Antiangiogenic potential of phytochemicals from Clerodendrum inerme (L.) Gaertn investigated through in silico and quantum computational methods.

Suppressing vascular endothelial growth factor (VEGF), its receptor (VEGFR2), and the VEGF/VEGFR2 signaling cascade system to inhibit angiogenesis has emerged as a possible cancer therapeutic target. The present work was designed to discover and evaluate bioactive phytochemicals from the Clerodendrum inerme (L.) Gaertn plant for their anti-angiogenic potential. Molecular docking of twenty-one phytochemicals against the VEGFR-2 (PDB ID: 3VHE) protein was performed, followed by ADMET profiling and molecular docking simulations. These investigations unveiled two hit compounds, cirsimaritin (- 12.29 kcal/mol) and salvigenin (- 12.14 kcal/mol), with the highest binding energy values when compared to the reference drug, Sorafenib (- 15.14 kcal/mol). Furthermore, only nine phytochemicals (cirsimaritin and salvigenin included) obeyed Lipinski's rule of five and passed ADMET filters. Molecular dynamics simulations run over 100 ns revealed that the protein-ligand complexes remained stable with minimal backbone fluctuations. The binding free energy values of cirsimaritin (- 52.35 kcal/mol) and salvigenin (- 55.89 kcal/mol), deciphered by MM-GBSA analyses, further corroborated the docking interactions. The HOMO-LUMO band energy gap (ΔE) was calculated using density-functional theory (DFT) and substantiated using density of state (DOS) spectra. The chemical reactivity analyses revealed that salvigenin exhibited the highest chemical softness value (6.384 eV), the lowest hardness value (0.07831 eV), and the lowest ΔE value (0.1566 eV), which implies salvigenin was less stable and chemically more reactive than cirsimaritin and sorafenib. These findings provide further evidence that cirsimaritin and salvigenin have the ability to prevent angiogenesis and the development of cancer. Nevertheless, more in vitro and in vivo confirmation is necessary.

Stress-mitigating behavior of glycine betaine to enhance growth performance by suppressing the oxidative stress in Pb-stressed barley genotypes.

The toxicity of lead (Pb) in agricultural soil is constantly increasing as a result of anthropogenic activities. Pb is one of the most phytotoxic metals in soil that accumulates in plant tissue, resulting in yield loss. It is currently becoming more popular to supplement glycine betaine (GB) for Pb-induced stress tolerance in crop plants. Currently, no report describes the use of GB as a stress mitigator for growth attributes and stress-specific biomarkers in barley plants under Pb stress conditions. Hence, the present research was designed to examine the stress-mitigating behavior of GB on various growth attributes including germination percentage, seed vigor index (SVI), radicle length, plant biomass (fresh and dry), shoot and root length, physiological attributes such as relative water content (RWC), and stress-specific biomarkers like electrolyte leakage (EL), and H2O2 content of two barley varieties viz. BH959 and BH946 at three Pb stress treatments (15 mM, 25 mM, and 35 mM), with and without GB (2 mM) supplementation in natural conditions. The present investigation showed that at the highest Pb stress (35 mM), the germination rate was reduced to zero, and the growth attributes and RWC of both barley varieties were also reduced as compared to the non-stressed plants (control) with an increase in Pb treatment. However, EL up to 70% and H2O2 content up to 30% increased with an increase in Pb stress concentration indicated by ROS accumulation, resulting in more oxidative stress. Additionally, GB application alleviated the toxic effect of Pb stress by improving the rate of germination by 33.3% and growth performance by reducing the ROS accumulation in terms of reducing stress biomarkers H2O2 by 25%, and EL by 12%. It has been revealed that the application of GB can minimize or reduce the toxic effects caused by Pb toxicity in both varieties, positively modulating plant growth performances and lowering oxidative stress. This research may provide a scientific basis for assessing Pb tolerance in barley plants and developing alternative approaches to protecting them from the severe effects of Pb toxicity.

Screening of phytochemicals from Clerodendrum inerme (L.) Gaertn as potential anti-breast cancer compounds targeting EGFR: an in-silico approach.

Breast cancer (BC) is the most prevalent malignancy among women around the world. The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor (RTK) of the ErbB/HER family. It is essential for triggering the cellular signaling cascades that control cell growth and survival. However, perturbations in EGFR signaling lead to cancer development and progression. Hence, EGFR is regarded as a prominent therapeutic target for breast cancer. Therefore, in the current investigation, EGFR was targeted with phytochemicals from Clerodendrum inerme (L.) Gaertn (C. inerme). A total of 121 phytochemicals identified by gas chromatography-mass spectrometry (GC-MS) analysis were screened against EGFR through molecular docking, ADMET analyses (Absorption, Distribution, Metabolism, Excretion, and Toxicity), PASS predictions, and molecular dynamics simulation, which revealed three potential hit compounds with CIDs 10586 [i.e. alpha-bisabolol (-6.4 kcal/mol)], 550281 [i.e. 2,(4,4-Trimethyl-3-hydroxymethyl-5a-(3-methyl-but-2-enyl)-cyclohexene) (-6.5 kcal/mol)], and 161271 [i.e. salvigenin (-7.4 kcal/mol)]. The FDA-approved drug gefitinib was used to compare the inhibitory effects of the phytochemicals. The top selected compounds exhibited good ADMET properties and obeyed Lipinski's rule of five (ROF). The molecular docking analysis showed that salvigenin was the best among the three compounds and formed bonds with the key residue Met 793. Furthermore, the molecular mechanics generalized born surface area (MMGBSA) calculations, molecular dynamics simulation, and normal mode analysis validated the binding affinity of the compounds and also revealed the strong stability and compactness of phytochemicals at the docked site. Additionally, DFT and DOS analyses were done to study the reactivity of the compounds and to further validate the selected phytochemicals. These results suggest that the identified phytochemicals possess high inhibitory potential against the target EGFR and can treat breast cancer. However, further in vitro and in vivo investigations are warranted towards the development of these constituents into novel anti-cancer drugs.Communicated by Ramaswamy H. Sarma.

Delayed diagnosis of bronchobiliary fistula complicating a pediatric living donor liver transplantation: a case report.

Bronchobiliary fistula (BBF) is a very rare condition in children. Only a few pediatric BBF cases have been reported, in the context of a ruptured hydatid cyst or liver abscess. BBF after living donor liver transplantation (LDLT) has not been reported in the pediatric literature. We report a 7-year-old female child with Wilson disease, who developed BBF post-LDLT. She had a clinically uneventful course in the immediate post-transplant period. She was readmitted on postoperative day (POD) 75 with a productive cough and respiratory difficulty, which was diagnosed as bilioptysis secondary to BBF. Endoscopic retrograde cholangiopancreaticography was attempted but failed. Exploratory laparotomy showed a fistula from the strictured biliary anastomotic site to the right thoracic cavity; it was excised, and a Roux-en-Y hepaticojejunostomy was performed. She tolerated the procedure well and remained clinically well on follow-up through POD 185. BBF is extremely rare in children. This is the first case report of BBF in a child following LDLT. BBF requires a high index of suspicion for a timely intervention to prevent subsequent complications.

Understanding Osteoporosis: Human Bone Density, Genetic Mechanisms, Gut Microbiota, and Future Prospects.

Osteoporosis is a systemic condition of the skeleton that leads to diminished bone mass, a breakdown in the bone tissue's microscopic architecture, and an elevated risk of breaking a bone. The elderly and women particularly after menopause are disproportionately affected, and the condition generally stays undiagnosed until a broken bone causes severe pain and immobility. Causes of osteoporosis include low bone mass, more than normal bone loss, changes in hormone levels (decreased estrogen or testosterone), certain diseases and therapies, and lifestyle factors like smoking and inactivity. The spine, hip, and forearm are particularly vulnerable to osteoporosis-related fractures. The purpose of this article is to present a thorough understanding of osteoporosis, including the disease's connection to bone density in humans, and the major part played by genetic pathways and gut flora. The causes of osteoporosis, the effects of aging on bone density, and why some groups experience a higher incidence of the disease than others are investigated. The paper also includes animal and human experiments investigating the link between gut flora and osteoporosis. Finally, it looks to the future and speculates on possible developments in osteoporosis prevention and therapy.

Emerging Nanotechnology-based Therapeutics: A New Insight into Promising Drug Delivery System for Lung Cancer Therapy.

BACKGROUND: Lung cancer is a foremost global health issue due to its poor diagnosis. The advancement of novel drug delivery systems and medical devices will aid its therapy. OBJECTIVE: In this review, the authors thoroughly introduce the ideas and methods for improving nanomedicine- based approaches for lung cancer therapy. This article provides mechanistic insight into various novel drug delivery systems (DDSs) including nanoparticles, solid lipid nanoparticles, liposomes, dendrimers, niosomes, and nanoemulsions for lung cancer therapy with recent research work. This review provides insights into various patents published for lung cancer therapy based on nanomedicine. This review also highlights the current status of approved and clinically tested nanoformulations for their treatment. METHODOLOGY: For finding scholarly related data for the literature search, many search engines were employed including PubMed, Science Direct, Google, Scihub, Google Scholar, Research Gate, Web of Sciences, and several others. Various keywords and phrases were used for the search such as "nanoparticles", "solid lipid nanoparticles", "liposomes", "dendrimers", "niosomes", "nanoemulsions", "lung cancer", "nanomedicine", "nanomaterial", "nanotechnology", "in vivo" and "in vitro". The most innovative and cutting-edge nanotechnology-based approaches that are employed in pre-clinical and clinical studies to address problems associated with lung cancer therapies are also mentioned in future prospects. A variety of problems encountered with current lung cancer therapy techniques that frequently led to inadequate therapeutic success are also discussed in the end. CONCLUSION: The development of nanoformulations at the pilot scale still faces some difficulties, but their prospects for treating lung cancer appear to be promising in the future. Future developments and trends are anticipated as the evaluation comes to a close.

Specialized pro-resolving lipid mediators regulate inflammatory macrophages: A paradigm shift from antibiotics to immunotherapy for mitigating COVID-19 pandemic.

The most severe clinical manifestations of the horrifying COVID-19 disease, that claimed millions of lives during the pandemic time, were Acute respiratory distress syndrome (ARDS), Coagulopathies, septic shock leading eventually to death. ARDS was a consequence of Cytokine storm. The viral SARS-COV2infection lead to avalanche of cytokines and eicosanoids causing "cytokine storm" and "eicosanoid storm." Cytokine storm is one of the macrophage-derived inflammatory responses triggered by binding of virus particles to ACE2 receptors of alveolar macrophages, arise mainly due to over production of various pro-inflammatory mediators like cytokines, e.g., interleukin (IL)-1, IL-2, and tumor necrosis factor (TNF)- α, causing pulmonary edema, acute respiratory distress, and multi-organ failure. Cytokine storm was regarded as the predictor of severity of the disease and was deemed one of the causes of the high mortality rates due to the COVID-19. The basis of cytokine storm is imbalanced switching between an inflammation increasing - pro-inflammatory (M1) and an inflammation regulating-anti-inflammatory (M2) forms of alveolar macrophages which further deteriorates if opportunistic secondary bacterial infections prevail in the lungs. Lack of sufficient knowledge regarding the virus and its influence on co-morbidities, clinical treatment of the diseases included exorbitant use of antibiotics to mitigate secondary bacterial infections, which led to the unwarranted development of multidrug resistance (MDR) among the population across the globe. Antimicrobial resistance (AMR) needs to be addressed from various perspectives as it may deprive future generations of the basic health immunity. Specialized pro-resolving mediators (SPMs) are generated from the stereoselective enzymatic conversions of essential fatty acids that serve as immune resolvents in controlling acute inflammatory responses. SPMs facilitate the clearance of injured tissue and cell debris, the removal of pathogens, and augment the concentration of anti-inflammatory lipid mediators. The SPMs, e.g., lipoxins, protectins, and resolvins have been implicated in exerting inhibitory influence on with cytokine storm. Experimental evidence suggests that SPMS lower antibiotic requirement. Therefore, in this review potential roles of SPMs in enhancing macrophage polarization, triggering immunological functions, hastening inflammation resolution, subsiding cytokine storm and decreasing antibiotic requirement that can reduce AMR load are discussed.

Polyaromatic Hydrocarbon Specific Ring Hydroxylating Dioxygenases: Diversity, Structure, Function, and Protein Engineering.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitously present in the environment. These compounds have demonstrated both mutagenic and carcinogenic properties. In the past few decades, scientists have constantly been looking for a possible route to their biological degradation. Bacterial ring hydroxylating dioxygenases (RHDs) implicated in the polycyclic aromatic hydrocarbon degradation comprise a large family of enzymes. RHD catalyzes the stereospecific oxidation of PAHs by incorporating molecular oxygen into inert aromatic nuclei. These biocatalysts hold the potential to completely transform and mineralize toxic forms of these compounds into non-toxic forms. RHDsmediated oxygenation produces cis-dihydrodiols, a chiral compound used in pharmaceutical industries. The Molecular investigation of 16S rRNA and key functional genes involved in pollutant degradation have revealed the dominant occurrence of phylum proteobacteria and actinobacteria in hydrocarbonpolluted environments. The present review is aimed at narrating the diversity, distribution, structural and functional characteristics of RHDs. The review further highlights key amino acids participating in RHDs catalysis. It also discusses the robustness of protein engineering methods in improving the structural and functional activity of the ring hydroxylating dioxygenases.

Techno-Functional Assessment of Riboflavin-Enriched Yogurt-Based Fermented Milk Prepared by Supplementing Riboflavin-Producing Probiotic Strains of Lactiplantibacillus plantarum.

Vitamin enrichment in fermented dairy products through the intervention of vitamin-producing probiotic strains during fermentation is a novel approach in the field of probioceuticals. In this study, riboflavin-enriched yogurt-based fermented milk was prepared by mixing 1% (v/v) riboflavin-producing strain [1.2 × 108 CFU/mL of Lactiplantibacillus plantarum MTCC 25432 or L. plantarum MTCC 25433 or L. plantarum MTCC 25434] with 2% (v/v) traditional yogurt cultures [Streptococcus thermophilus NCDC 295 and L. delbrueckii subsp. bulgaricus NCDC 293; each of 1.3 × 107 CFU/mL]. The yogurt-based fermented milk prepared with traditional yogurt cultures (2%, v/v) was served as a control. The prepared yogurt-based fermented milk samples were analyzed and compared for riboflavin content, antimicrobial activity, physicochemical, and functional properties. As a result, the yogurt-based fermented milk prepared with L. plantarum MTCC 25432 produced a significantly higher amount of riboflavin (2.49 mg/L) as compared with MTCC 25433 (2.33 mg/L), MTCC 25434 (2.14 mg/L), and control (1.70 mg/L). The probiotic supplementation to yogurt cultures maintained the pH and titratable acidity in the range of 4.1-4.4 and 1.0-1.05% (lactic acid/100 mL), as recommended by Indian yogurt standards. The rheological, texture, and antimicrobial properties of yogurt-based fermented milk were enhanced with the addition of riboflavin-producing probiotic strains. Moreover, all yogurt-based fermented milk samples prepared in this study were acceptable as per the sensory evolution scores. In conclusion, the use of riboflavin-producing L. plantarum strains along with standard yogurt cultures could be the best approach to enhancing riboflavin content in yogurt-based fermented milk and fulfilling the daily riboflavin requirement in humans.

Biogenic Phytochemicals Modulating Obesity: From Molecular Mechanism to Preventive and Therapeutic Approaches.

The incidence of obesity and over bodyweight is emerging as a major health concern. Obesity is a complex metabolic disease with multiple pathophysiological clinical conditions as comorbidities are associated with obesity such as diabetes, hypertension, cardiovascular disorders, sleep apnea, osteoarthritis, some cancers, and inflammation-based clinical conditions. In obese individuals, adipocyte cells increased the expression of leptin, angiotensin, adipocytokines, plasminogen activators, and C-reactive protein. Currently, options for treatment and lifestyle behaviors interventions are limited, and keeping a healthy lifestyle is challenging. Various types of phytochemicals have been investigated for antiobesity potential. Here, we discuss pathophysiology and signaling pathways in obesity, epigenetic regulations, regulatory mechanism, functional ingredients in natural antiobesity products, and therapeutic application of phytochemicals in obesity.

Implant survival in patients with neuropsychiatric, neurocognitive, and neurodegenerative disorders: A meta-analysis.

Neurologic disorders impede oral hygiene measures and routine clinical follow-up, along with the various drugs used may jeopardise oral health and the peri- implant tissue health. A total of 7 studies were considered eligible for the current systematic review. The overall estimated effect was categorized as significant where P < 0.05. Funnel plot was used to assess the publication bias within the studies. Difference in means was used as principal summary measure. P value <0.05 was considered as statistically significant. 1069 implants survived in test group and 4677 implants survived in control group (odds ratio: 2.58, 95% CI: 1.93-3.43) indicating significant success in patient without any disorders or taking medications for these disorders. Subgroup analysis was done to check the implant survival rate in patients taking selective serotonin reuptake inhibitors (SSRI) compared with SSRI non-users. Subgroup analysis showed that SSRI non-users had higher implant survival rate than patients taking SSRI (odds ratio: 2.45, 95% CI: 1.82-3.31). Serotonin significantly inhibits bone mineralization and osteoblast differentiation. The presence of any form of neuropsychiatric or neuromuscular disorders precludes proper oral hygiene and may contribute towards implant failure.

Localized probiotic-guided pocket recolonization in the treatment of chronic periodontitis: a randomized controlled clinical trial.

PURPOSE: This randomized clinical placebo-controlled trial was conducted to evaluate the effectiveness of Lactobacillus reuteri as a probiotic in guided pocket recolonization (GPR) for the treatment of chronic periodontitis (CP) adjunctive to scaling and root planing (SRP). METHODS: Forty-eight CP patients were randomly assigned to 3 treatment groups: group 1 (SRP+placebo), group 2 (SRP+single application of probiotic), and group 3 (SRP+incremental application of probiotic). Clinical parameters were evaluated at baseline and at 8, 12, and 24 weeks, whereas biochemical parameters were measured at baseline and 12 weeks. RESULTS: At 24 weeks, the probing pocket depth and clinical attachment level improved in all 3 groups from baseline with no significant intergroup differences; however, a statistically significant difference was observed in localized plaque and gingival scores between groups 1 and 3 (P<0.05). At 12 weeks, matrix metalloproteinase-8 (MMP-8), nitric oxide (NO), and gingipains-R (Rgps) levels improved in all 3 groups, with statistically significant differences between groups 1 and 3 for MMP-8 and NO (P<0.05), but no difference for Rgps levels. CONCLUSIONS: Within its limitations, the results of this study show that incremental 3-time application of L. reuteri as a probiotic led to improvements in clinical and biochemical parameters. This protocol can be a useful adjunct to SRP in the non-surgical management of CP. TRIAL REGISTRATION: Clinical Trials Registry - India Identifier: CTRI/2017/03/008231.

Results of modified thread technique for the treatment of wrist ganglion.

BACKGROUND: Ganglion cyst is the commonest swelling around the wrist. It usually presents as a painless swelling. There is no consensus as to the exact cause and the ideal modality of its treatment. Surgical excision has the best cure rates but has its share of complications. The aim of this study was to evaluate whether a modified thread technique can give reasonably good results with a low complication rate in patients with wrist ganglion. MATERIAL AND METHODS: One hundred and sixteen patients with wrist ganglion underwent a modified thread technique in which a sterile silk suture was passed through the ganglion, the contents of the ganglion were expressed out completely by firm pressure and the thread was tied over a sterile gauze piece forming a single loop. The thread was removed once serosanginous discharge was seen at entry point of the thread into the cyst. RESULTS: One hundred and eight patients were available for final analysis with minimum six months follow up. There was no recurrence in ninety eight patients giving success rate of ninety one percent. Recurrence was only seen in patients where complete evacuation of the contents of ganglion could not be achieved. Nine patients had minor complications in the form of superficial infection in two patients and mild pain around thread entry point in seven patients. CONCLUSION: Modified thread technique for the treatment of wrist ganglion is a minimally invasive, low cost, day care procedure which can give reasonably good results with a very low complication rate.

Andrew's bridge system: A boon for huge ridge defect in aesthetic zone.

Tooth loss may pose a challenge for prosthetics when several missing teeth are associated with huge vertical and horizontal bone defects due to cleft palate, road traffic accidents, congenital defects etc. This case report presents prosthetic rehabilitation of a 22 year old male patient of cleft lip and palate with missing upper front teeth along with severe ridge defect since 1 year due to surgical intervention in premaxillary region. The extensive soft and hard tissue defect in aesthetic region was evident and it made the prosthetic rehabilitation more challenging. Among treatment options, fixed partial denture (FPD) was not feasible due to long edentulous span and extensive soft and hard tissue loss. Psychologically, patient was not ready for removable prosthesis. Patient was also not ready for next implant or bone augmentation surgery procedure. The patient presented with Kennedy class IV edentulous area with Seibert's class III ridge defect, so fixed-removable prosthesis was planned to compensate soft and hard tissue defect. The patient with several missing teeth and extensive visible bony defect in the anterior region was successfully rehabilitated using fixed-removable Andrew's bridge system. Although it is not commonly used by dentist so this present case report shows effective management of huge defect case by very simple and conservative technique.

Proteomic approach and expression analysis revealed the differential expression of predicted leptospiral proteases capable of ECM degradation.

Leptospira, the causative agent of leptospirosis is known to have many proteases with potential to degrade extracellular matrix. However, a multipronged approach to identify, classify, characterize and elucidate their role has not been attempted. Our proteomic approach using high-resolution LC-MS/MS analysis of Triton X-114 fractions of Leptospira interrogans resulted in the identification of 104 proteases out of 130 proteases predicted by MEROPS. In Leptospira approximately 3.5% of the genome complements for proteases, which include catalytic types of metallo-, serine-, cysteine-, aspartic-, threonine- and asparagine- peptidases. Comparison of proteases from different serovars revealed that M04, M09B, M14A, M75, M28A, A01 and U73 protease families are exclusively present in pathogenic form. The M23 and S33 protease families are represented with >14 members in Leptospira. The differential expression under physiological temperature (37 °C) and osmolarity (300 mOsM) showed that proteases belonging to the catalytic type of Metallo-peptidases are upregulated significantly in pathogenic conditions. In silico prediction and characterization of the proteases revealed that several proteases are membrane anchored and secretory, classical as well as non-classical system. The study demonstrates the diversity and complexity of proteases, while maintaining conservation across the serovars in Leptospira and their differential expression under pathogenic conditions.