Current Medicinal Chemistry - Volume 32, Issue 42, 2025

Tuberculosis (TB) is a leading cause of death from a single infectious disease worldwide. Early and accurate diagnosis is advantageous for timely detection and prompt treatment, thereby reducing the risk of disease transmission, which is essential for effective TB control. Biomarkers provide a valuable resource for TB diagnosis. Proteomic technologies have emerged as a powerful tool in biomarker discovery. In this perspective, we explore how proteomic technologies contribute to the discovery of TB diagnostic biomarkers. We also address the challenges and discuss prospective methods to augment the performance of biomarkers in diagnosing TB.

Branched-chain amino acids (BCAAs) are essential amino acids for humans and play an indispensable role in many physiological and pathological processes. Branched-chain amino acid aminotransferase (BCAT) is a key enzyme that catalyzes the metabolism of BCAAs. BCAT is upregulated in many cancers and implicated in the development and progress of some other diseases, such as metabolic and neurological diseases; and therefore, targeting BCAT might be a potential therapeutic approach for these diseases. There are two isoforms of BCAT, i.e., cytoplasmic BCAT1 (or BCATc) and mitochondrial BCAT2 (or BCATm). The discovery of BCAT inhibitors was initiated by Warner-Lambert, a subsidiary of Pfizer, in 2000, followed by many other pharmaceutical companies, such as GlaxoSmithKline (GSK), Ergon, Icagen, Agios, and Bayer. Strategies of high-throughput screening (HTS), DNA-Encoded library technology (ELT), and fragment-based screening (FBS) have been employed for hit identification, followed by structural optimization. Despite low selectivity, both BCAT1 and BCAT2 selective inhibitors were individually developed, each with a few chemical structural classes. The most advanced BCAT1 inhibitor is BAY-069, discovered by Bayer, which has a potent enzymatic inhibitory activity against BCAT1 and a decent in vitro and in vivo pharmacokinetic profile but displayed weaker cellular inhibitory activity and almost no anti-proliferative activity. There are no BCAT inhibitors currently under investigation in clinical trials. Further studies are still needed to discover BCAT inhibitors with a more druggable profile for proof of concept. This review focuses on the latest progress of studies on the understanding of the physiology and pathology of BCAT and the discovery and development of BCAT inhibitors. The structure-activity relationship (SAR) and the druggability, and the challenges of BCAT inhibitors are discussed, with the aim of inspiring the discovery and development of BCAT inhibitors in the future.

Signs and symptoms that persist or worsen beyond the “acute COVID-19” stage are referred to as long-COVID. These patients are more likely to suffer from multiple organ failure, readmission, and mortality. According to a recent theory, long-lasting COVID-19 symptoms may be caused by abnormal autonomic nervous system (ANS) activity, such as hypovolemia, brain stem involvement, and autoimmune reactions. Furthermore, COVID-19 can also cause impaired fertility in women, which may also be related to inflammation and immune responses. Currently, few treatments are available for long-COVID symptoms. This article reviews the major effects of COVID-19 on the nervous system and female fertility, as well as offers potential treatment approaches.

Neuroblastoma (NB) is a rare embryonal neuroendocrine tumor that primarily affects children aged 5 years old or younger. In advanced stages, NB requires a multifaceted treatment approach, including a combination of surgery, chemo, and radiation therapy. However, high-risk NB is still associated with poor prognosis, long-term side effects, and a high chance of relapse. To counter the drawbacks of conventional treatments, the antitumor properties of natural substances have been extensively studied in recent years. Curcumin (CUR) is a polyphenol of the plants of the Curcuma longa species and is well-known for its potent biological activities, such as antioxidant, anti-inflammatory, and anticancer properties. CUR may function as a potential therapeutic compound in NB cells by decreasing cell viability, proliferation, and migration, while inducing oxidative stress and apoptosis in cancer cells. Different molecular pathways have been suggested for this anti-cancer activity of CUR, such as caspase-3 activation, p53 and Bcl-2 signaling pathways, inhibition of AKT and FOXO3 nuclear translocation, and regulation of the chaperoning system proteins. Despite its favorable effects, CUR faces several challenges in treating cancer, such as low bioavailability and bioactivity. Consequently, recent studies have focused on the development of CUR nanoformulations and new drug delivery systems, aiming to overcome these barriers. This review provides an updated summary of the recent literature regarding CUR’s protective role in NB and the potential underlying mechanisms. In conclusion, CUR and its nanoformulations show great potential for NB management, and we suggest additional well-designed basic and preclinical studies to explore CUR's efficiency in detail, especially its therapeutic effectiveness in humans.

Gastrointestinal tumors, including colorectal and liver cancer, are among the most prevalent and lethal solid tumors. These malignancies are characterized by worsening prognoses and increasing incidence rates. Traditional therapeutic approaches often prove ineffective. Recent advancements in high-throughput sequencing and sophisticated RNA modification detection technologies have uncovered numerous RNA chemical alterations significantly associated with the pathogenesis of various diseases, notably cancer. These discoveries have opened new avenues for therapeutic intervention. This article delves into epigenetic modifications, with a particular emphasis on RNA alterations such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), 1-methyladenosine (m1A), 7-methylguanosine (m7G), and N4-acetylcysteine (ac4C). It examines the functions and mechanisms of action of regulatory entities known as “Writers,” “Readers,” and “Erasers” to these modifications. Additionally, it outlines various methodologies for detecting these RNA modifications. Conventional techniques include radioactive isotope incorporation, two-dimensional thin-layer chromatography (2D-TLC), mass spectrometry, and immunological detection methods. Specialized methods such as bisulfite sequencing and reverse transcription stops are also discussed. Furthermore, the article underscores the significance of these modifications in the development, progression, and therapeutic targeting of gastrointestinal tumors, including esophageal, gastric, colorectal, liver, and pancreatic cancers. This exploration provides foundational insights for enhancing diagnostic accuracy, treatment efficacy, and prognostic assessment in gastrointestinal oncology.

In the current review, we aim to elucidate the advancements concerning the roles and fundamental mechanisms of intermittent fasting (IF) and fasting-mimicking diet (FMD) in cancers. As a dietary intervention, IF and FMD potentially impede tumor growth by modulating multiple signaling pathways, such as AKT, Nrf2, and AMPK pathways. Moreover, IF and FMD have been reported to be associated with the tumor immune response by regulating various immune cells including tumor-associated macrophages (TAMs), monocytic myeloid-derived suppressor cells (MDSCs), T cells, and B cells. Additionally, IF and FMD can enhance the efficacy and tolerability of therapy, concurrently reducing therapy-induced side effects. Furthermore, several clinical trials have underscored the safety, feasibility, and positive impact on the quality of life associated with IF and FMD, thereby augmenting the effectiveness of conventional anti-tumor therapies while ameliorating treatment-related side effects. This review provides a comprehensive synthesis of findings and elucidates the underlying mechanisms of IF and FMD in cancer progression and therapy.

Heart failure (HF), a widespread public health issue, affects about 26 million people all around the world, and its incidence and prevalence are still growing. Measuring serum biomarkers is beneficial in diagnosing HF and evaluating its prognosis. During the previous decade, various investigations have focused on identifying new HF biological markers that would have additional and/or superior prognostic, diagnostic, or classification value. While heart-specific biological markers, such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), are commonly applied in clinical practice, there is still an unmet need for new markers in HF management. Insulin-like growth factor-binding protein-7 (IGFBP7), a cellular senescence marker, has been considered as a candidate biomarker in HF. This study aims to comprehensively reveal the underlying mechanism connecting IGFBP-7 to HF and review studies evaluating the prognostic or diagnostic performance of IGFBP-7 in combination with or in contrast with other potential HF biological markers. Increased IGFBP7 levels are associated with a set of functional and structural heart abnormalities such as diastolic dysfunction. Increased IGFBP7 concentrations seem to be an indicator of cardiac overload or injury and are related to HF major risk factors, including atherosclerosis, diabetes, and renal function. IGFBP7 is predictive of short and long-term outcomes in the HF population and can independently predict the rate of hospitalization and HF-related mortality.

Mitochondria, the complex powerhouses of eukaryotic cells, lie at the core of energy production, metabolism, and signaling. Mitochondrial dysfunctions underlie a wide range of human diseases, and there is a need for simple and effective tools to target and study these organelles. This review focuses on the applications of mitochondria-targeted cationic probes. It provides an up-to-date review of recent publications investigating the effects of these cationic probes, which are designed to manipulate mitochondrial function and detect dysfunction in different cell lines. In addition, it analyzes the effects of mitochondria-targeted fluorescence cationic probes in vivo and in vitro studies, and their effects in probe studies.