Current Medicinal Chemistry - Volume 31, Issue 25, 2024

Electrochemical detection methods are the more appropriate detection methods when it comes to the sensitive and specific determination of biomarkers. Biomarkers are the biological targets for disease diagnosis and monitoring. This review focuses on recent advances in label-free detection of biomarkers for infectious disease diagnosis. The current state of the art for rapid detection of infectious diseases and their clinical applications and challenges were discussed. Label-free electroanalytical methods are probably the most promising means to achieve this. We are currently in the early stages of the emerging technology of using label-free electrochemistry of proteins to develop biosensors. To date, antibody-based biosensors have been intensively developed, although many improvements in reproducibility and sensitivity are still needed. Moreover, there is no doubt that a growing number of aptamers and hopefully label-free biosensors based on nanomaterials will soon be used for disease diagnosis and therapy monitoring. And also here in this review article, we have discussed recent developments in the diagnosis of bacterial and viral infections, as well as the current status of the use of label-free electrochemical methods for monitoring inflammatory diseases.

Detection of emergent biomolecules or biomarkers remains crucial for early diagnosis in advancing healthcare monitoring and biomedicine. The possibility for rapid detection, real-time monitoring, high sensitivity, low detection limit, good selectivity, and low cost is central, among other significant issues for advancing point-of-care diagnosis. Carbon-based nanocomposites have been employed as sensing materials for various biomarkers due to their high surface-to-volume ratio, high electrical conductivity, chemical stability, and biocompatibility. The carbon nanomaterials, such as carbon nanotubes (CNTs), graphene (GR), carbon quantum dots (CQDs), carbon fibres (CFs), and their nanocomposites have broadly integrated with numerous sensing electrode materials for the detection of biomarkers under various experimental settings. The present review includes the recent advances in the development of carbon nanomaterials-based electrochemical sensors and biosensors for biomedical applications. The preparation, electrode preparation, effective utilization of carbon-derived nanomaterials, and their sensing performances towards numerous biomarkers have been highlighted. The state-of-the-merit, challenges, and prospects for designing carbon nanocomposites-based electrochemical sensor/biosensor platforms for biomedical diagnostics have also been described.

The need for wearable bioelectronics continues to grow, and this technology might significantly alter the medical field. In order to diagnose and treat a patient, conventional medicine takes a “reactive” approach and waits for symptoms to appear first. Therefore, it is preferable to progress toward continuous non-invasive wearable biomonitoring, a preventative strategy that may assist individuals in diagnosing or treating illnesses at the earliest stages, sometimes before any outward symptoms have appeared. Wearable physiological sensors, such as the Apple Watch and FitBit, have arrived on the market as a result of technology advances and have quickly become commonplace. However, few devices currently exist that can report directly on these biomarkers of relevance. This is mostly due to the challenges involved in real-time fluid sampling and generating correct readouts utilising extremely selective and sensitive sensors. Sweat is an excretory fluid that is only allowed to be used in order to reduce invasiveness, but this restriction places additional strain on sensors owing to the diluted concentration of the relevant biomarkers and the changes in pH, salinity, and other biophysical parameters that directly influence the read-out of real-time biosensors. Sweat is favoured amid slightly invasive biofluids due to its low concentration of interfering chemicals and the fact that it may be collected without touching the mucosal layers. This review offers a concise outline of the latest advances in sweat-based wearable sensors, their promise in healthcare monitoring, and the problems faced in analysis based on sweat.

The new class of nanomaterials termed carbon dots: a quasi-spherical nanoparticle having a size less than 10 nm, possesses some unique characteristics like good aqueous solubility, colloidal stability, resistance to photobleaching, and fluorescence tunability, resulting in the unfolding of their various properties and their usage in different applications. Materials that are naturally derived or produced by living organisms are termed ‘biogenic’. Over the past few years, there has been a gradual increase in the use of naturally derived materials in synthesizing carbon dots. Green precursors or biogenic materials are of low cost, readily available, renewable, and environmentally benign. Most importantly, they provide essential benefits not found in synthesized carbon dots. This review focuses on the use of biogenic materials for the synthesis of biogenic carbon dots developed in the past five years. It also briefly explains different synthetic protocols used, along with some significant findings. Thereafter, an overview of the use of biogenic carbon dots (BCDs) in different applications like chemo and biosensors, drug delivery, bioimaging, catalysis and energy applications, etc., is discussed. Thus biogenic carbon dots are future sustainable materials that are now fast replacing conventional carbon quantum prepared from other sources.

This review focuses on recent trends in the binding study of various antimalarial agents with serum albumins in detail. Serum albumin has a significant role in the transport of drugs and endogenous ligands. The nature and magnitude of serum albumin and drug interactions have a tremendous impact on the pharmacological behavior and toxicity of that drug. Binding of drug to serum albumin not only controls its free and active concentration, but also provides a reservoir for a long duration of action. This ultimately affects drug absorption, distribution, metabolism, and excretion. Such interaction determines the actual drug efficacy as the drug action can be correlated with the amount of unbound drug. With the advancement in spectroscopic techniques and simulation studies, binding studies play an increasingly important role in biophysical and biomedical science, especially in the field of drug delivery and development. This review assesses the insight we have gained so far to improve drug delivery and discovery of antimalarials on the basis of a plethora of drug-serum protein interaction studies done so far.

Prostate cancer is ranked second among the most common male cancers. Androgen deprivation therapy (ADT) has long been the first-line treatment and the basis for all other therapies, reducing circulating androgens to castration levels and preventing disease development. Nevertheless, ADT monotherapy may not always limit disease development, and even at low testosterone levels, hormone-sensitive prostate cancer will become castration-resistant. Recent research demonstrates that prostate cancer can have a range of potentially actionable genetic abnormalities; no medications that target these variations have yet been shown to elicit therapeutic advantages. Despite their established efficacy in the management of other cancers, advanced genetic or immunological approaches are not regularly used to treat prostate cancer patients. As a result, there is an unmet demand for medicines that offer a better chance of survival than the existing castration- resistance prostate cancer (CRPC) therapy regimens. The use of oligodeoxynucleotides (ODN) and peptides in decoy technology have been developed as novel therapeutic approaches. Decoy ODNs bind to a particular transcription factor with high affinity and may suppress gene transcription. Peptide decoys bind to specific ligands with high specificity and inhibit signaling pathways. Recent evidence supports the notion that these techniques are promising and attractive in the fight against cancer. In the present review, we discuss the use of decoy technology as a novel therapeutic approach against prostate cancer.

Metabolic Syndrome (MetS) refers to a set of medical conditions including insulin resistance, central obesity, atherogenic dyslipidemia, and hypertension. Due to these dysregulations, if not treated, MetS could increase the risk of CVA, CVD, and diabetes. As described by WHO, CVD is the leading cause of mortality in the world which motivates researchers to investigate the management of its risk factors, especially MetS. It is reported that oxidative stress secondary to the abundant generation of free radicals oxygen species (ROS) and the ensuing altered redox status play an important role as a mediator in MetS. As a result, using new antioxidant agents with higher bioavailability has been proposed as an efficient treatment. Curcumin (a polyphenol of the diarylheptanoids class), which is used as a traditional medicine for various diseases including cardiovascular diseases and diabetes, is characterized by its antioxidant properties which, at least in part, are mediated via the activation of the Nrf2/ARE signaling pathway. Nrf2 is a transcription factor that plays a key role in regulating internal defense systems and increases antioxidant levels to decrease oxidative damage and cell apoptosis. Nrf2 expression and stability are enhanced by curcumin, leading to a higher rate of Nrf2 migration to the cell nucleus to regulate ARE gene expression, thus protecting cells against oxidative stress. In this article, we provide a comprehensive review of the molecular effect of curcumin and its derivatives via Nrf2 regulation in several conditions, such as diabetes, hypertension, dyslipidemia, and obesity.

Background and Objective: Blood cystatin C level has been introduced as a promising biomarker to detect early kidney injury in cirrhotic patients. The purpose of this meta-analysis was to investigate the association of blood cystatin C level with allcause mortality in patients with liver cirrhosis. Methods: PubMed, ScienceDirect, and Embase databases were searched from the inception to November 15, 2022. Observational studies evaluating the value of blood cystatin C level in predicting all-cause mortality in patients with ACS were selected. The pooled hazard risk (HR) with 95% confidence intervals (CI) was calculated using a random effect model meta-analysis. Results: Twelve studies with 1983 cirrhotic patients were identified. The pooled adjusted HR of all-cause mortality was 3.59 (95% CI 2.39-5.39) for the high versus low group of cystatin C level. Stratified analysis by study design, characteristics of patients, geographical region, sample size, and length of follow-up further supported the predictive value elevated cystatin C level. Conclusion: Elevated cystatin C level was an independent predictor of poor survival in patients with liver cirrhosis. Detection of blood cystatin C level may provide important prognostic information in cirrhotic patients.

Background: Hypertrophic Cardiomyopathy (HCM) is characterized by myocardial hypertrophy, fibrosis, and sarcomeric disarray. Objective: To evaluate the expression levels of circulating miR-21 and -29 in patients with HCM and their association with clinical characteristics and myocardial fibrosis. Methods: In this case-control study, 27 subjects with HCM, 13 subjects with hypertensive cardiomyopathy, and 10 control subjects were enrolled. Evaluation of patients’ functional capacity was made by the six-minute walk test. Echocardiographic measurements of left ventricle systolic and diastolic function were conducted. Cardiac magnetic resonance late gadolinium enhancement (LGE) -through a semiquantitative evaluation- was used in the assessment of myocardial fibrosis extent in HCM patients. The expression of miR-21 and -29 in peripheral blood samples of all patients was measured via the method of quantitative reverse transcription polymerase chain reaction. Results: Circulating levels of miR-21 were higher in both hypertensive and HCM (p<0.001) compared to controls, while expression of miR-29 did not differ between the three studied groups. In patients with HCM and LGE-detected myocardial fibrosis in more than 4 out of 17 myocardial segments, delta CT miR-21 values were lower than in patients with myocardial LGE in 3 or fewer myocardial segments (2.71 ± 1.06 deltaCT vs. 3.50 ± 0.55 deltaCT, p<0.04), indicating the higher expression of circulating miR-21 in patients with more extensive myocardial fibrosis. Conclusion: MiR-21 was overexpressed in patients with HCM and hypertensive cardiomyopathy. Importantly, in patients with HCM, more extensive myocardial fibrosis was associated with higher levels of miR-21.

Background: While granulatamides A and B have been previously isolated, their biological activities have been only partially examined. The aim of this study was to synthesize granulatamide B (4b), a tryptamine-derivative naturally occurring in Eunicella coral species, using the well-known procedure of Sun and Fürstner and its 12 structural analogues by modifying the side chain, which differs in length, degree of saturation as well as number and conjugation of double bonds. Methods: The prepared library of compounds underwent comprehensive assessment for their biological activities, encompassing antioxidative, antiproliferative, and antibacterial properties, in addition to in vivo toxicity evaluation using a Zebrafish model. Compound 4i, which consists of a retinoic acid moiety, exhibited the strongest scavenging activity against ABTS radicals (IC⁵⁰ = 36 ± 2 μM). In addition, 4b and some of the analogues (4a, 4c and 4i), mostly containing an unsaturated chain and conjugated double bonds, showed moderate but non-selective activity with certain IC⁵⁰ values in the range of 20-40 μM. Results: In contrast, the analogue 4l, a derivative of alpha-linolenic acid, was the least toxic towards normal cell lines. Moreover, 4b was also highly active against Gram-positive Bacillus subtilis with an MIC of 125 μM. Nevertheless, both 4b and 4i, known for the best-observed effects, caused remarkable developmental abnormalities in the zebrafish model Danio rerio. Conclusion: Since modification of the side chain did not significantly alter the change in biological activities compared to the parent compound, granulatamide B (4b), the substitution of the indole ring needs to be considered. Our group is currently carrying out new syntheses focusing on the functionalization of the indole core.

Background: Retinal pigment epithelium (RPE) 65 is a key enzyme in the visual cycle involved in the regeneration of 11-cis-retinal. Mutations in the human RPE65 gene cause Leber’s congenital amaurosis (LCA), a severe form of an inherited retinal disorder. Animal models carrying Rpe65 mutations develop early-onset retinal degeneration. In particular, the cones degenerate faster than the rods. To date, gene therapy has been used successfully to treat RPE65-associated retinal disorders. However, gene therapy does not completely prevent progressive retinal degeneration in patients, possibly due to the vulnerability of cones in these patients. In the present study, we tested whether leukemia inhibitory factor (LIF), a trophic factor, protects cones in rd12 mice harboring a nonsense mutation in Rpe65. Methods: LIF was administered to rd12 mice by intravitreal microinjection. Apoptosis of retinal cells was analyzed by TUNEL assay. The degeneration of cone cells was evaluated by immunostaining of retinal sections and retinal flat-mounts. Signaling proteins regulated by LIF in the retinal and cultured cells were determined by immunoblotting. Results: Intravitreal administration of LIF activated the STAT3 signaling pathway, thereby inhibiting photoreceptor apoptosis and preserving cones in rd12 mice. Niclosamide (NCL), an inhibitor of STAT3 signaling, effectively blocked STAT3 signaling and autophagy in cultured 661W cells treated with LIF. Co-administration of LIF with NCL to rd12 mice abolished the protective effect of LIF, suggesting that STAT3 signaling and autophagy mediate the protection. Conclusion: LIF is a potent factor that protects cones in rd12 mice. This finding implies that LIF can be used in combination with gene therapy to achieve better therapeutic outcomes for patients with RPE65-associated LCA.

Background: Recent studies have unveiled disulfidptosis as a phenomenon intimately associated with cellular damage, heralding new avenues for exploring tumor cell dynamics. We aimed to explore the impact of disulfide cell death on the tumor immune microenvironment and immunotherapy in lung adenocarcinoma (LUAD). Methods: We initially utilized pan-cancer transcriptomics to explore the expression, prognosis, and mutation status of genes related to disulfidptosis. Using the LUAD multi- -omics cohorts in the TCGA database, we explore the molecular characteristics of subtypes related to disulfidptosis. Employing various machine learning algorithms, we construct a robust prognostic model to predict immune therapy responses and explore the model's impact on the tumor microenvironment through single-cell transcriptome data. Finally, the biological functions of genes related to the prognostic model are verified through laboratory experiments. Results: Genes related to disulfidptosis exhibit high expression and significant prognostic value in various cancers, including LUAD. Two disulfidptosis subtypes with distinct prognoses and molecular characteristics have been identified, leading to the development of a robust DSRS prognostic model, where a lower risk score correlates with a higher response rate to immunotherapy and a better patient prognosis. NAPSA, a critical gene in the risk model, was found to inhibit the proliferation and migration of LUAD cells. Conclusion: Our research introduces an innovative prognostic risk model predicated upon disulfidptosis genes for patients afflicted with Lung Adenocarcinoma (LUAD). This model proficiently forecasts the survival rates and therapeutic outcomes for LUAD patients, thereby delineating the high-risk population with distinctive immune cell infiltration and a state of immunosuppression. Furthermore, NAPSA can inhibit the proliferation and invasion capabilities of LUAD cells, thereby identifying new molecules for clinical targeted therapy.