Overcoming chemoresistance and radio resistance in prostate cancer: The emergent role of non-coding RNAs.

Prostate cancer (PCa) continues to be a major health concern worldwide, with its resistance to chemotherapy and radiation therapy presenting major hurdles in successful treatment. While patients with localized prostate cancer generally have a good survival rate, those with metastatic prostate cancer often face a grim prognosis, even with aggressive treatments using various methods. The high mortality rate in severe cases is largely due to the lack of treatment options that can offer lasting results, especially considering the significant genetic diversity found in tumors at the genomic level. This comprehensive review examines the intricate molecular mechanisms governing resistance in PCa, emphasising the pivotal contributions of non-coding RNAs (ncRNAs). We delve into the diverse roles of microRNAs, long ncRNAs, and other non-coding elements as critical regulators of key cellular processes involved in CR & RR. The review emphasizes the diagnostic potential of ncRNAs as predictive biomarkers for treatment response, offering insights into patient stratification and personalized therapeutic approaches. Additionally, we explore the therapeutic implications of targeting ncRNAs to overcome CR & RR, highlighting innovative strategies to restore treatment sensitivity. By synthesizing current knowledge, this review not only provides a comprehension of the chemical basis of resistance in PCa but also identifies gaps in knowledge, paving the way for future research directions. Ultimately, this exploration of ncRNA perspectives offers a roadmap for advancing precision medicine in PCa, potentially transforming therapeutic paradigms and improving outcomes for patients facing the challenges of treatment resistance.

Resveratrol-Laden Nano-Systems in the Cancer Environment: Views and Reviews.

The genesis of cancer is a precisely organized process in which normal cells undergo genetic alterations that cause the cells to multiply abnormally, colonize, and metastasize to other organs such as the liver, lungs, colon, and brain. Potential drugs that could modify these carcinogenic pathways are the ones that will be used in clinical trials as anti-cancer drugs. Resveratrol (RES) is a polyphenolic natural antitoxin that has been utilized for the treatment of several diseases, owing to its ability to scavenge free radicals, control the expression and activity of antioxidant enzymes, and have effects on inflammation, cancer, aging, diabetes, and cardioprotection. Although RES has a variety of pharmacological uses and shows promising applications in natural medicine, its unpredictable pharmacokinetics compromise its therapeutic efficacy and prevent its use in clinical settings. RES has been encapsulated into various nanocarriers, such as liposomes, polymeric nanoparticles, lipidic nanocarriers, and inorganic nanoparticles, to address these issues. These nanocarriers can modulate drug release, increase bioavailability, and reach therapeutically relevant plasma concentrations. Studies on resveratrol-rich nano-formulations in various cancer types are compiled in the current article. Studies relating to enhanced drug stability, increased therapeutic potential in terms of pharmacokinetics and pharmacodynamics, and reduced toxicity to cells and tissues are the main topics of this research. To keep the readers informed about the current state of resveratrol nano-formulations from an industrial perspective, some recent and significant patent literature has also been provided. Here, the prospects for nano-formulations are briefly discussed, along with machine learning and pharmacometrics methods for resolving resveratrol's pharmacokinetic concerns.

Nanotechnology-Based Drug Delivery Approaches of Mangiferin: Promises, Reality and Challenges in Cancer Chemotherapy.

Mangiferin (MGF), a xanthone derived from Mangifera indica L., initially employed as a nutraceutical, is now being explored extensively for its anticancer potential. Scientists across the globe have explored this bioactive for managing a variety of cancers using validated in vitro and in vivo models. The in vitro anticancer potential of this biomolecule on well-established breast cancer cell lines such as MDA-MB-23, BEAS-2B cells and MCF-7 is closer to many approved synthetic anticancer agents. However, the solubility and bioavailability of this xanthone are the main challenges, and its oral bioavailability is reported to be less than 2%, and its aqueous solubility is also 0.111 mg/mL. Nano-drug delivery systems have attempted to deliver the drugs at the desired site at a desired rate in desired amounts. Many researchers have explored various nanotechnology-based approaches to provide effective and safe delivery of mangiferin for cancer therapy. Nanoparticles were used as carriers to encapsulate mangiferin, protecting it from degradation and facilitating its delivery to cancer cells. They have attempted to enhance the bioavailability, safety and efficacy of this very bioactive using drug delivery approaches. The present review focuses on the origin and structure elucidation of mangiferin and its derivatives and the benefits of this bioactive. The review also offers insight into the delivery-related challenges of mangiferin and its applications in nanosized forms against cancer. The use of a relatively new deep-learning approach to solve the pharmacokinetic issues of this bioactive has also been discussed. The review also critically analyzes the future hope for mangiferin as a therapeutic agent for cancer management.

Synthesis, biological evaluation and mechanistic studies of 4-(1,3-thiazol-2-yl)morpholine-benzimidazole hybrids as a new structural class of antimicrobials.

In spite of several attempts to develop newer pharmacophores as potential antimicrobial agents, the benzimidazole scaffold is still considered as one of the most sought after structural component towards the design of compounds that act against a wide spectrum of microbes. Herein, we report the design and synthesis of a new structural class of 4-(1,3-thiazol-2-yl)morpholine-benzimidazole hybrids as antimicrobial agents. The most potent analog, 6g shows IC50 of 1.3 µM, 2.7 µM, 10.8 µM, 5.4 µM and 10.8 µM against Cryptococcus neoformans, Candida albicans, Candida parapsilosis, Escherichia coli and Staphylococcus aureus, respectively. Interestingly 6g exhibits selectivity towards the cryptococcal cells with fungicidal behavior. Propidium iodide uptake study shows permeabilization of pathogenic cells in the presence of 6g. Flow cytometric analysis confirms that cell death is predominantly due to apoptosis. Moreover, electron microscopic analysis specifies that it shrinks, disrupts and initiate pore(s) formation in the cell membrane leading to cell lysis.

Synthetic amino acids-based short amphipathic peptides exhibit antifungal activity by targeting cell membrane disruption.

Availability of a limited number of antifungal drugs created a necessity to develop new antifungals with distinct mode of action. Investigation on a new series of peptides led us to identify Boc-His-Trp-His[1-(4-tert-butylphenyl)] (10g) as the most promising inhibitor exhibiting IC50 value of 4.4 µg/mL against Cryptococcus neoformans. Analog 10g exhibit high selectivity to fungal cells and was nonhemolytic and noncytotoxic at its minimum inhibitory concentration. 10g produced fungicidal effect on growing cryptococcal cells and displayed synergistic effect with amphotericin B. Overall cationic character of 10g resulted in interaction with negatively charged fungal membrane while hydrophobicity enhanced penetration inside the cryptococcal cells causing hole(s) formation and disruption to the membrane as evident by the scanning electron microscopy, transmission electron microscopy, and confocal laser scanning microscopy analyses. Flow cytometric investigation revealed rapid death of fungal cells by apopotic pathway.

Anticryptococcal activity and mechanistic studies of short amphipathic peptides.

Cryptococcus neoformans, an opportunistic fungal pathogen, causes cryptococcosis in immunocompromised persons. A series of modified L-histidines-containing peptides are synthesized that exhibit promising activity against C. neoformans. Analog 11d [L-His(2-adamantyl)-L-Trp-L-His(2-phenyl)-OMe] produced potency with an IC50 of 3.02 µg/ml (MIC = 5.49 µg/ml). This peptide is noncytotoxic and nonhaemolytic at the MIC and displays synergistic effects with amphotericin B at subinhibitory concentration. Mechanistic investigation of 11d using microscopic tools indicates cell wall and membrane disruption of C. neoformans, while flow cytometric analysis confirms cell death by apoptosis. This study indicates that 11d exhibits antifungal potential and acts via the rapid onset of action.

Design, synthesis, and applications of ring-functionalized histidines in peptide-based medicinal chemistry and drug discovery.

Modified and synthetic α-amino acids are known to show diverse applications. Histidine, which possesses numerous applications when subjected to synthetic modifications, is one such amino acid. The utility of modified histidines varies widely from remarkable biological activities to catalysis, and from nanotechnology to polymer chemistry. This renders histidine residue an important place in scientific research. Histidine is a well-studied scaffold and constitutes the active site of various enzymes catalyzing important reactions in the biological systems. A rational modification in histidine structure with a distinctly developed protocol extensively changes its physical and chemical properties. The utilization of modified histidines in search of potent, target selective and proteostable scaffolds is vital in the development of bioactive peptides with enhanced drug-likeliness. This review is a compilation and analysis of reported side-chain ring modifications at histidine followed by applications of ring-modified histidines in the synthesis of various categories of bioactive peptides and peptidomimetics.

Synthetic amino acids-derived peptides target Cryptococcus neoformans by inducing cell membrane disruption.

We investigated synthetic amino acid-based approach to design short peptide-based antibiotics. Tautomerically restricted, amphiphilic 1-aryl-l-histidines along with hydrophobic tryptophan were utilized to synthesize the designed peptides. l-Trp-l-His(1-biphenyl)-NHBzl (12e, IC50 = 1.91 µg/mL; MIC = 3.46 µg/mL) and l-His[1-(4-n-butylphenyl)]-l-Trp-l-His[1-(4-n-butylphenyl)]-NHBzl (16d, IC50 = 1.36 µg/mL; MIC = 2.46 µg/mL) produced potency against Cryptococcus neoformans. Peptides with moderate antibacterial activities (IC50s = 4.40-8.80 µg/mL) were also identified. The mechanism of action and cellular changes revealed that membrane disruption due to interactions of the positively charged peptides with the negatively charged membrane of the cryptococcal cells result in permeabilization, leading to pore formation. The internal localization of the peptides instigated the interactions with DNA causing fragmentation of the genetic material, which together with membrane disruption led to cell death. Flow cytometric analysis points to cells death by apoptotic pathway. Time kill kinetics and synergistic study confirmed the fungicidal nature and synergism with amphotericin B.

Antifungal evaluation and mechanistic investigations of membrane active short synthetic peptides-based amphiphiles.

The quest for new class of peptide-based antibiotics has steered this research towards the design and synthesis of short sequences possessing modified amphiphilic histidine along with hydrophobic tryptophan residues. The new structural class of dipeptides Trp-His(1-Bn)-OMe/NHBn and tripeptides His(1-Bn)-Trp-His(1-Bn)-OMe/NHBn demonstrated promising antifungal and antibacterial activities with membrane lytic action. The illustration of desirable hydrophilic-lipophilic balance appeared in the dipeptide Trp-His[1-(3,5-di-tert-butylbenzyl)]-NHBn (13d) that produced the most promising antifungal activity with IC50 value of 2.10 µg/mL and MIC = 3.81 µg/mL against C. neoformans and antibacterial activity against E. faecalis and S. aureus with identical IC50 value of 4.40 µg/mL and MIC of 8.0 µg/mL. Peptide 13d did not exhibit cytotoxicity and hemolysis at the MIC value and above. This quintessence amphiphilicity was further corroborated by the mechanistic elucidations, which revealed that, peptide act by utilizing charge and hydrophobicity as the primary characteristic tools. Owing to their fundamental affinity, the negatively charged fungal membrane is enacted upon by the positively charged peptide, whereas the intrinsic hydrophobicity of the peptide allowed penetration into the lipophillic core of the fungal cell membrane. Consequently, the integrity of cell membrane is compromised leading to increased fluidity. The membrane eventually disintegrates thereby creating a hollow pore and appearance of a doughnut into the cell when visualized under SEM. The cell death mechanism and damage to the cell wall and intracellular organelles have been elucidated with the help of flow cytometry, TEM and CLSM studies.

Ring-Modified Histidine-Containing Cationic Short Peptides Exhibit Anticryptococcal Activity by Cellular Disruption.

Delineation of clinical complications secondary to fungal infections, such as cryptococcal meningitis, and the concurrent emergence of multidrug resistance in large population subsets necessitates the need for the development of new classes of antifungals. Herein, we report a series of ring-modified histidine-containing short cationic peptides exhibiting anticryptococcal activity via membrane lysis. The N-1 position of histidine was benzylated, followed by iodination at the C-5 position via electrophilic iodination, and the dipeptides were obtained after coupling with tryptophan. In vitro analysis revealed that peptides Trp-His[1-(3,5-di-tert-butylbenzyl)-5-iodo]-OMe (10d, IC50 = 2.20 µg/mL; MIC = 4.01 µg/mL) and Trp-His[1-(2-iodophenyl)-5-iodo)]-OMe (10o, IC50 = 2.52 µg/mL; MIC = 4.59 µg/mL) exhibit promising antifungal activities against C. neoformans. When administered in combination with standard drug amphotericin B (Amp B), a significant synergism was observed, with 4- to 16-fold increase in the potencies of both peptides and Amp B. Electron microscopy analysis with SEM and TEM showed that the dipeptides primarily act via membrane disruption, leading to pore formation and causing cell lysis. After entering the cells, the peptides interact with the intracellular components as demonstrated by confocal laser scanning microscopy (CLSM).

ß-Carbolines as potential anticancer agents.

ß-Carbolines are indole alkaloids having a tricyclic pyrido[3,4-b]indole ring in their structure. Since the isolation of first ß-carboline from Peganum harmala in 1841, the isolation and synthesis of various ß-carboline derivatives surged in the following centuries. ß-Carboline derivatives due to their widespread availability from natural sources, structural flexibility, quick reactivity and interaction with varied anticancer targets such as DNA (intercalation, groove binding, etc.), enzymes (GPX4, topoisomerases, kinases, etc.) and proteins (tubulin, ABCG2/BRCP1, etc.) have established themselves as promising lead compounds for the synthesis of various anticancer active agents. The current review covers the synthesis and isolation, anticancer activity, mechanism of action and SAR of various ß-carboline containing molecules, its derivatives and congeners.

Peptides as Potential Anticancer Agents.

Cancer consists of heterogeneous multiple cell subpopulation which at a later stage develop resistant phenotypes, which include resistance to pro-apoptotic stimuli and/or cytotoxic resistance to anticancer compounds. The property of cancerous cells to affect almost any part of the body categorizes cancer to many anatomic and molecular subtypes, each requiring a particular therapeutic intervention. As several modalities are hindered in a variety of cancers and as the cancer cells accrue varied types of oncogenic mutations during their progression the most likely benefit will be obtained by a combination of therapeutic agents that might address the diverse hallmarks of cancer. Natural compounds are the backbone of cancer therapeutics owing to their property of affecting the DNA impairment and restoration mechanisms and also the gene expression modulated via several epigenetic molecular mechanisms. Bioactive peptides isolated from flora and fauna have transformed the arena of antitumour therapy and prompt progress in preclinical studies is promising. The difficulties in creating ACP rest in improving its delivery to the tumour site and it also must maintain a low toxicity profile. The substantial production costs, low selectivity and proteolytic stability of some ACP are some of the factors hindering the progress of peptide drug development. Recently, several publications have tried to edify the field with the idea of using peptides as adjuvants with established drugs for antineoplastic use. This review focuses on peptides from natural sources that precisely target tumour cells and subsequently serve as anticancer agents that are less toxic to normal tissues.

Short Antimicrobial Peptides.

BACKGROUND: After the era of serendipitous discovery of penicillin and outburst in the discovery and development of highly efficient antibiotics, a surge in resistance against the target specific drugs was observed, primarily due to a combination of selective pressure of antibiotics use and spontaneous mutations. As per the World Health Organization, antibiotic resistance is one of the greatest threats to the mankind. OBJECTIVE: Short antimicrobial peptides (SAMPs) can be considered as a viable therapeutic alternative to conventional antibiotics in tackling resistant microbes. The ubiquitous nature of SAMPs combined with their ability to act via non-specific modes of action, high activity against a wide spectrum of drug-sensitive and drug-resistant microbes, and relative insusceptibility against the development of resistance adds to their desirability as new generation antibiotics. RESULTS: Due to the natural tendency of peptides to get metabolized by proteolytic enzymes, modification of naturally occurring SAMPs is desirable. The modifications can be done either by incorporating unnatural or modified amino acids into the peptide chain or by protecting C and N termini. The characteristic feature of SAMPs is their hydrophobicity and cationicity, which aid in the effective killing of microbes by selectively binding target and lysing the microbial cells with less deleterious effects on the host cells as compared to AMPs and other conventional antibiotics. CONCLUSION: Herein, we discussed the arsenal of short peptides and peptidomimetics starting from the smallest unit possible - a dipeptide to a decapeptide along with their activity profiles as antimicrobials. Recently, various SAMPs have paved their ways from in vitro studies to clinical trials, as evident from the most recent patent (EP1951194) on oral hygiene. This step by step growth of SAMPs has restored the hope in peptide-based therapeutics, which may prove an essential tool in eradicating antimicrobial resistance and tackling various microbial infections.

Synthesis, molecular docking and anti-diabetic evaluation of 2,4-thiazolidinedione based amide derivatives.

A series of thiazolidinedione based amide derivatives were designed, synthesized and docked against the PPARγ receptor target. 11 compounds from the series with good glide scores were selected for in vivo antidiabetic study based on streptozotocin induced diabetic rat model. It was observed that 4 compounds (6c, 6e, 6m &6n) showed significantly good antidiabetic activity in comparison to rosiglitazone and pioglitazone as reference drugs. Compound 6c appeared as the most potent derivative in lowering blood glucose level and showed excellent interaction with SER 342, ILE 281, pi-pi interaction with ARG 288 and halogen bond interaction with LYS 367. Further, PPARγ transactivation and gene expression studies of compound 6c were carried out to investigate the possible mechanism of action through PPARγ modulation. Compound 6c exhibited 53.65% transactivation and elevated PPARγ gene expression by 2.1 folds. The biochemical parameters (AST, ALT and ALP levels) were found within the range with no noteworthy damage to liver.