing novel antibiotics are discussed, along with hurdles in the regulatory process that hinder progress in this critical field. Proposals for modifying the regulatory process to facilitate antibiotic development are presented. The withdrawal of major pharmaceutical firms from antibiotic research is examined, along with potential strategies to re-engage their interest. The article also outlines initiatives to overcome economic challenges and incentivize antibiotic development, emphasizing international collaborations and partnerships. Finally, the article sheds light on government-led initiatives against antibiotic resistance, with a specific focus on the Middle East. It discusses the proactive measures taken by governments in the region, such as Saudi Arabia and the United Arab Emirates, to combat this global threat. In the face of antibiotic resistance, a multifaceted approach is imperative. This article provides valuable insights into the complex landscape of antibiotic development, regulatory challenges, and collaborative efforts required to ensure a future where antibiotics remain effective tools in safeguarding public health.

AI-driven Discovery of Celecoxib and Dexamethasone for Exploring their Mode of Action as Human Interleukin (IL-6) Inhibitors to Treat COVID-19-induced Cytokine Storm in Humans.

BACKGROUND: In the case of COVID-19 patients, it has been observed that the immune system of the infected person exhibits an extreme inflammatory response known as cytokine release syndrome (CRS) where the inflammatory cytokines are swiftly produced in quite large amounts in response to infective stimuli. Numerous case studies of COVID-19 patients with severe symptoms have documented the presence of higher plasma concentrations of human interleukin-6 (IL-6), which suggests that IL-6 is a crucial factor in the pathophysiology of the disease. In order to prevent CRS in COVID-19 patients, the drugs that can exhibit binding interactions with IL-6 and block the signaling pathways to decrease the IL-6 activity may be repurposed. METHODS: This research work focused on molecular docking-based screening of the drugs celecoxib (CXB) and dexamethasone (DME) to explore their potential to interact with the binding sites of IL-6 protein and reduce the hyper-activation of IL-6 in the infected personnel. RESULTS: Both of the drugs were observed to bind with the IL-6 (IL-6 receptor alpha chain) and IL-6Rα receptor with the respective affinities of -7.3 kcal/mol and -6.3 kcal/mol, respectively, for CXB and DME. Moreover, various types of binding interactions of the drugs with the target proteins were also observed in the docking studies. The dynamic behaviors of IL-6/IL-6Rα in complex with the drugs were also explored through molecular dynamics simulation analysis. The results indicated significant stabilities of the acquired drug-protein complexes up to 100 ns. CONCLUSION: The findings of this study have suggested the potential of the drugs studied to be utilized as antagonists for countering CRS in COVID-19 ailment. This study presents the studied drugs as promising candidates both for the clinical and pre-clinical treatment of COVID-19.

Systematic review of clinical practice guidelines for traumatic dental injuries.

BACKGROUND/AIMS: Traumatic dental injuries (TDI) are considered a public health problem due to their high prevalence and associated physical, economic, psychological and social consequences. Hence, good Clinical Practice Guidelines are essential to achieving a favourable prognosis. The aim of this review was to appraise the existing Clinical Practice Guidelines (CPGs) on TDI using AGREE II and AGREE-REX. MATERIALS AND METHODS: A systematic search for existing guidelines on TDI was performed on PubMed, EMBASE, CINAHL, Cochrane Library, ProQuest, National Institute for Health Care Excellence, BMJ Best Practice, Trip database, Guideline International Network, Scottish Intercollegiate Guidelines Network, World Health Organisation, Web of Science and 'Ministry of Health worldwide' databases. Four appraisers independently appraised the included CPGs. The AGREE II tool was applied to assess the methodological quality, while AGREE REX assessed the quality of recommendations of the included guidelines. RESULTS: Of the 7736 titles screened, three guidelines, namely the International Association of Dental Traumatology Guidelines (IADT), and the Italian and Malaysian guidelines, were included for the final analysis. These guidelines were published between 2019 and 2020. The AGREE II analysis demonstrated scores above 80% for the IADT and Italian guidelines for the scope and purpose domain. Overall, the Malaysian guidelines achieved the highest score for all domains. The AGREE REX analysis indicated variability in implementation across the nine items, with five that scored above the midpoint of 4.0 on the response scale. Both the Italian and the IADT guidelines had a similar score for the values and preference domains (36.36%). CONCLUSIONS: Several deficiencies exist in the methodological quality of existing CPGs on TDI. Future guidelines should consider improvements for domains such as 'rigour of development', 'stakeholder involvement' and 'applicability' to overcome the existing limitations.

Microwave-Assisted Functionalization of Multi-Walled Carbon Nanotubes for Biosensor and Drug Delivery Applications.

Microwave-assisted synthetic methods have emerged as a popular technique for surface modification and the functionalization of multi-walled carbon nanotubes (MWCNTs) for diverse drug delivery applications. Microwave-induced functionalization of MWCNTs provides a high functionalization and requires less time than conventional techniques. Microwave methods are simple, fast, and effective for the covalent and noncovalent conjugation of MWCNTs with various biomolecules and polymers. The present review focuses on the synthetic and drug delivery applications of microwave irradiation techniques (MITs) for the functionalization of MWCNTs, using amino acids and other molecular frameworks containing amino groups, vitamins, proteins, epoxy moieties, metal nanoparticles, and polymers.

Sustainable development goals and ending ECC as a public health crisis.

Early Childhood Caries (ECC) remains a global issue despite numerous advancements in research and interventional approaches. Nearly, 530 million children suffer from untreated dental caries of primary teeth. The consequences of such untreated dental caries not only limit the child's chewing and eating abilities but also, significantly impact the child's overall growth. Research has demonstrated that ECC is associated with nearly 123 risk factors. ECC has also been associated with local pain, infections, abscesses, and sleep pattern. Furthermore, it can affect the child's emotional status and decrease their ability to learn or perform their usual activities. In high-income countries, dental care continues to endorse a "current treatment-based approach" that involves high-technology, interventionist, and specialized approaches. While such approaches provide immediate benefit at an individual level, it fails to intercept the underlying causes of the disease at large. In low-income and middle-income countries (LMICs), the "current treatment approach" often remains limited, unaffordable, and unsuitable for the majority of the population. Rather, dentistry needs to focus on "sustainable goals" and integrate dental care with the mainstream healthcare system and primary care services. Dental care systems should promote "early first dental visits," when the child is 1 year of age or when the first tooth arrives. The serious shortages of appropriately trained oral healthcare personnel in certain regions of the world, lack of appropriate technologies and isolation of oral health services from the health system, and limited adoption of prevention and oral health promotion can pose as critical barriers. The oral health care systems must focus on three major keystones to combat the burden of ECC-1. Essential oral health services are integrated into healthcare in every country ensuring the availability of appropriate healthcare accessible and available globally, 2. Integrating oral and general healthcare to effectively prevent and manage oral disease and improve oral health, 3. Collaborating with a wide range of health workers to deliver sustainable oral health care tailored to cater to the oral health care needs of local communities.

A Study to Identify the Most Common Reasons to Wean among Breastfeeding Mothers in UAE.

BACKGROUND: Despite the great benefits of breastfeeding for the mother and the child, many mothers face a lot of challenges and issues during lactation, which might lead to early weaning. AIM: The aim of this study was to assess the factors that can lead to early weaning and to identify the most common reasons to early weaning among breastfeeding mothers. MATERIALS AND METHODS: This was a cross-sectional, questionnaire-based survey study. Eight hundred and fifty questionnaires were distributed to lactating mothers, but only 820 were returned making the response rate of 96.5%. Breastfeeding mothers in Ajman and Sharjah, United Arab Emirates (UAE) participated in the study. STATISTICAL ANALYSIS: The results were analyzed using the Statistical Package for the Social Sciences (SPSS) software, version 20. IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp. Descriptive statistics were used to summarize the data concerning the demographic characteristics. Categorical variables (such as nationality and educational level) were described by using frequency, percentages, bar chart, and pie chart. RESULTS: The results revealed that 29% of respondents stopped breastfeeding for some reason. The main reasons stated by the participants were low milk supply (25.8%) and pain, congestion, and abscess (19.22%) followed by new pregnancy (17.5%), which were the most identified reasons for early discontinuation of breastfeeding. CONCLUSION: Our study indicated that the misconception of weaning because of a new pregnancy has declined in the UAE compared to a study conducted 3 years ago. A positive improvement was also observed in terms of weaning due to personal desire compared to previous years among mothers as they became more aware of the benefits of breastfeeding.