From nature to cancer therapy: Evaluating the Streptomyces clavuligerus secondary metabolites for potential protein kinase inhibitors.

The study aimed to evaluate the antioxidant, protein kinase inhibitory (PKIs) potential, cytotoxicity activity of Streptomyces clavuligerus extract. DPPH assay revealed a robust free radical scavenging capacity (IC50 28.90 ± 0.24 µg/mL) of organic extract with a maximum inhibition percentage of 61 ± 1.04%. PKIs assay revealed the formation of a whitish bald zone by S. clavuligerus extracts which indicates the presence of PKIs. The cytotoxicity activity of organic fraction of extract through Sulforhodamine B assay on MCF-7, Hop-62, SiHa, and PC-3 cell lines demonstrated the lowest GI50 value against the MCF-7 cell line followed by the PC-3 cell line, showing potent growth inhibitory potential against human breast cancer and human prostate cancer cell line. HR-LCMS analysis identified multiple secondary metabolites from the organic and aqueous extracts of S. clavuligerus when incubated at 30°C under 200 rpm for 3 days. All the secondary metabolites were elucidated for their potential to inhibit RTKs by molecular docking, molecular dynamic simulation, MM/GBSA calculations, and free energy approach. It revealed the superior inhibitory potential of epirubicin (Epi) and dodecaprenyl phosphate-galacturonic acid (DPGA) against fibroblast growth factors receptor (FGFR). Epi also exhibited excellent inhibitory activity against the platelet-derived growth factor receptor (PDGFR), while DPGA effectively inhibited the vascular endothelial growth factor receptor. Additionally, the presence Epi in S. clavuligerus extract was validated through the HPLC technique. Thus, our findings highlight a superior inhibitory potential of Epi against FGFR and PDGFR RTKs than the FDA-approved drug.

A comprehensive review on ayurvedic herb Leptadenia reticulata (Jeevanti): a phytochemistry and pharmacological perspective.

Leptadenia reticulata is a vital Ayurvedic medicinal herb, commonly known as Jivanti or Jiv, and contains revitalising, rejuvenating, and lactogenic activities. It has been used in traditional medicine for treating respiratory disorders, wounds, inflammation, cough, dehydration, tuberculosis, colitis, chickenpox, dysentery, eye diseases, night blindness, fever, and snake bites. It is a perennial herb of Indian origin belonging to the Asclepiadaceae family and has been utilised for its therapeutic properties since ancient times. It is a key ingredient in several marketed herbal drugs, including chyawanprash, speman, and leptaden. Several potent compounds, including ß-sitosterol, γ-sitosterol, phytol, α-amyrin, ß-amyrin, apigenin, reticulin, deniculatin, leptaculatin, diosmetin, and rutin are present in this herb and attributed various pharmacological activities, including antidiabetic, antimicrobial, antioxidant, anti-abortifacient, anticancer, antipyretic, analgesic, anti-inflammatory, and antiulcer properties. This review provides an in-depth analysis of the distribution, ethnobotanical use, botanical description, phytocompounds, and pharmacological activities of Leptadenia reticulata.

Leptadenia reticulata is a vital Ayurvedic herb containing revitalising, rejuvenating, and lactogenic activities.It is present in polyherbal formulations chyawanprash, speman, and leptaden.Its secondary metabolites have anticancer, anticholesterol, antidiabetic, antiabortifacient, and anti-inflammatory potential.This review shows the distribution, morphology, and therapeutic potential of Leptadenia reticulata.A summary of the phytochemicals present in Leptadenia reticulata will also be provided.

A Cross-Sectional Survey on the Use of Tobacco, Attempts on Cessation, and Locus of Control Among College Students.

Background Socio-cultural considerations (such as drug availability) and psychological traits play a significant role in predicting whether a person will use drugs in the future and dependency on the drugs. Second-, third-, and fourth-hand smoking and E-cigarettes are influencing factors for the use of tobacco in college students. This study conducted research to ascertain whether there is a potential relationship between tobacco consumption and various factors, including internal and external control sites and demographics. Materials and methods Participants in the study were found by walk-up distribution at multiple campus-wide smoking places, department announcements, and on-campus advertisements. Social media and participant references were also used in this study as recruitment tools. In addition, the locus of control questionnaire also identifies if the participating individual had extrinsic or intrinsic reinforcing routines. The classification of the participating individuals into respective internal and external locus of control was in accordance with their response survey after which a statistical analysis was done. Results This study found an association between smoking on campus and reported attempts to quit. Additionally, there is a strong association (r(85) = 0.31, p < 0.01) between reported tobacco use status and cigarette use on campus. Participants' gender and smoking status also had r(85) = 0.39, p-value < 0.01 correlation. The bulk of respondents indicated that they were seniors and off-campus living concluding for 36% (n = 34) and 60% (n = 51) of the total. Twenty-seven percent (n = 24) of the respondents were first-year college students and the rest 33% (n = 29) said their parents had no college education at all or incomplete college education. Conclusion Whenever there is a strong perception of organizational support for anti-tobacco policies, and improving compliance, there is a drastic increase in cigarette cessation and a drop in tobacco usage among those who still smoke. Perceived organizational support is strongly and positively connected with cessation among the organization's members.

Evaluation of Position of Mental Foramen in Dentulous Population by Digital Panoramic Radiography.

Need for the Study: The mental branch of the trigeminal nerve, which supplies sensation to the lower lip, originates in the mandibular canal, making it an essential anatomical structure for dentists and oral surgeons to access. It is not well known that there is a spectrum of normal that includes variants in which there may be more than one nerve entry site, which means that if the mental foramen is not protected, normal feeling in the lower lip may be lost permanently. The diagnostic value of global radiographic landmarks like the mandibular trench and the dental foramen in identifying skeletal problems has been investigated. Materials and Methods: Four hundred patients over 40 who fit the inclusion/exclusion criteria were chosen. Patients were recruited from Vananchal Dental College and Hospital, Garhwa's Out Patient section for Oral Medicine, Diagnosis, and Radiology. The following patients with their consent are subjected for digital orthopantomography (Cephalometric Device for Rotograph EVOD Ref 930790001, SN 14112930, Villa Sistem Medical) and the captured images are then interpreted for the variations in mandibular canal. Result: The results of our study are as follows: In this study, the mean age of the subjects was 47.27 years, with a range of 40-75 yearsMajority of cases were females (53.75%) and 46.25% were males.The top of the residual ridge, located between the mental foramen and the mandibular canal, is clearly visible to all observers (grade I).Only 1.75% of the people surveyed had a bifid canal, despite the fact that the majority of the people surveyed had a single mandibular canal on both sides (98.25%).Right side mean was 18,682.017, whereas left side mean was 16,331.851; nevertheless, this difference was not statistically significant (P = 0.0860 NS). Conclusion: The dental foramen was located close to where the mandible and the area housing the next premolar met. These findings may be utilized to improve the safety of peri-apical surgical procedures. Therefore, it is therapeutically relevant to get insight into the structural alterations of the mental foramen and locate its location in preoperative radiological scans.

Exploring plant-based alpha-glucosidase inhibitors: promising contenders for combatting type-2 diabetes.

Objective: This systematic review aimed to provide comprehensive details on the α-G inhibitory potential of various bioactive compounds derived from natural sources.Methods: A comprehensive literature search was conducted using various databases and search engines, including Science Direct, Google Scholar, SciFinder, Web of Science, and PubMed until May, 2023.Results and conclusions: The enzyme alpha-glucosidase (α-G) is found in the brush border epithelium of the small intestine and consists of duplicated glycoside hydrolase (GH31) domain. It involves the conversion of disaccharides and oligosaccharides into monosaccharides by acting on alpha (1 → 4) and (1 → 6) linked glucose residue. Once absorbed, glucose enters the bloodstream and elevates postprandial glucose, which is associated with the development of type 2 Diabetes (T2D). Epidemic obesity, cardiovascular disease, and nephropathy are linked to T2D. Traditional medicinal plants with α-G inhibitory potential are commonly used to treat T2D due to the adverse effects of currently used α-G inhibitors miglitol, acarbose, and voglibose. Various bioactive compounds derived from natural sources, including lupenone, Wilforlide A, Baicalein, Betulinic acid, Ursolic acid, Oleanolic acid, Katononic acid, Carnosol, Hypericin, Astilbin, lupeol, betulonic acid, Fagomine, Lactucaxanthin, Erythritol, GP90-1B, Procyanidins, Galangin, and vomifoliol retain α-G inhibitory potential for regulating hyperglycaemia.

Phytochemical profiling and evaluation of the antidiabetic potential of Ichnocarpus frutescens (Krishna Sariva): kinetic study, molecular modelling, and free energy approach.

This research explored novel antidiabetic drugs from natural sources using the Ayurvedic Rasayana herb Ichnocarpus frutescens through invitro enzyme assay, kinetics study, and computational approaches. Invitro enzyme inhibition assay demonstrated the promising inhibitory activity of root extract against alpha-amylase (α-A) and alpha-glucosidase (α-G) enzyme with IC50 value 7.34 ± 0.22 mg/ml and 4.40 ± 0.25 mg/ml respectively. Enzyme kinetic study revealed the competitive inhibition of both proteins by Ichnocarpus frutescens extract. High-Resolution Liquid Chromatography Mass Spectrometer and Docking study revealed the better binding energy of phytoconstituents 23-Acetoxysoladulcidine, Atrovirinone, Bismurrayaquinone A, Lamprolobine, Zygadenine, and Gambiriin A3 than standard drug acarbose. Molecular modelling showed stable protein-ligands binding interaction during the 100 ns simulation. It revealed comparable Root Mean Square Deviation, Radius of Gyration, and Solvent Accessible Surface Area of these compounds with acarbose. The active site residues of both proteins remained stable and showed significantly less Root Mean Square Fluctuation. Molecular Mechanics with Generalised Bonn Surface Area analysis has illustrated the similar inhibitory activity of Zygadenine for α-A, 23-Acetoxysoladulcidine, and Gambiriin A3 for α-G protein, compared to the FDA-approved drug acarbose. Thus, the study suggested that the root of Ichnocarpus frutescens can be used as α-A and α-G inhibitors and be considered a compelling lead for the medication of type 2 diabetes.Communicated by Ramaswamy H. Sarma.

Atrovirinone, 23-Acetoxysoladulcidine, Bismurrayaquinone A, Gambiriin A3, Zygadenine, and Lamprolobine are the major phytoconstituents identified from Ichnocarpus frutescens.The computational study suggested that this compound possesses α-A and α-G inhibition potential.Invitro study confirmed the competitive mode of inhibition of both enzymes by root extract of Ichnocarpus frutescens.The antidiabetic potential of Ichnocarpus frutescens was investigated for the first time by kinetic study and insilico approach.

HR-LCMS and evaluation of anti-diabetic activity of Hemidesmus indicus (anantmool): Kinetic study, and molecular modelling approach.

This study delved into the exploration of novel antidiabetic medications acquired from natural resources, utilizing the Ayurvedic Rasayana herb Hemidesmus indicus through cutting-edge chemoprofiling and molecular modelling techniques. The methanolic extract of Hemidesmus indicus root exhibited the highest extractive yield (24.70 ± 0.08 %) and contained substantial levels of total phenolic and flavonoid content as 154.15 ± 1.24 mg Gallic Acid Equivalent/g extract and 70.61 ± 0.35 Quercetin Equivalent/g extract respectively. Invitro study revealed the potent inhibitory potential of methanolic extract of the herb against essential carbohydrate hydrolytic enzymes α-amylase (IC50 = 4.19 ± 0.04 mg/ml) and α-glucosidase (IC50 = 5.78 ± 0.10 mg/ml). Further, the enzyme kinetic study demonstrated the competitive mode of inhibition of both enzymes. HR-LCMS analysis identified the major phytoconstituents present in the extracts, including Solanocapsine, Cyclovirobuxine C, Lucidine B, Zygadenine, Aspidospermidine, silychristin, 3beta-3-Hydroxy-18-lupen-21-one, Manglupenone, and 19-Noretiocholanolone. Molecular docking, molecular dynamic simulation, and MM/GBSA analysis have proved stable, rigid, compact, and folded form of complexes during the entire 100 ns simulation, illustrating Zygadenine, Solanocapsine, and Cyclovirobuxine C as the superior inhibitors of α-A protein, while Zygadenine, Plumieride, and Phlegmarine exhibited greater inhibitory behaviour towards α-G protein than the FDA-approved drug acarbose. Collectively, our findings indicate that the Hemidesmus indicus could be a promising source of α-A and α-G inhibitors, potentially serving as a lead in order to develop medications for type-2 diabetes.

Discovery of the allosteric inhibitor from actinomyces metabolites to target EGFRCSTMLR mutant protein: molecular modeling and free energy approach.

EGFR (epidermal growth factor receptor), a surface protein on the cell, belongs to the tyrosine kinase family, responsible for cell growth and proliferation. Overexpression or mutation in the EGFR gene leads to various types of cancer, i.e., non-small cell lung cancer, breast, and pancreatic cancer. Bioactive molecules identified in this genre were also an essential source of encouragement for researchers who accomplished the design and synthesis of novel compounds with anticancer properties. World Health Organization (WHO) report states that antibiotic resistance is one of the most severe risks to global well-being, food safety, and development. The world needs to take steps to lessen this danger, such as developing new antibiotics and regulating their use. In this study, 6524 compounds derived from Streptomyces sp. were subjected to drug-likeness filters, molecular docking, and molecular dynamic simulation for 1000 ns to find new triple mutant EGFRCSTMLR (EGFR-L858R/T790M/C797S) inhibitors. Docking outcomes revealed that five compounds showed better binding affinity (- 9.074 to - 9.3 kcal/mol) than both reference drug CH7233163 (- 6.11 kcal/mol) and co-crystallized ligand Osimertinib (- 8.07 kcal/mol). Further, molecular dynamic simulation confirmed that ligand C_42 exhibited the best interaction at the active site of EGFR protein and comprised a better average radius of gyration (3.87 Å) and average SASA (Solvent Accessible Surface Area) (82.91 Å2) value than co-crystallized ligand (4.49 Å, 222.38 Å2). Additionally, its average RMSD (Root Mean Square Deviation) (3.25 Å) and RMSF (Root Mean Square Fluctuation) (1.54 Å) values were highly similar to co-crystallized ligand (3.07 Å, 1.54 Å). Compared to the reference ligand, it also demonstrated conserved H-bond interactions with the residues MET_793 and GLN_791 with strong interaction probability. In conclusion, we have found a potential drug with no violation of the rule of three, Lipinski's rule of five, and 26 other vital parameters having great potential in medicinal and pharmaceutical industries applications and can overcome synthetic drug issues.

An Exploratory Research Comparing Oral Health, Pattern of Substance Abuse and Nicotine Dependence among LGBT, Female Sex Workers and Heterogenders.

AIM: Lesbian, gay, bisexual, transgender, and queer (LGBTQ), female sex workers (FSW), and heterogenders are those unconventional groups of the society who are identified with major unacceptance. Thus, the present study is conducted to assess and compare the oral health status, substance abuse pattern and nicotine dependence using Fagerstrom nicotine dependence scale (FNDP) among the LGBTQ, FSW, and heterogender in a defined location of Gautam Buddha Nagar, district in West U.P. MATERIALS AND METHODS: The present exploratory research included three study groups, the LGBTQ, FSW, and heterogenders (HG) residing in the same habitat. Purposive snowball sampling was conducted for the accessibility of the unapproachable population in the defined geographical location at Gautam Budha Nagar, district in West Uttar Pradesh. The data collection of a total of 177 participants was done using a pre-validated, pretested proforma consisting of three different parts including WHO oral health assessment form for adults, 2013, questionnaire regarding pattern of substance abuse and FNDS. Data were recorded and statistically analyzed using SPSS. RESULTS: Prevalence of oral health disorders including dental caries, periodontal disease as well as oral mucosal lesions were more commonly found among the LGBTQ participants followed by FSW and the differences were found to be statistically significant. In context of altered habits, 100% of the participants in the present study were reported with smokeless tobacco habits whereas majority of the FSW were reported with a habit of smoking tobacco. CONCLUSION: In addition to belonging to ethnic and sexual minority, and having minimal or low education status, and low socioeconomic status, the present study groups are reported to have suboptimal access to quality healthcare and are further reported with high level of substance abuse as well as nicotine dependence. CLINICAL SIGNIFICANCE: The present study is an attempt to provide base line data for further research and provide data to the policy makers so as to increase the healthcare access to the present groups. How to cite this article: Sharma S, Shukla S, Kamate SK, et al. An Exploratory Research Comparing Oral Health, Pattern of Substance Abuse and Nicotine Dependence among LGBT, Female Sex Workers and Heterogenders. J Contemp Dent Pract 2023;24(12):991-997.

Aurora kinase B siRNA-loaded lactoferrin nanoparticles potentiate the efficacy of temozolomide in treating glioblastoma.

AIM: To investigate the efficacy of lactoferrin nanoparticles (LfNPs) in delivering siRNA across the blood-brain barrier to treat glioblastoma multiforme (GBM) and with an additional objective of potentiation of conventional temozolomide (TMZ) chemotherapy. METHODS: Aurora kinase B (AKB) siRNA-loaded nanoparticles (AKB-LfNPs) were prepared with milk protein, lactoferrin, by water in oil emulsion method. AKB-LfNPs were tested in cell lines and in GBM orthotopic mouse model with and without TMZ treatment. RESULTS: AKB silencing, cytotoxicity and cell cycle arrest by these LfNPs were shown to be effective on GL261 cells. Tumor growth was significantly lower in AKB-LfNPs alone and in combination with TMZ treated mice and increased the survival by 2.5-times. CONCLUSION: Treatment of AKB-LfNPs to GBM mice improves life expectancy and has potential to combine with conventional chemotherapy.

Evaluation of Antiproliferative Activity, Safety and Biodistribution of Oxaliplatin and 5-Fluorouracil Loaded Lactoferrin Nanoparticles for the Management of Colon Adenocarcinoma: an In Vitro and an In Vivo Study.

PURPOSE: Colon adenocarcinoma is the most common form of gastro intestinal tract cancer, predominantly in ageing population. Chemotherapy with 5-Fluorouracil and oxaliplatin is an indispensable treatment regimen, nevertheless having limitation of systemic toxicity and lower therapeutic index. The present study is based on evaluation of anti-proliferative potential, pharmacokinetics parameters, safety profile, biodistribution and efficacy of 5-FU/oxaliplatin loaded lactoferrin nanoparticles in cell lines and wistar rats in order to overcome the above limitation. METHODS: Nanoparticles were prepared by Water-in-oil process. The anti-proliferative efficacy and mode of cellular entry was evaluated in COLO-205 cells. The pharmacokinetics and biodistribution analysis were performed in healthy rats while efficacy and safety assay were performed in ACF induced rats. RESULTS: 5-FU and oxaliplatin loaded nanoparticles shows enhanced antiproliferative activity as compare to free drugs in COLO-205 cells. Lactoferrin nanoparticles also improve the pharmacokinetics profile, safety parameters and efficacy of 5-FU and Oxaliplatin. CONCLUSION: Lactoferrin nanoparticles demonstrated an attractive drug delivery module to manage the colon adenocarcinoma as it has improved the antiproliferative activity of 5-FU and Oxaliplatin against colon adenocarcinoma cells. Moreover, it also improves the pharmacokinetic profile and safety parameters of the same drug in wistar rat.

Receptor-mediated targeted delivery of DNA using Lactoferrin nanoparticles.

Efficient gene delivery facilitated by non-viral vectors, is comparatively safer alternative than viral carriers. Current approaches to gene delivery largely depends on methods that overcome cellular and tissue barriers impeding efficient DNA delivery. While the conventional delivery systems have the drawback of low cellular uptake and off target effects, the receptor-mediated gene delivery system has shown remarkable breakthrough. In that context exploiting the specific receptor targeting properties of lactoferrin protein, we have developed pDNA loaded lactoferrin protein nanoparticles (pDNA-LfNPs). pDNA-LfNPs were spherical in shape within the size range of 140±20nm. They were found to be resistant against nuclease digestion and stable under long storage. Additionally, LfNPs were biocompatible and have targeting ability to facilitate gene uptake by receptor mediated internalization in lactoferrin receptor expressing cell lines. It is also evident from our studies that Lf nanoparticles did not exhibit any cytotoxicity even at the highest concentration. Here we first time report the use of lactoferrin nanoparticles as a gene delivery carrier with targeting abilities.

Overcoming blood brain barrier with a dual purpose Temozolomide loaded Lactoferrin nanoparticles for combating glioma (SERP-17-12433).

Targeted delivery of drugs to the brain is challenging due to the restricted permeability across the blood brain barrier (BBB). Gliomas are devastating cancers and their positive treatment outcome using Temozolomide (TMZ) is limited due to its short plasma half-life, systemic toxicity and limited access through the blood-brain barrier (BBB). Nanoparticles made of Lactoferrin (Lf) protein, have been shown to enhance the pharmacological properties of drugs. Here, we report the specific ability of Lf nanoparticles to cross BBB and target over-expressed Lf receptors on glioma for enhanced TMZ delivery. TMZ-loaded Lf nanoparticles (TMZ-LfNPs) were prepared by our previously reported sol-oil method. While the Lf protein in the NP matrix aids in transcytosis across the BBB and preferential tumor cell uptake, the pH responsiveness leads to TMZ release exclusively in the tumor microenvironment. Delivery through LfNPs results in an enhanced and sustained intracellular concentration of TMZ in GL261 cells in vitro along with improving its in vivo pharmacokinetics and brain accumulation. TMZ-LfNPs treatment results in a significant reduction of tumor volume, higher tumor cell apoptosis and improved median survival in glioma bearing mice. These results demonstrate that LfNPs present an efficient TMZ delivery platform for an effective treatment of gliomas.

Lactoferrin nanoparticle mediated targeted delivery of 5-fluorouracil for enhanced therapeutic efficacy.

Malignant melanoma is an aggressive form of skin cancer with high mortality rates. Common treatments for malignant melanoma involve a combination of radiotherapy and chemotherapy with fluorouracil (5-FU). A major challenge with melanoma treatment is active resistance to chemotherapeutic drugs. Superior treatment outcome lies on balance involving optimum therapeutic doses and the side effects associated with dose escalation. The study aimed to efficiently entrap 5-FU in lactoferrin nanoparticles (LfNPs) in an attempt to enhance its therapeutic efficacy. 5-FU loaded lactoferrin nanoparticles (5-FU-LfNPs) were prepared by sol-oil method with a narrow size distribution of 150±20nm 5-FU-LfNPs exhibits high encapsulation efficiency (64±2.3%) and increased storage stability at 4°C. Competitive ligand binding and lysosomal colocalization studies suggested a receptor mediated uptake for LfNPs internalization in B16F10 cells. Moreover, 5-FU-LfNPs show a pH dependent drug release similar to endosomal pH (pH 5 and 6). In addition compared to free 5-FU, 5-FU- LfNPs showed a higher intracellular uptake, prolonged retention and improved cytotoxicity (2.7-fold) in melanoma cells (B16F10). To conclude, LfNPs represent a superior nano-carrier for the targeted delivery of 5-FU in melanoma cells intended for the efficient treatment of melanoma though detailed in vivo investigations are warranted.

Neuroprotective effect of curcumin-loaded lactoferrin nano particles against rotenone induced neurotoxicity.

Curcumin is known to have neuroprotective role and possess antioxidant, anti-inflammatory activities. Rotenone, a flavonoid induced neurotoxicity in dopaminergic cells is being widely studied in Parkinson's Disease (PD) research. In the present study, curcumin loaded lactoferrin nano particles prepared by sol-oil chemistry were used to protect dopaminergic cell line SK-N-SH against rotenone induced neurotoxicity. These curcumin loaded nano particles were of 43-60 nm diameter size and around 100 nm hydrodynamic size as assessed by transmission electron microscopy, atomic force microscopy and dynamic light scattering analysis respectively. The encapsulation efficiency was 61.3% ± 2.4%. Cellular uptake of curcumin through these nano particles was confirmed by confocal imaging and spectrofluorimetric analysis. The curcumin loaded lactoferrin nanoparticles showed greater intracellular drug uptake, sustained retention and greater neuroprotection than soluble counterpart. Neuroprotective activity was characterized through viability assays and by estimating ROS levels. Furthermore rotenone induced PD like features were characterized by decrease in tyrosine hydroxylase expression and increase in α-synuclein expression. Taken together curcumin loaded lactoferrin nanoparticles could be a promising drug delivery strategy against neurotoxicity in dopaminergic neurons.