MO1156,7-DIHYDROXYCOUMARIN AMELIORATE EXPERIMENTAL NEPHROLITHIASIS BY INHIBITING MLKL PHOSPHORYLATION

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Smita Prajapati ◽  
Bhawna Tomar ◽  
Anjali Srivastava ◽  
Shrikant Ramesh Mulay
Keyword(s):  
Kidney Diseases ◽  
Computational Modelling ◽  
Natural Compounds ◽  
In Vivo Studies ◽  
High Content Screening ◽  
Potential Candidate ◽  
Dynamic Simulations ◽  
Caox Crystal

Abstract Background and Aims Intrarenal deposition of organic and inorganic minerals attributes towards the pathogenesis of nephrolithiasis. Various current studies implicates crystal mineralization involves necroinflammation for the progression of crystal induced chronic kidney diseases (CKD). We hypothesized that 6,7-dihydroxycoumarin (6,7-DHC) inhibits calcium oxalate (CaOx) induced necroptosis and ameliorates nephrolithiasis. Method We used an in vitro unbiased high content screening for identifying natural compounds that inhibits CaOx induced necroptosis. Molecular docking and molecular dynamic simulations were done to study the interaction between 6,7-DHC - MLKL. Further, for in vivo studies mice and rats models of nephrolithiasis were used. Renal injuries, CaOx deposition and fibrosis were evaluated using histological analysis. Protein expressions were assessed using immunoblots. Data was analysed using one way ANOVA. Results An unbiased in vitro high content screening of a library of 24 natural compounds identified 6,7-DHC as a potential candidate. Further, pretreatment with 6,7-DHC protected human and mouse cells from CaOx crystal mediated necroptosis in vitro. Treatment with 6,7-DHC also protected both mice and rats from nephrolithiasis. Computational modelling have revealed 6,7-DHC interacts with MLKL and inhibits its phosphorylation by ATP which is a key event in necroptosis signaling cascade. Conclusion All together our studies indicates that 6,7-DHC owns a novel pharmacological inhibitory property towards MLKL and it could serve as a lead molecule for further development of novel coumarin based MLKL inhibitors. Moreover, our findings also suggests that 6,7-DHC could be used as a therapeutic strategy for combating nephrolithiasis.

scholarly journals Structure-function relationships in mitochondrial transcriptional condensates

2022 ◽  
Author(s):  
Marina Feric ◽  
Azadeh Sarfallah ◽  
Furqan Dar ◽  
Dmitry Temiakov ◽  
Rohit V Pappu ◽  
...  
Keyword(s):  
Structure Function ◽  
Computational Modelling ◽  
In Vivo Studies ◽  
Bulk Solution ◽  
The Core ◽  
Functional Consequences ◽  
Cellular Machinery ◽  
And Function

Phase separation organizes many membraneless structures in cells. The functional consequences of concentrating cellular machinery into biomolecular condensates, however, is largely unclear. Here, we use in vitro reconstitutions, in vivo studies, and computational modelling to uncover structure-function relationships of mitochondrial (mt-) transcriptional condensates. In vitro, we find that the core mt-transcription machinery — consisting of POLRMT, TFAM, TFB2M, and DNA — forms viscoelastic, multi-phasic condensates. Strikingly, the rates of condensate-mediated transcription are considerably lower than equivalent reactions in bulk solution. Dampened rates are associated with reduced diffusivities of components that become kinetically arrested in non-equilibrium, vesicular condensates. Perturbation of mt-components in vivo and computational simulations recapitulate the transcription-dependent reorganizations observed in vitro. Our findings demonstrate close, bidirectional interdependence between structure and function of transcriptional condensates.

scholarly journals Dental Pulp Stem Cell-Derived Secretome and Its Regenerative Potential

2021 ◽  
Vol 22 (21) ◽  
pp. 12018
Author(s):  
Julia K. Bar ◽  
Anna Lis-Nawara ◽  
Piotr Grzegorz Grelewski
Keyword(s):  
Dental Pulp ◽  
Therapeutic Potential ◽  
Nerve Tissue ◽  
In Vivo Studies ◽  
Deciduous Teeth ◽  
Cartilage Defects ◽  
Potential Candidate ◽  
Paracrine Effect

The therapeutic potential of the dental pulp stem (DSC) cell-derived secretome, consisting of various biomolecules, is undergoing intense research. Despite promising in vitro and in vivo studies, most DSC secretome-based therapies have not been implemented in human medicine because the paracrine effect of the bioactive factors secreted by human dental pulp stem cells (hDPSCs) and human exfoliated deciduous teeth (SHEDs) is not completely understood. In this review, we outline the current data on the hDPSC- and SHED-derived secretome as a potential candidate in the regeneration of bone, cartilage, and nerve tissue. Published reports demonstrate that the dental MSC-derived secretome/conditional medium may be effective in treating neurodegenerative diseases, neural injuries, cartilage defects, and repairing bone by regulating neuroprotective, anti-inflammatory, antiapoptotic, and angiogenic processes through secretome paracrine mechanisms. Dental MSC-secretomes, similarly to the bone marrow MSC-secretome activate molecular and cellular mechanisms, which determine the effectiveness of cell-free therapy. Many reports emphasize that dental MSC-derived secretomes have potential application in tissue-regenerating therapy due to their multidirectional paracrine effect observed in the therapy of many different injured tissues.

scholarly journals The Role of Selected Natural Biomolecules in Sperm Production and Functionality

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5196
Author(s):  
Eva Tvrdá ◽  
Filip Benko ◽  
Tomáš Slanina ◽  
Stefan S. du Plessis
Keyword(s):  
Molecular Mechanisms ◽  
Structural Integrity ◽  
Biological Effects ◽  
Natural Compounds ◽  
In Vivo Studies ◽  
Dna Integrity ◽  
Sperm Production ◽  
Reproductive Dysfunction

Emerging evidence from in vivo as well as in vitro studies indicates that natural biomolecules may play important roles in the prevention or management of a wide array of chronic diseases. Furthermore, the use of natural compounds in the treatment of male sub- or infertility has been proposed as a potential alternative to conventional therapeutic options. As such, we aimed to evaluate the effects of selected natural biomolecules on the sperm production, structural integrity, and functional activity. At the same time, we reviewed their possible beneficial or adverse effects on male reproductive health. Using relevant keywords, a literature search was performed to collect currently available information regarding molecular mechanisms by which selected natural biomolecules exhibit their biological effects in the context of male reproductive dysfunction. Evidence gathered from clinical trials, in vitro experiments and in vivo studies suggest that the selected natural compounds affect key targets related to sperm mitochondrial metabolism and motion behavior, oxidative stress, inflammation, DNA integrity and cell death. The majority of reports emphasize on ameliorative, stimulating and protective effects of natural biomolecules on the sperm function. Nevertheless, possible adverse and toxic behavior of natural compounds has been indicated as well, pointing out to a possible dose-dependent impact of natural biomolecules on the sperm survival and functionality. As such, further research leading to a deeper understanding of the beneficial or adverse roles of natural compounds is necessary before these can be employed for the management of male reproductive dysfunction.

Prevention of abdominal adhesion by a polycaprolactone/phospholipid hybrid film containing quercetin and Ag nanoparticles

Nanomedicine ◽  
2021 ◽  
Author(s):  
Reza Hosseinpour-Moghadam ◽  
Shahram Rabbani ◽  
Arash Mahboubi ◽  
Sayyed Abbas Tabatabai ◽  
Azadeh Haeri
Keyword(s):  
Sustained Release ◽  
Histochemical Staining ◽  
In Vivo Studies ◽  
In Vitro Tests ◽  
Potential Candidate ◽  
Control Groups ◽  
Coating Films ◽  
Poly Caprolactone

Aim: To develop quercetin-loaded poly(caprolactone) (PCL)/soybean phosphatidylcholine (PC) films coated with silver (Ag) to prevent the formation of postoperative adhesions (POA). Materials & methods: Films were prepared using the solvent casting method, coated with Ag, and underwent  in vitro tests. In vivo studies were conducted employing an animal model of sidewall defect and cecum abrasion. Results: Films showed sustained release behavior of quercetin and Ag. Coating films with Ag improved their antimicrobial activity. In vivo studies confirmed superior antiadhesion properties of films compared with the control groups evaluated by gross observation, histochemical staining and immunohistochemistry analyses. Conclusion: Ag-Q-PCL-PC films are a potential candidate to prevent POA by acting as a sustained release delivery system and physical barrier.

scholarly journals Fluctuations of Histone Chemical Modifications in Breast, Prostate, and Colorectal Cancer: An Implication of Phytochemicals as Defenders of Chromatin Equilibrium

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 829 ◽  
Author(s):  
Marek Samec ◽  
Alena Liskova ◽  
Lenka Koklesova ◽  
Veronika Mestanova ◽  
Maria Franekova ◽  
...  
Keyword(s):  
Cancer Research ◽  
Chromatin Structure ◽  
Natural Compounds ◽  
In Vivo Studies ◽  
Regulation Of Transcription ◽  
Natural Substances ◽  
Incidence And Mortality ◽  
Posttranslational Histone Modifications

Natural substances of plant origin exert health beneficiary efficacy due to the content of various phytochemicals. Significant anticancer abilities of natural compounds are mediated via various processes such as regulation of a cell’s epigenome. The potential antineoplastic activity of plant natural substances mediated by their action on posttranslational histone modifications (PHMs) is currently a highly evaluated area of cancer research. PHMs play an important role in maintaining chromatin structure and regulating gene expression. Aberrations in PHMs are directly linked to the process of carcinogenesis in cancer such as breast (BC), prostate (PC), and colorectal (CRC) cancer, common malignant diseases in terms of incidence and mortality among both men and women. This review summarizes the effects of plant phytochemicals (isolated or mixtures) on cancer-associated PHMs (mainly modulation of acetylation and methylation) resulting in alterations of chromatin structure that are related to the regulation of transcription activity of specific oncogenes, which are crucial in the development of BC, PC, and CRC. Significant effectiveness of natural compounds in the modulation of aberrant PHMs were confirmed by a number of in vitro or in vivo studies in preclinical cancer research. However, evidence concerning PHMs-modulating abilities of plant-based natural substances in clinical trials is insufficient.

scholarly journals The Cancer Chemopreventive and Therapeutic Potential of Tetrahydrocurcumin

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 831 ◽  
Author(s):  
Ching-Shu Lai ◽  
Chi-Tang Ho ◽  
Min-Hsiung Pan
Keyword(s):  
Therapeutic Potential ◽  
In Vivo Studies ◽  
Potential Candidate ◽  
Solubility In Water ◽  
Xenobiotic Detoxification ◽  
Naturally Occurring ◽  
Anti Cancer ◽  
Effective Drugs

In recent decades, cancer has been one of the leading causes of death worldwide. Despite advances in understanding the molecular basis of tumorigenesis, diagnosis, and clinical therapies, the discovery and development of effective drugs is an active and vital field in cancer research. Tetrahydrocurcumin is a major curcuminoid metabolite of curcumin, naturally occurring in turmeric. The interest in tetrahydrocurcumin research is increasing because it is superior to curcumin in its solubility in water, chemical stability, bioavailability, and anti-oxidative activity. Many in vitro and in vivo studies have revealed that tetrahydrocurcumin exerts anti-cancer effects through various mechanisms, including modulation of oxidative stress, xenobiotic detoxification, inflammation, proliferation, metastasis, programmed cell death, and immunity. Despite the pharmacological similarities between tetrahydrocurcumin and curcumin, the structure of tetrahydrocurcumin determines its distinct and specific molecular mechanism, thus making it a potential candidate for the prevention and treatment of cancers. However, the utility of tetrahydrocurcumin is yet to be evaluated as only limited pharmacokinetic and oral bioavailability studies have been performed. This review summarizes research on the anti-cancer properties of tetrahydrocurcumin and describes its mechanisms of action.

scholarly journals Resveratrol: A Double-Edged Sword in Health Benefits

Biomedicines ◽  
2018 ◽  
Vol 6 (3) ◽  
pp. 91 ◽  
Author(s):  
Bahare Salehi ◽  
Abhay Mishra ◽  
Manisha Nigam ◽  
Bilge Sener ◽  
Mehtap Kilic ◽  
...  
Keyword(s):  
Current Data ◽  
In Vivo Studies ◽  
Natural Food ◽  
Potential Candidate ◽  
Food Ingredient ◽  
Anticancer Properties ◽  
Trans Stilbene ◽  
Bacteria And Fungi

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) belongs to polyphenols’ stilbenoids group, possessing two phenol rings linked to each other by an ethylene bridge. This natural polyphenol has been detected in more than 70 plant species, especially in grapes’ skin and seeds, and was found in discrete amounts in red wines and various human foods. It is a phytoalexin that acts against pathogens, including bacteria and fungi. As a natural food ingredient, numerous studies have demonstrated that resveratrol possesses a very high antioxidant potential. Resveratrol also exhibit antitumor activity, and is considered a potential candidate for prevention and treatment of several types of cancer. Indeed, resveratrol anticancer properties have been confirmed by many in vitro and in vivo studies, which shows that resveratrol is able to inhibit all carcinogenesis stages (e.g., initiation, promotion and progression). Even more, other bioactive effects, namely as anti-inflammatory, anticarcinogenic, cardioprotective, vasorelaxant, phytoestrogenic and neuroprotective have also been reported. Nonetheless, resveratrol application is still being a major challenge for pharmaceutical industry, due to its poor solubility and bioavailability, as well as adverse effects. In this sense, this review summarized current data on resveratrol pharmacological effects.

scholarly journals Tetrandrine alleviates podocyte injury via calcium-dependent calpain-1 signaling blockade

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yin Ding ◽  
Xuanli Tang ◽  
Yuhui Wang ◽  
Dongrong Yu ◽  
Caifeng Zhu ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Kidney Diseases ◽  
In Vivo Studies ◽  
Chinese Drug ◽  
Calpain Activity ◽  
Podocyte Injury ◽  
Intracellular Ca

Abstract Background Podocytes have become a crucial target for interventions in proteinuric kidney diseases. Many studies have reported that overexpression of transient receptor potential cation channel protein 6 (TRPC6) in podocyte injury upregulates intracellular Ca2+ influx and stimulates Ca2+-dependent protease calpain-1 signaling. The traditional Chinese drug, tetrandrine, a nonselective Ca2+ channel blocker, has long been used to treat chronic kidney disease. This research aimed to explore the possible mechanisms underlying the anti-proteinuric properties of tetrandrine. Methods We investigated the involvement of tetrandrine in Ca2+ dependent calpain-1 signaling in mouse podocytes and adriamycin-induced nephropathy rats. Cyclosporine A (CsA) and U73122 were used as positive controls. Cell viability, cytotoxicity, Ca2+ concentration, calpain activity, and mRNA and protein expression levels of calpain-1 signaling pathways were examined. The clinical and pathological changes were measured. Results Tetrandrine decreased intracellular Ca2+ influx in cultured TRPC6-overexpressing podocytes. In both in vitro and in vivo studies, the administration of tetrandrine downregulated calpain activity and the expression of calpain-1 and restored the expression of downstream Talin-1 and nephrin. Compared to CsA, tetrandrine treatment exhibited superior inhibitory effects on calpain activity and calpain-1 expression. Conclusions Tetrandrine has therapeutic potential in podocyte damage by blocking Ca2+-dependent activation of the calpain-1 signaling pathway. Tetrandrine reduced proteinuria, improved renal function, and alleviate renal pathological damage.

scholarly journals Drug Delivery Systems of Natural Products in Oncology

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4560 ◽  
Author(s):  
Marisa Colone ◽  
Annarica Calcabrini ◽  
Annarita Stringaro
Keyword(s):  
Drug Delivery ◽  
Natural Products ◽  
Specific Activity ◽  
Natural Compounds ◽  
Delivery Systems ◽  
In Vivo Studies ◽  
Cellular Mechanisms ◽  
Anticancer Efficacy

In recent decades, increasing interest in the use of natural products in anticancer therapy field has been observed, mainly due to unsolved drug-resistance problems. The antitumoral effect of natural compounds involving different signaling pathways and cellular mechanisms has been largely demonstrated in in vitro and in vivo studies. The encapsulation of natural products into different delivery systems may lead to a significant enhancement of their anticancer efficacy by increasing in vivo stability and bioavailability, reducing side adverse effects and improving target-specific activity. This review will focus on research studies related to nanostructured systems containing natural compounds for new drug delivery tools in anticancer therapies.

scholarly journals Identification of Natural Compounds (Proanthocyanidin and Rhapontin) as High-Affinity Inhibitor of SARS-CoV-2 Mpro and PLpro using Computational Strategies

2021 ◽  
Author(s):  
Mohamed AlAjmi ◽  
Asim Azhar ◽  
Sadaf Hasan ◽  
Abdullah Alshabr ◽  
Afzal Hussain ◽  
...  
Keyword(s):  
Hydrophobic Interactions ◽  
Economic Loss ◽  
Natural Compounds ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
In Vivo Studies ◽  
Protein Inhibitor ◽  
Active Site Residues

IntroductionThe emergence of a new and highly pathogenic coronavirus (SARS-CoV-2) in Wuhan (China) and its spread worldwide has resulted in enormous social and economic loss. Amongst many proteins encoded by SARS-CoV-2 genome, the main protease (Mpro) or chymotrypsin-like cysteine protease (3CLpro) and Papain-like protease (PLpro) serve as an attractive drug target.Material and methodsWe screened a library of 2267 natural compounds against Mpro and PLpro using high throughput virtual screening (HTVS). 50 top-scoring compounds against each protein in HTVS were further evaluated by standard-precision (SP) docking. Compounds with SP docking energy of ≤ -8.0 kcal mol-1 against Mpro and ≤ -5.0 kcal mol-1 against PLpro were subjected to extra-precision (XP) docking. Finally, six compounds against each target proteins were identified and subjected to Prime/MM-GBSA free energy calculations. Compounds with the lowest Prime/MM-GBSA energy were subjected to molecular dynamics simulation to evaluate the stability of protein-ligand complexes.ResultsProanthocyanidin and Rhapontin were identified as the most potent inhibitors of Mpro and PLpro, respectively. Analysis of protein-inhibitor interaction revealed that both protein-inhibitor complexes were stabilized by hydrogen bonding and hydrophobic interactions. Proanthocyanidin interacted with the catalytic residues (His41 and Cys145) of Mpro, while Rhapontin contacted the active site residues (Trp106, His272, Asp286) of PLpro. The docking energies of Proanthocyanidin and Rhapontin towards their respective targets were -10.566 and -10.022 kcal/mol.ConclusionsThis study's outcome may serve Proanthocyanidin and Rhapontin as a scaffold to build more potent inhibitors with desirable drug-like properties. However, it requires further validations by in vitro and in vivo studies.

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