Recent advancements in Cancer Targeting Therapy with the Hyaluronic Acid as a Potential Adjuvant / Avances recientes en la terapia dirigida al cáncer con el ácido hialurónico como adyuvante potencial

Introducción: El compuesto natural no sulfatado, el ácido hialurónico (HA), es un mucopolisacárido que tiene un papel esencial en la biología celular, es un elemento fundamental de la célula viva. Ha juega un papel esencial en la administración dirigida de medicamentos, recientemente ha adquirido mucha atención debido a varias ventajas como la biocompatibilidad, la biodegradabilidad, la no inmunogenicidad y la no toxicidad. Métodos: Esta revisión narrativa se basa en la literatura buscada en PubMed y la base de datos de Elsevier desde enero a mayo de 2021 utilizando las siguientes palabras clave: “Hyaluronic acid”, “Hyaluronic acid in cancer thera-py”, “Hyaluronic acid in cancer targeting”, “Hyaluronic acid in drug targeting”. Se consideraron las investigaciones publicadas en los últimos cinco años, sin embargo, en las referencias cruzadas, no se siguió tal línea de tiempo. Resultados: A partir de la literatura, se encuentra que HA puede reconocer distintos receptores que se revelan anormalmente en grandes cantidades en la superficie exterior de tejidos o células cancerosas; por lo tanto, se pue-de usar para la conjugación con fármacos contra el cáncer, lo que facilita su actividad terapéutica mejorada sobre las células cancerosas que las células normales. También se encuentra que los sistemas de administración de fár-macos basados en HA proporcionan mayor estabilidad y solubilidad de los agentes anticancerígenos en entornos biológicos. Con base a estos hallazgos y ventajas, el HA se ha investigado abundantemente como un biomaterial prometedor para la evolución de varios sistemas de administración como micelas, liposomas, hidrogeles, nanopar-tículas, etc. Según investigaciones recientes, el sistema basado en HA proporciona inmunoterapia, terapia génica, quimioterapia dirigida y terapia combinada con enormes aplicaciones en la evolución de una terapia altamente eficaz y rentable para el tratamiento del cáncer. (AU)

Introduction: The non-sulfated natural compound, Hyaluronic acid (HA), is a mucopolysaccharide that has an es-sential role in cellular biology; it is a fundamental element of the living cell. HA plays an essential role in targeted drug delivery; it has recently acquired much attention because of various advantages like biocompatibility, biode-gradability, non-immunogenicity, and non-toxicity. Methods: This narrative review is based on the literature searched with keywords Hyaluronic acid, Hyaluronic acid in cancer therapy, Hyaluronic acid in cancer targeting, Hyaluronic acid in drug targeting, was done on PubMed and Elsevier database from January to May 2021. Research published in the last five years was considered; however, no such timeline is followed in cross-referencing. Results: From the literature, it is found that HA can recognize distinct receptors that are abnormally revealed in large numbers on the outer surface of cancerous tissues or cells; hence can be used for conjugation with anticancer drugs, facilitating their enhanced therapeutic activity over the cancer cells than normal cells. It is also found that HA-based systems also provide increased stability and solubility of anticancer agents in biological surroundings. Based on these findings and advantages, HA is conjugated with various delivery systems like micelles, liposomes, hydrogels, nanoparticles, etc. As per recent research, the HA-based system provides immunotherapy, gene therapy, targeted chemotherapy, and combination therapy with enormous applications in the evolution of highly efficacious and cost-effective therapy for the ministration of cancer. (AU)

Deciphering the Potential of Pre and Pro-Vitamin D of Mushrooms against Mpro and PLpro Proteases of COVID-19: An In Silico Approach.

Vitamin D's role in combating the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus causing COVID-19, has been established in unveiling viable inhibitors of COVID-19. The current study investigated the role of pre and pro-vitamin D bioactives from edible mushrooms against Mpro and PLpro proteases of SARS-CoV-2 by computational experiments. The bioactives of mushrooms, specifically ergosterol (provitamin D2), 7-dehydrocholesterol (provitamin-D3), 22,23-dihydroergocalciferol (provitamin-D4), cholecalciferol (vitamin-D3), and ergocalciferol (vitamin D2) were screened against Mpro and PLpro. Molecular docking analyses of the generated bioactive protease complexes unravelled the differential docking energies, which ranged from -7.5 kcal/mol to -4.5 kcal/mol. Ergosterol exhibited the lowest binding energy (-7.5 kcal/mol) against Mpro and PLpro (-5.9 kcal/mol). The Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) and MD simulation analyses indicated that the generated complexes were stable, thus affirming the putative binding of the bioactives to viral proteases. Considering the pivotal role of vitamin D bioactives, their direct interactions against SARS-CoV-2 proteases highlight the promising role of bioactives present in mushrooms as potent nutraceuticals against COVID-19.

Neuroprotective effects of combined trimetazidine and progesterone on cerebral reperfusion injury.

Cerebral ischemia-reperfusion injury induces multi-dimensional damage to neuronal cells through exacerbation of critical protective mechanisms. Targeting more than one mechanism simultaneously namely, inflammatory responses and metabolic energy homeostasis could provide additional benefits to restrict or manage cerebral injury. Being proven neuroprotective agents both, progesterone (PG) and trimetazidine (TMZ) has the potential to add on the individual therapeutic outcomes. We hypothesized the simultaneous administration of PG and TMZ could complement each other to synergize, or at least enhance neuroprotection in reperfusion injury. We investigated the combination of PG and TMZ on middle cerebral artery occlusion (MCAO) induced cerebral reperfusion injury in rats. Molecular docking on targets of energy homeostasis and apoptosis assessed the initial viability of PG and TMZ for neuroprotection. Animal experimentation with MCA induced ischemia-reperfusion (I/R) injury in rats was performed on five randomized groups. Sham operated control group received vehicle (saline) while the other four I-R groups were pre-treated with vehicle (saline), PG (8 â€‹mg/kg), TMZ treated (25 â€‹mg/kg), and PG â€‹+ â€‹TMZ (8 and 25 â€‹mg/kg) for 7 days by intraperitoneal route. Neurological deficit, infarct volume, and oxidative stress were evaluated to assess the extent of injury in rats. Inflammatory reactivity and apoptotic activity were determined with alterations in myeloperoxidase (MPO) activity, blood-brain barrier (BBB) permeability, and DNA fragments. Reperfusion injury inflicted cerebral infarct, neurological deficit, and shattered BBB integrity. The combination treatment of PG and TMZ restricted cellular damage indicated by significant (p â€‹< â€‹0.05) decrease in infarct volume and improvement in free radical scavenging ability (SOD activity and GSH level). MPO activity and LPO decreased which contributed in improved BBB integrity in treated rats. We speculate that inhibition of inflammatory and optimum energy utilization would critically contribute to observed neuroprotection with combined PG and TMZ treatment. Further exploration of this neuroprotective approach for post-recovery cognitive improvement is worth investigating.

Finding potent inhibitors for COVID-19 main protease (Mpro): an in silico approach using SARS-CoV-3CL protease inhibitors for combating CORONA.

SARS-CoV-2 is liable for the worldwide coronavirus disease (COVID-19) exigency. This pandemic created the need for all viable treatment strategies available in the market. In this scenario, computer-aided drug design techniques can be efficiently applied for the quick identification of promising drug repurposing candidates. In the current study, we applied the molecular docking approach in conjugation with molecular dynamics (MD) simulations to find out potential inhibitors against Mpro of SARS-CoV-2 from previously reported SARS-3CL protease inhibitors. Our results showed that N-substituted isatin derivatives and pyrazolone compounds could be used as a potent inhibitor and may possess an anti-viral activity against SARS-CoV-2. However, further experimental investigation and validation of the selected hits are required to find out their suitability for clinical trials. Communicated by Ramaswamy H. Sarma.

Synthesis, Molecular Docking and Evaluation of 3-{4-[2-amino-4-(substitutedphenyl)-2H-[1, 3] oxazin/thiazin-6-yl} 2-phenyl-3H-quinazolin-4-one Derivatives for their Anticonvulsant Activity.

BACKGROUND: According to the WHO, around 50 million people worldwide are suffering from epilepsy. It is due to the repeated occurring of seizures. These seizures are caused by sudden which may vary from a brief lapse of attention or muscle jerks, to severe and prolonged convulsions. OBJECTIVES: The aim of the present work was to synthesize 2-phenyl substituted quinazolinone derivatives and to evaluate them for anticonvulsant and neurotoxic activity. METHODS: A series of novel 3-{4-[2-amino-4-(substitutedphenyl)-2H-[1.3] oxazin/thiazin-6-yl} 2- phenyl-3H-quinazolin-4-one derivatives were synthesized and evaluated for their anticonvulsant activity. The structures of the compound have been confirmed by spectral analysis. The molecular docking was performed for all the synthesized compounds to assess their binding mode to Gamma- aminobutyric acid type A (GABAA) receptor in order to rationalize their anticonvulsant activities in a qualitative way. Anticonvulsant activities of compounds were screened by using (Maximal electroshock) MES induced seizures and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in Wistar rats of either sex. None of the compounds demonstrated any sign of neurotoxicity. RESULT: Compounds 3-{4-[2-amino-4-(4-nitro-phenyl)-2H-[1, 3] oxazin-6-yl} 2-phenyl-3H-quinazolin- 4-one (5a) have shown significant activity against tonic seizure by the MES model and 3-{4-[2-amino- 4-(4-nitro-phenyl)-2H-[1, 3] thiazin-6-yl} 2-phenyl-3H-quinazolin-4-one (5d) against clonic seizure by scPTZ induced seizure model. CONCLUSION: All the newly synthesized compounds had significant anticonvulsant activity. The same two compounds 5a and 5d showed promising activity, while the other compounds have moderate activity. The proposed work is to effort towards the development and identification of novel molecules as anticonvulsant agents by the synthesis of some novel quinazolinone derivatives with improved biological activity.

Synthetic and Natural Monoamine Oxidase Inhibitors as Potential Lead Compounds for Effective Therapeutics.

Monoamine oxidases A and B (MAO-A and B) play a critical role in the metabolism of intracellular neurotransmitters of the central nervous system. For decades, MAO inhibitors have proven their clinical efficacy as potential drug targets for several neurological and neurodegenerative diseases. Use of first generation non selective MAO inhibitors as neuropsychiatric drugs elicited several side effects like hypertensive crisis and cheese reaction. Therefore their use is now limited due to non-selectivity towards MAO isoforms and inhibition of metabolizing enzymes like cytochrome P450. Development of selective and specific MAO inhibitors like moclobemide, toloxatone improves their efficacy as disease-modifying effects in monotherapy as well as adjunctive therapy. Recently a lot of research has been done to elucidate the pharmacological potential of medicinal plants and their isolated bioactive constituents having MAO inhibitory activity. Herbs containing MAO inhibitors are extensively used for the development of potent synthetic drugs and as safe and effective alternatives to the available synthetic drugs in the treatment of neurodegenerative diseases such as depression, Parkinson and Alzheimer's. In several diseases like Parkinson natural MAO inhibitors prevented the neuron denaturalization by their dual action via enhancing neurotransmission of dopamine as well as lowering the generation of free radicals and toxins. Currently development of selective MAO inhibitors is still under study to achieve more effective therapies by using Computer Aided Drug Designing, Ligand-based models and structure-activity hypothesis. These approaches also facilitate understanding the interaction of newly designed molecule with MAO enzymes and the rationalization of probable mechanisms of action.

Hansch Analysis of Novel Acetamide Derivatives as Highly Potent and Specific MAO-A Inhibitors.

BACKGROUND: A quantitative structure-activity relationship (QSAR) study of novel Acetamide derivatives as specific Mono amino oxidase (MAO) A inhibitory agents was performed with 28 compounds to derive QSAR models for better activity and lesser side effects. METHODS: Various thermodynamic, electronic and steric parameters were calculated using Chem 3D package of molecular modeling software Chemoffice 7.0. QSAR models were generated employing sequential multiple regression method using in-house statistical program VALSTAT. The best models were selected from the various statistically significant equations. RESULTS: The study revealed that an increase in the bulkiness of the substituent's and molecular solvent accessible surface area is beneficial to the biological activity and the substitution of two interacting groups should be separated by more than three atoms will give better biological activity. Model also suggests that the presence of the comparatively less lipophilic group may increase MAO-A inhibitory activity and substituent that decrease the flexibility and increase rigidity of the nucleus will enhance the activity. The best QSAR model was selected, having a correlation coefficient (r) = 0.93271, coefficient of determination (r2) = 0.8509 with a standard deviation of predictivity (SDEP) = 0.31287 and cross validated squared correlation coefficient (Q2) = 0.92. The predictive ability of the selected model was also confirmed by leave one out cross validation and r2 predicted (r2 pred) was 0.764. CONCLUSION: This study may be useful in the designing of more potent substituted acetamide derivatives as specific MAOA inhibitors.

In-vitro cytotoxicity study of methanolic fraction from Ajuga Bracteosa wall ex. benth on MCF-7 breast adenocarcinoma and hep-2 larynx carcinoma cell lines.

OBJECTIVE: Ajuga bracteosa Wall ex Benth (Labiatae) is popularly known in India as Neelkanthi. A decoction of the leaves, flowers, and barks is used in India for the treatment of cancer including diabetes, malaria, and inflammation etc. The main objective of this study is to investigate the cytotoxic potential of Ajuga bracteosa. MATERIALS AND METHODS: Successive solvent extraction of Ajuga bracteosa in petroleum ether, methanol, and water extracts was done. These extracts were tested against human breast adenocarcinoma (MCF-7) and larynx carcinoma (Hep-2) tumor cell lines, using the thiazolyl blue test (MTT) assay. RESULTS: The methanolic fraction of Ajuga bracteosa had shown the significant results against MCF-7 and Hep-2 tumor cell lines. The methanolic, petroleum ether and aqueous extract from Ajuga bracteosa, presented an IC50 value at 24 h of 10, 65, 70 µg/ml and 5, 30, 15 µg/ml on MCF-7 and Hep-2 cells, respectively. Steroids compounds namely ß-sitosterol and unknown constituents were identified in the most active methanol extract of Ajuga bracteosa wall ex Benth. These known and unknown compounds exhibited cytotoxic potential against MCF-7 and Hep-2 cancer cells. CONCLUSION: Among all the tested extracts, methanolic extract can be considered as potential sources of anti-cancer compounds. Further studies are necessary for more extensive biological evaluations.

Wound healing activity of Sida cordifolia Linn. in rats.

INTRODUCTION: The present study provides a scientific evaluation for the wound healing potential of ethanolic (EtOH) extract of Sida cordifolia Linn. (SCL) plant. MATERIALS AND METHODS: Excision, incision and burn wounds were inflicted upon three groups of six rats each. Group I was assigned as control (ointment base). Group II was treated with 10% EtOH extract ointment. Group III was treated with standard silver sulfadiazine (0.01%) cream. The parameters observed were percentage of wound contraction, epithelialization period, hydroxyproline content, tensile strength including histopathological studies. RESULT: It was noted that the effect produced by the ethanolic extract of SCL ointment showed significant (P < 0.01) healing in all wound models when compared with the control group. All parameters such as wound contraction, epithelialization period, hydroxyproline content, tensile strength and histopathological studies showed significant (P < 0.01) changes when compared with the control. CONCLUSION: The ethanolic extract ointment of SCL effectively stimulates wound contraction; increases tensile strength of excision, incision and burn wounds.

A novel series of 2,5-disubstituted 1,3,4-oxadiazoles: synthesis and SAR study for their anticonvulsant activity.

In search for a better anticonvulsant drug and the importance of semicarbazones and 2,5-disubstituted 1,3,4-oxadiazoles as anticonvulsant pharmacophore, a series of novel substituted semicarbazones were designed, synthesized, and evaluated for their anticonvulsant activity. The chemical structures of the synthesized molecules were confirmed by elemental and spectral (IR, (1) H NMR, (13) C NMR and MS) analysis. The anticonvulsant activities of the compounds were investigated using maximal electroshock seizure and subcutaneous pentylenetetrazole (scPTZ) models. Efforts were also made to establish structure-activity relationships among synthesized compounds. The results of the present study validated that the pharmacophore model with four binding sites is essential for anticonvulsant activity.

Synthesis and anticonvulsant evaluation of some novel 2,5-disubstituted 1,3,4-thiadiazoles: pharmacophore model studies.

A novel series of N'-{5-[(1H-indol-3-ylmethyl)-1,3,4-thiadiazol-2-yl}-N4-(4-substituted benzaldehyde)-semicarbazones, N1-{5-[(1H-indol-3-ylmethyl)-1,3,4-thiadiazol-2-yl}-N4-[1-(4-substituted phenyl)ethanone]-semicarbazones and N1-{5-[(1H-indol-3-ylmethyl)-1,3,4-thiadiazol-2-yl}-N4-[1-(4-substituted phenyl) (phenyl) methanone]-semicarbazones were synthesized and evaluated for their anticonvulsant potential using maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPFZ) models. The minimal motor impairment (neurotoxicity) was determined by rotorod test. The results of the present study confirmed the requirements of various structural features of four binding site pharmacophore model for anticonvulsant activity.

Design, synthesis and biological evaluation of some novel benzimidazole derivatives for their potential anticonvulsant activity.

Selective GABA(A) receptor ligands are widely used clinically to reduce the occurrence of convulsions. Hence there is an intense interest in developing new benzimidazole derivatives demonstrating high selectivity and high affinity for GABA(A) receptors. With the purpose of designing new chemical entities with an enhanced binding affinity for GABA(A)/BZd receptor complex, we carried out a QSAR study on benzotriazine derivatives. We studied 28 potent GABA(A) receptor ligands; derivatives of benzotriazines, using a combination of various tested physicochemical, steric, electronic and thermodynamic descriptors to determine the quantitative correlation between binding affinity and structural features. The developed and validated final model showed a good correlative and predictive ability expressed by a squared correlation co-efficient (r(2)) of 0.954. The equation indicated that the binding affinity is strongly dependent upon the thermodynamic properties (CDE, DDE and PC). Correlation between these properties and anticonvulsant activity was used to synthesize compounds possessing potent anticonvulsant activity. Most of the compounds showed an ability to inhibit the maximum electroshock (MES) and pentylenetetrazole (PTZ)-induced convulsions. Compound 1A, i.e. 2-(4-Chloro-phenyl)-5-nitro-1H-benzimidazole exhibited maximum activity in both the convulsion models.

Wound healing potential of methanolic extract of Trichosanthes dioica Roxb (fruits) in rats.

AIM OF THE STUDY: The present study provides a scientific evaluation for the wound healing potential of methanolic (MeOH) extract of TDR fruits. MATERIALS AND METHODS: Excision and incision wounds were inflicted upon three groups of six rats each. Group I was assigned as control (ointment base), Group II was treated with standard silver sulfadiazine (0.01%) cream. Group III was treated with 5% MeOH extract ointment. The parameters observed were percentage of wound contraction, epithelialization period, hydroxyproline content, tensile strength including histopathological studies. RESULTS: It was noted that the effect produced by the extract ointment showed significant (P<0.01) healing in both the wound models when compared with control group. All parameters such as wound contraction, epithelialization period, hydroxyproline content, tensile strength and histopathological studies showed significant changes when compared to control. CONCLUSION: The result shows that TDR extract ointment demonstrates wound healing potential in both excision and incision models.