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The revolutions happened in the novel drug delivery system promises the arise of a good carrier for the drug delivery. Revelation of nano particulate bearer frameworks constitute one of the descriptive word way to deal with the conveyance of pharmaceutical specialists. It's water like properties secure and monitor delicate organic particles, and this property of keeping up unity nature, generally a high level of surface presentation nature of aquasomes are used in focusing of genius dynamic atoms like peptide and protein hormones, antigen and qualities to specific dominion. Aquasome in view of modifier novel medication conveyance framework is having a decent future anticipated that due would its arrangement of giving better natural movement of conformationally delicate medication contenders and the fundamental medication contenders that conveyed through aquasomes are peptide and protein hormones. Instrument of activity of aquasomes is controlled by its surface science. They primarily convey the substance through incorporation of atomic protecting, particular focusing on, and they takes after moderate and maintained discharge process. Aquasomes having the curious sugar covering over their artistic center, these has all the earmarks of being promising bearers for the conveyance of an extensive variety of conformational tricky iotas with better common activity. Aquasome in light of self-assembled novel medication conveyance framework is having great future advantages because of its features of giving better organic action of conformationally touchy medication substances and the principle sedate elements that conveyed through aquasomes are peptide and protein hormones. [ABSTRACT FROM AUTHOR]

Upregulation of stress chaperone Mortalin has been closely linked to the malignant transformation of cells, tumorigenesis, the progression of tumors to highly aggressive stages, metastasis, drug resistance, and relapse. Various in vitro and in vivo assays have provided evidence of the critical role of Mortalin upregulation in promoting cancer cell characteristics, including proliferation, migration, invasion, and the inhibition of apoptosis, a consistent feature of most cancers. Given its critical role in several steps in oncogenesis and multi-modes of action, Mortalin presents a promising target for cancer therapy. Consequently, Mortalin inhibitors are emerging as potential anti-cancer drugs. In this review, we discuss various inhibitors of Mortalin (peptides, small RNAs, natural and synthetic compounds, and antibodies), elucidating their anti-cancer potentials.

Survivin, a member of the IAP family, functions as a homodimer and inhibits caspases, the key enzymes involved in apoptosis. Several Survivin inhibitors, including YM-155, Debio1143, EM1421, LQZ-7I, and TL32711, have emerged as potential anticancer drugs awaiting validation in clinical trials. Due to the high cost and adverse side effects of synthetic drugs, natural compounds with similar activity have also been in demand. In this study, we conducted molecular docking assays to evaluate the ability of Wi-A and Wi-N to block Survivin dimerization. We found that Wi-A, but not Wi-N, can bind to and prevent the homodimerization of Survivin, similar to YM-155. Therefore, we prepared a Wi-A-rich extract from Ashwagandha leaves (Wi-AREAL). Experimental analyses of human cervical carcinoma cells (HeLa and ME-180) treated with Wi-AREAL (0.05-0.1%) included assessments of viability, apoptosis, cell cycle, migration, invasion, and the expression levels (mRNA and protein) of molecular markers associated with these phenotypes. We found that Wi-AREAL led to growth arrest mediated by the upregulation of p21 WAF1 and the downregulation of several proteins (CDK1, Cyclin B, pRb) involved in cell cycle progression. Furthermore, Wi-AREAL treatment activated apoptosis signaling, as evidenced by reduced PARP-1 and Bcl-2 levels, increased procaspase-3, and elevated Cytochrome C. Additionally, treating cells with a nontoxic low concentration (0.01%) of Wi-AREAL inhibited migration and invasion, as well as EMT (epithelial-mesenchymal transition) signaling. By combining computational and experimental approaches, we demonstrate the potential of Wi-A and Wi-AREAL as natural inhibitors of Survivin, which may be helpful in cancer treatment.

The global spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) since 2019 has led to a continuous evolution of viral variants, with the latest concern being the Omicron (B.1.1.529) variant. In this study, classical molecular dynamics simulations were conducted to elucidate the biophysical aspects of the Omicron spike protein's receptor-binding domain (RBD) in its interaction with human angiotensin-converting enzyme 2 (hACE2) and a neutralizing antibody, comparing it to the wildtype (WT). To model the Omicron variant, 15 in silico mutations were introduced in the RBD region of WT (retrieved from PDB). The simulations of WT spike-hACE2 and Omicron spike-hACE2 complexes revealed comparable binding stability and dynamics. Notably, the Q493R mutation in the Omicron spike increased interactions with hACE2, particularly with ASP38 and ASP355. Additionally, mutations such as N417K, T478K, and Y505H contributed to enhanced structural stability in the Omicron variant. Conversely, when comparing WT with Omicron in complex with a neutralizing antibody, simulation results demonstrated poorer binding dynamics and stability for the Omicron variant. The E484K mutation significantly decreased binding interactions, resulting in an overall decrease in binding energy (∼-57 kcal/mol) compared to WT (∼-84 kcal/mol). This study provides valuable molecular insights into the heightened infectivity of the Omicron variant, shedding light on the specific mutations influencing its interactions with hACE2 and neutralizing antibodies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cancer metastasis, a highly complex process wherein cancer cells move from the primary site to other sites in the body, is a major hurdle in its therapeutics. A large array of synthetic chemotherapeutic molecules used for the treatment of metastatic cancers, besides being extremely expensive and unaffordable, are known to cause severe adverse effects leading to poor quality of life (QOL) of the patients. In this premise, natural compounds (considered safe, easily available and economic) that possess the potential to inhibit migration of cancer cells are deemed useful and hence are on demand. Cucurbitacin-B (19-(10→9β)-abeo-10-lanost-5-ene triterpene, called Cuc-B) is a steroid mostly found in plants of Cucurbitaceae family. It has been shown to possess anticancer activity although the molecular mechanism remains poorly defined. We present evidence that Cuc-B has the ability to interact with mortalin and HDM2 proteins that are enriched in cancer cells, suppress wild type p53 function and promote cancer cell migration. Computational analyses showed that Cuc-B interacts with mortalin similar to MKT077 and Withanone, both have been shown to reactivate p53 function and inhibit cell migration. Furthermore, Cuc-B interacted with HDM2 similar to Y30, a well-known inhibitor of HDM2. Experimental cell and molecular analyses demonstrated the downregulation of several proteins, critically involved in cell migration in Cuc-B (low non-toxic doses)-treated cancer cells and exhibited inhibition of cell migration. The data suggested that Cuc-B is a potential natural drug that warrants further mechanistic and clinical studies for its use in the management of metastatic cancers.Communicated by Ramaswamy H. Sarma.

Temperature-sensitive plasmids are useful for genome engineering and several synthetic biology applications. There are only limited reports on temperature-sensitive plasmids for Rhodococcus and none for Gordonia. Here, we report the construction of a temperature-sensitive pRC4 replicon that is functional in Rhodococcus and Gordonia. The amino acid residues were predicted for the temperature-sensitive phenotype in the pRC4 replicon using in silico methods and molecular simulation of the DNA-binding replication protein with the origin of replication. The amino acid residues were mutated, and the temperature-sensitive phenotype was validated in Gordonia sp. IITR100. Similar results were also observed in Rhodococcus erythropolis, suggesting that the temperature-sensitive phenotype was exhibited across genera., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Genetic mutations in p53 are frequently associated with many types of cancers that affect its stability and activity through multiple ways. The Ser46 residue present in the transactivation domain2 (TAD2) domain of p53 undergoes phosphorylation that blocks its degradation by MDM2 and leads to cell cycle arrest/apoptosis/necrosis upon intrinsic or extrinsic stresses. On the other hand, unphosphorylated p53 mutants escape cell arrest or death triggered by these molecular signaling axes and lead to carcinogenesis. Phosphorylation of Ser in the TAD2 domain of p53 mediates its interactions with transcription factor p62, yielding transcriptional activation of downstream pro-apoptotic genes. The p53 phosphorylation causes string-like elongated conformation that increases its binding affinity with the PH domain of p62. On the other hand, lack of phosphorylation causes helix-like motifs and low binding affinity to p62. We undertook molecular simulation analyses to investigate the potential of some natural small molecules (Withanone (Wi-N) & Withaferin-A (Wi-A) from Ashwagandha; Cucurbitacin-B (Cuc-B) from bitter Cucumber; and Caffeic acid phenethyl ester (CAPE) and Artepillin C (ARC) from honeybee propolis) to interact with p62-binding region of p53 and restore its wild-type activity. We found that Wi-N, Wi-A, and Cuc-B have the potential to restore p53-p62 interaction for phosphorylation-deficient p53 mutants. Wi-N, in particular, caused a reversal of the α-helical structure into an elongated string-like conformation similar to the wild-type p53. These data suggested the use of these natural compounds for the treatment of p53 Ser46 mutant harbouring cancers. We also compared the efficiency of Wi-N, Wi-A, Cuc-B, CAPE, and ARC to abrogate Mortalin-p53 binding resulting in nuclear translocation and reactivation of p53 function and provide experimental evidence to the computational analysis. Taken together, the use of these small molecules for reactivation of p53 in cancer cells is suggested., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Mortalin, a heat shock family protein enriched in cancer cells, is known to inactivate tumor suppressor protein p53. Abrogation of mortalin-p53 interaction and reactivation of p53 has been shown to trigger growth arrest/apoptosis in cancer cells and hence, suggested to be useful in cancer therapy. In this premise, we earlier screened a chemical library to identify potential disruptors of mortalin-p53 interaction, and reported two novel synthetic small molecules (5-[1-(4-methoxyphenyl) (1,2,3,4-tetraazol-5-yl)]-4-phenylpyrimidine-2-ylamine) and (4-[(1E)-2-(2-phenylindol-3-yl)-1-azavinyl]-1,2,4-triazole) called Mortaparib and Mortaparib Plus , respectively. These compounds were shown to possess anticancer activity that was mediated through targeting mortalin and PARP1 proteins, essential for cancer cell survival and proliferation. Here, we report characterization of the third compound, {4-[(4-amino-5-thiophen-2-yl-1,2,4-triazol-3-yl)sulfanylmethyl]-N-(4-methoxyphenyl)-1,3-thiazol-2-amine}, isolated in the same screening. Extensive computational and molecular analyses suggested that the new compound has the capability to interact with mortalin, p53, and PARP1. We provide evidence that this new compound, although required in high concentration as compared to the earlier two compounds (Mortaparib and Mortaparib Plus ) and hence called Mortaparib Mild , also downregulates mortalin and PARP1 expression and functions in multiple ways impeding cancer cell proliferation and migration characteristics. Mortaparib Mild is a novel candidate anticancer compound that warrants further experimental and clinical attention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Meidinna, Shefrin, Sari, Zhang, Dhanjal, Kaul, Sundar and Wadhwa.)

Alopecia or hair loss is a benign treatable disorder which, over time, becomes chronic, affecting a significant fraction of the population that affects the patient's self-esteem and quality of life. The existing treatment regimen for alopecia is inadequate for drug delivery directly to hair follicles to result in continuous hair growth. The challenges are due to multiple-dose regimes and patient non-adherence, where it requires motivated clinical attention. Developing a prolonged drug delivery system by exploration of specific pathways to advance the delivery system into nanomedicine would be beneficial for clinical advancement. In this review, factors affecting the progress of the current therapeutic regimen towards controlled release nanomedicine (CRNM's) are analysed for existing clinical unmet needs, current treatment strategy, and research efforts taken in this direction. Correspondingly, changes in anatomy and pathophysiology of hair growth being analyzed in detail to focus the exact scenario of hair growth cycle and supplementation of medication. Besides, the current treatment regimen with various classes of drugs, their different pathways, and dosing limitations are analyzed. Possibilities of research effort for prolonged drug delivery are discussed in detail, including marketed products, clinical trials as well as various patents filed in the direction. Repurposing of multiple therapeutics using the nanotechnology platform, subsequently, results in a strategy to develop nanomedicine to treat alopecia, which could develop into several technologies (CRNM's), fore coming years from now., (Copyright © 2020 Elsevier B.V. All rights reserved.)

We have earlier reported anticancer activity in Withaferin A (Wi-A), a withanolide derived from Ashwagandha ( Withania somnifera ) and caffeic acid phenethyl ester (CAPE), an active compound from New Zealand honeybee propolis. Whereas Wi-A was cytotoxic to both cancer and normal cells, CAPE has been shown to cause selective death of cancer cells. In the present study, we investigated the efficacy of Wi-A, CAPE, and their combination to ovarian and cervical cancer cells. Both Wi-A and CAPE were seen to activate tumor suppressor protein p53 by downregulation of mortalin and abrogation of its interactions with p53. Downregulation of mortalin translated to compromised mitochondria integrity and function that affected poly ADP-ribose polymerase1 (PARP1); a key regulator of DNA repair and protein-target for Olaparib, drugs clinically used for treatment of breast, ovarian and cervical cancers)-mediated DNA repair yielding growth arrest or apoptosis. Furthermore, we also compared the docking capability of Wi-A and CAPE to PARP1 and found that both of these could bind to the catalytic domain of PARP1, similar to Olaparib. We provide experimental evidences that (i) Wi-A and CAPE cause inactivation of PARP1-mediated DNA repair leading to accumulation of DNA damage and activation of apoptosis signaling by multiple ways, and (ii) a combination of Wi-A and CAPE offers selective toxicity and better potency to cancer cells.

In the present investigation, the effect of timolol maleate loaded ocuserts was studied as an alternative for conventional anti-glaucoma formulation. Ocuserts were prepared using natural polymer sodium alginate and ethyl cellulose. Physico-chemical properties along with drug entrapment efficiency (94-98%), content uniformity (93.1% ± 0.264-98.00% ± 0.321), in vitro drug release (83.42% ± 0.35 at end of 12 h), ex vivo permeation all showed satisfactory results, which was found to follow zero order kinetics. Ex vivo permeation studies showed better results, revealed that the permeability coefficient was dependent on polymer type. The sterility test accelerated stability studies and in vivo studies such as eye irritancy test, in vivo drug release of the optimized ocusert was determined. The anti-glaucoma activity was measured using Schiotz tonometer at different time interval. Significant reduction in Intra ocular pressure (IOP) within 3 days was observed in case of rabbits treated with ocusert in comparison to the rabbit treated with marketed eye drop formulation. Hence timolol maleate loaded ocuserts proved to be a promising and viable alternative over conventional eye formulation for the sustained and controlled ophthalmic drug delivery, targeting the drug within the ocular globe thus improving patient compliance for the treatment of glaucoma., (Copyright © 2018 Elsevier B.V. All rights reserved.)