Medicinal Research Reviews最新文献

The development of standard drugs for some unusual cancers, including estrogen-nonresponsive breast cancer, is somewhat difficult within a very short time. So, considering the current situation, phytoestrogen may be a potential candidate for unraveling chemotherapeutics agents. The reason for this review article is to manifest overall information regarding the effects of phytoestrogen on triple-negative breast cancer (TNBC), along with its related cellular and molecular pathways in different TNBC models. Data was retrieved by systematic searches according to PRISMA guidelines, and commonly used tools and servers are BioRender, ChemDraw professional 16.0, Schrodinger, and ADMETlab 2.0. TNBC may be caused due to dysregulation of several signaling mechanisms such as Wnt/β-catenin, hedgehog, MAPK, notch, PI3K/AKT/mTOR, hippo, NF-κB, and JAK/STAT signaling cascades. Among all phytoestrogens (n = 150), 48 compounds are therapeutically effective on TNBC in some in vitro and preclinical models. Chemotherapeutics activities are regulated through varieties of mechanisms, including targeting signaling pathways such as phosphor-Akt, PI3K/AKT/mTOR, NF-κB, TNF-α; apoptosis such as FASL, Bcl2, Bax, Bak, Bad, apfa1, ASK1, Capase, and PARP; metastasis such as MMPs (1,2,3,9), Wnt/-β catenin, angiogenesis (E&N Cadherin, Vimentin), cell proliferation (cyclins-A, B1, D1, E1, and CDKs 1, 6,7), inflammatory molecules (TNF-α, NF-κB, IL-1β, IL-8), regulating tumor suppressor genes (p21, p27, p51, p53) and some nonspecific pathways like DNA damage and repair (γH2AX, RAD51, and surviving), autophagy (mTOR, ULK1, and cathepsin B), epigenetic (HDAC1, DNMT1, telomerase production) and metabolism regulation (glucose regulation-GLUT1 and GLUT4), showing antioxidant and many other pathways. Some selective phytoestrogens exert synergistic activities with conventional cancer drugs as well radiotherapy like as conventional mechanism and reverse drug resistance through regulation of the EMT process, signaling pathways, drug sensitizing, miRNA regulation, and improving drug uptake. Nano-based phytoestrogen can target TNBC cells, stimulate drug accumulation, and improve drug efficacies, making phytoestrogens more effective agents in treating TNBC. Additionally, an in-silico pharmacokinetics study reveals that phytoestrogen possesses suitable pharmacokinetic characteristics with minor toxicity. So, phytoestrogen can be a potential candidate drug against TNBC until standard and fully effective pharma drugs are available at markets.

Epstein–Barr virus (EBV), the first identified human tumor virus, significantly influences the immune microenvironment of associated cancers. EBV-induced expression of viral antigens by tumor cells triggers immune recognition and elicits a pro-inflammatory response. While mild inflammation may help eliminate malignant cells, intense inflammation can accelerate tumor progression. Moreover, EBV can establish lifelong latency in human hosts, characterized by low immunogenicity of its proteins and noncoding RNAs. This enables tumor cells to evade immune detection and impair immune cell function, disrupting immune homeostasis. Consequently, EBV-associated malignancies pose a considerable public health challenge globally, often complicating the prognosis of cancer patients under conventional treatment. With deeper research into the oncogenic expressions and mechanisms of EBV, novel targeted therapies against EBV are gaining prominence. This review discusses recent advancements in understanding how EBV helps tumor cells evade immune surveillance and induce immune dysfunction. It also examines the clinical potential of targeting EBV-associated tumors, providing fresh perspectives on the mechanisms and therapeutic strategies for these cancers.

The use of photoswitchable ligand to control the protein functionalities and related downstream effects in an on-off manner is an active research area in photopharmacology and medicinal chemistry. Temporal control grants a privilege to identify the crucial role of a particular receptor in biological occurrences without destroying the protein permanently. Additionally, light can be applied site-selectively to regulate protein functionality with cellular and sub-cellular levels of spatial resolutions. The spatiotemporal resolution enables the probing of a specific receptor, a receptor isoform, or a particular signalling pathway. This reversible and fast spatiotemporal control is highly beneficial in studying protein functionalities in highly dynamic biological processes, including but not limited to signal transduction, neurotransmission, cell divisions, immune response, protein folding, and protein degradation. Though several light-active ligands have been developed to control protein functionality in an on-off manner efficiently, only a few reports on protein functionality with spatial resolution exist in the literature. Major challenges to achieve efficient photoswitches to study protein functionalities are efficient synthesis strategy, photostability of the ligand, bidirectional visible light switching ability and most importantly precise controlling of the local concentration of desired photoisomer using light. The site-specific localization of the active photoisomer depends on multiple factors like the nature of the photoswitch, the binding affinity of both photoisomers, molecular diffusion and light irradiation conditions. The present review discusses suitable techniques and the role of different factors in achieving cellular and subcellular dimension control in protein functionality. Multiple strategies are discussed, along with their advantages and limitations, to explore the enormous potentiality of these approaches in manipulating protein functionality.

Astrocytes undergo a reactive transformation in central nervous system (CNS) disorders, manifesting significant heterogeneity in morphology, molecules, function, and spatial distribution. Just like all cells, astrocytes necessitate energy for their basic functions. Energy production proves critical for the survival and development of astrocytes, as well as their fate determination and functional diversity. The activation process of astrocytes involves a metabolic shift in energy, yet our understanding of how this change impacts the heterogeneity of reactive astrocytes remains limited. In this comprehensive review, we begin by outlining the advancements in research on reactive astrocytes in CNS disorders, establishing a crucial association between the energy metabolism of reactive astrocytes and their molecular and functional aspects. Following this, we delve into a thorough analysis of the energy metabolic transitions of reactive astrocytes within the context of CNS diseases. Starting from the essential pathways of energy metabolism, we present a novel perspective, shedding light on the molecular and functional heterogeneity of reactive astrocytes by considering the heterogeneity in energy metabolism. In conclusion, we propose that the modulation of energy metabolism in reactive astrocytes, coupled with the promotion of their functionality toward disease recovery, represents a cutting-edge and promising strategy for the treatment of CNS diseases.

Antitubercular drug discovery progress in the last decade, especially research on the biological function, target inhibition and diagnosis of tuberculosis (TB) diagnosis has considerably advanced. The application of target-based drug discovery techniques have become a more powerful tool for medicinal chemists in developing new therapeutic strategies, such as its application in the identification/validation of new targets, new leads, and drug candidates with optimized efficacy. This has been further evidenced by the recent approval of delamanid and bedaquiline for the treatment of MDR-TB and XDR-TB, respectively. While a TB drug pipeline has shown great development, high attrition rates must constantly replenish the pipeline with high-quality leads acting through the inhibition of new targets. This review provides a critical analysis of the approaches used to advance hit compounds into viable lead candidates as well as the possible influence of new targets on drug development in the near future. Finally, we concluded with the present challenges that are faced in TB drug development.

Targeted protein degradation (TPD) has emerged as a significant therapeutic approach for a variety of diseases, including cancer. Advances in TPD techniques, such as molecular glue (MG) and lysosome-dependent strategies, have shown substantial progress since the inception of the first PROTAC in 2001. The PROTAC methodology represents the forefront of TPD technology, with ongoing evaluation in more than 20 clinical trials for the treatment of diverse medical conditions. Two prominent PROTACs, ARV-471 and ARV-110, are currently undergoing phase III and II clinical trials, respectively. Traditional PROTACs are encountering obstacles such as limited binding affinity and a restricted range of E3 ligase ligands for facilitating the protein of interest (POI) degradation. Covalent medicines offer the potential to enhance PROTAC efficacy by enabling the targeting of previously considered “undruggable” shallow binding sites. Strategic alterations allow PROTAC to establish covalent connections with particular target proteins, including Kirsten rat sarcoma viral oncogene homolog (KRAS), Bruton's tyrosine kinase (BTK), epidermal growth factor receptor (EGFR), as well as E3 ligases such as DDB1 and CUL4 associated factor 16 (DCAF16) and Kelch-like ECH-associated protein 1 (Keap1). The concept of covalent degradation has also been utilized in various new forms of degraders, including covalent molecule glue (MG), in-cell click-formed proteolysis targeting chimera (CLIPTAC), HaloPROTAC, lysosome-targeting chimera (LYTAC) and GlueTAC. This review focuses on recent advancements in covalent degraders beyond covalent PROTACs and examines obstacles and future directions pertinent to this field.

Proteins hold pivotal importance since many diseases manifest changes in protein activity. Proteomics techniques provide a comprehensive exploration of protein structure, abundance, and function in biological samples, enabling the holistic characterization of overall changes in organisms. Nowadays, the breadth of emerging methodologies in proteomics is unprecedentedly vast, with constant optimization of technologies in sample processing, data collection, data analysis, and its scope of application is steadily transitioning from the bench to the clinic. Here, we offer an insightful review of the technical developments in proteomics and its applications in biomedicine over the past 5 years. We focus on its profound contributions in profiling disease spectra, discovering new biomarkers, identifying promising drug targets, deciphering alterations in protein conformation, and unearthing protein–protein interactions. Moreover, we summarize the cutting-edge technologies and potential breakthroughs in the proteomics pipeline and provide the principal challenges in proteomics. Based on these, we aspire to broaden the applicability of proteomics and inspire researchers to enhance our understanding of complex biological systems by utilizing such techniques.

The Semliki Forest virus (SFV) complex comprises of arboviruses that are transmitted by arthropod vectors and cause acute febrile illness in humans. In the last seven decades, re-emergence of these viruses has resulted in numerous outbreaks globally, affecting regions including Africa, Americas, Asia, Europe and the Caribbean. These viruses are transmitted to humans by the bite of infected mosquitoes. Symptoms of infection include high fever, severe joint pain, skin rash, muscle pain and headache. Fatal cases were reported, and mortality rate increased during the epidemic of these viruses. There is therefore a need to control the spread of these emerging arboviruses. Given that vaccination is one of the most effective ways to protect populations against viral outbreaks, efforts have been made to develop and test potential vaccine candidates. However, there are still no licensed vaccines available against the medically important viruses in the SFV complex. This review first summarizes the current knowledge of the SFV complex disease pathogenesis. Next, seven strategies that have been applied in vaccine development against these viruses are reviewed, indicating the immune response and efficacies of these vaccine candidates in in vivo models of infection. Finally, the more promising candidates that have entered clinical trials are discussed and insights into the future development of vaccines for viruses of the SFV complex are given.