ACS Pharmacology and Translational Science最新文献

The tumor-associated antigen MUC1 is an attractive target for immunotherapy, however, its weak immunogenicity limits the induction of antitumor immune responses. To overcome this limitation, in this study, MUC1 glycopeptide was covalently linked with a diphtheria toxin-derived T-helper epitope (DT_331-345). Subsequently, the resulting DT-MUC1 glycopeptide was physically mixed with natural killer T cell agonist αGalCer to explore their immunomodulatory synergy. Biological results demonstrated that compared to MUC1+αGalCer and DT-MUC1 groups, the specific IgG antibody titer of DT-MUC1+αGalCer group increased by 189- and 3-fold, respectively, indicating that the diphtheria toxin-derived T-helper epitope synergistically enhanced MUC1 immunogenicity with αGalCer. Moreover, the DT-MUC1+αGalCer vaccine induced potent cellular immune responses and significantly inhibited the growth of B16-MUC1 tumors in vivo. Furthermore, it was found that the anti-MUC1 IgG antibody titer induced by DT-MUC1+αGalCer was equivalent to that induced by palmitoylated DT-MUC1+αGalCer (P1-DT-MUC1+αGalCer) and significantly higher than that induced by doubly palmitoylated DT-MUC1+αGalCer (P2-DT-MUC1+αGalCer), suggesting that the easily synthesized DT-MUC1 may not require lipid chain modification and already possess good amphiphilicity. This is the first time that a diphtheria toxin-derived helper T-helper epitope was covalently linked to a glycopeptide antigen to enhance its immunogenicity, and this study may provide an effective vaccine design strategy for MUC1-targeted antitumor vaccines and offer novel insights into the design of fully synthetic peptide vaccines.

Neuropeptide Y (NPY) is a highly conserved neuropeptide with widespread distribution in the central nervous system and diverse physiological functions. While extensively studied for its inhibitory effects on pain at the spinal cord level, its role in pain modulation within the brain remains less clear. This review aims to summarize the complex landscape of supraspinal NPY signaling in pain processing. We discuss the expression and function of NPY receptors in key pain-related brain regions, including the parabrachial nucleus, periaqueductal gray, amygdala, and nucleus accumbens. Additionally, we highlight the potent efficacy of NPY in attenuating pain sensitivity and nociceptive processing throughout the central nervous system. NPY-based therapeutic interventions targeting the central nervous system represent a promising avenue for novel analgesic strategies and pain-associated comorbidities.

Neuropeptide Y (NPY) is a highly conserved neuropeptide with widespread distribution in the central nervous system and diverse physiological functions. While extensively studied for its inhibitory effects on pain at the spinal cord level, its role in pain modulation within the brain remains less clear. This review aims to summarize the complex landscape of supraspinal NPY signaling in pain processing. We discuss the expression and function of NPY receptors in key pain-related brain regions, including the parabrachial nucleus, periaqueductal gray, amygdala, and nucleus accumbens. Additionally, we highlight the potent efficacy of NPY in attenuating pain sensitivity and nociceptive processing throughout the central nervous system. NPY-based therapeutic interventions targeting the central nervous system represent a promising avenue for novel analgesic strategies and pain-associated comorbidities.

Epilepsy affects more than 70 million individuals of all ages worldwide and remains one of the most severe chronic noncommunicable neurological diseases globally. Several neurotransmitters, membrane protein channels, receptors, enzymes, and, more recently noted, various pathways, such as inflammatory and mTORC complexes, play significant roles in the initiation and propagation of seizures. Over the past two decades, significant developments have been made in the diagnosis and treatment of epilepsy. Various pharmacological drugs with diverse mechanisms of action and other treatment options have been developed to control seizures and treat epilepsy. These options include surgical treatment, nanomedicine, gene therapy, natural products, nervous stimulation, a ketogenic diet, gut microbiota, etc., which are in various developmental stages. Despite a plethora of drugs and other treatment options, one-third of affected individuals are resistant to current medications, while the majority of approved drugs have severe side effects, and significant changes can occur, such as pharmacoresistance, effects on cognition, long-term problems, drug interactions, risks of poor adherence, specific effects for certain medications, and psychological complications. Therefore, the development of new drugs and other treatment options that have no or minimal adverse effects is needed to combat this deadly disease. In this Review, we comprehensively summarize and explain all of the treatment options that have been approved or are in developmental stages for epilepsy as well as their status in clinical trials and advancements.

Epilepsy affects more than 70 million individuals of all ages worldwide and remains one of the most severe chronic noncommunicable neurological diseases globally. Several neurotransmitters, membrane protein channels, receptors, enzymes, and, more recently noted, various pathways, such as inflammatory and mTORC complexes, play significant roles in the initiation and propagation of seizures. Over the past two decades, significant developments have been made in the diagnosis and treatment of epilepsy. Various pharmacological drugs with diverse mechanisms of action and other treatment options have been developed to control seizures and treat epilepsy. These options include surgical treatment, nanomedicine, gene therapy, natural products, nervous stimulation, a ketogenic diet, gut microbiota, etc., which are in various developmental stages. Despite a plethora of drugs and other treatment options, one-third of affected individuals are resistant to current medications, while the majority of approved drugs have severe side effects, and significant changes can occur, such as pharmacoresistance, effects on cognition, long-term problems, drug interactions, risks of poor adherence, specific effects for certain medications, and psychological complications. Therefore, the development of new drugs and other treatment options that have no or minimal adverse effects is needed to combat this deadly disease. In this Review, we comprehensively summarize and explain all of the treatment options that have been approved or are in developmental stages for epilepsy as well as their status in clinical trials and advancements.

In patients with myocardial infarction, one of the complications that may occur after revascularization is myocardial ischemia-reperfusion injury (IRI), characterized by a depleted myocardial oxygen supply and absence of blood flow recovery after reperfusion, leading to expansion of myocardial infarction, poor healing of myocardial infarction and reversal of left ventricular remodeling, and an increase in the risk for major adverse cardiovascular events such as heart failure, arrhythmia, and cardiac cell death. As a risk factor for cardiovascular disease, diabetes mellitus increases myocardial susceptibility to myocardial IRI through various mechanisms, increases acute myocardial infarction and myocardial IRI incidence, decreases myocardial responsiveness to protective strategies and efficacy of myocardial IRI protective methods, and increases diabetes mellitus mortality through myocardial infarction. This Review summarizes the mechanisms, existing therapeutic strategies, and potential therapeutic targets of myocardial IRI in diabetic states, which has very compelling clinical significance.

In patients with myocardial infarction, one of the complications that may occur after revascularization is myocardial ischemia-reperfusion injury (IRI), characterized by a depleted myocardial oxygen supply and absence of blood flow recovery after reperfusion, leading to expansion of myocardial infarction, poor healing of myocardial infarction and reversal of left ventricular remodeling, and an increase in the risk for major adverse cardiovascular events such as heart failure, arrhythmia, and cardiac cell death. As a risk factor for cardiovascular disease, diabetes mellitus increases myocardial susceptibility to myocardial IRI through various mechanisms, increases acute myocardial infarction and myocardial IRI incidence, decreases myocardial responsiveness to protective strategies and efficacy of myocardial IRI protective methods, and increases diabetes mellitus mortality through myocardial infarction. This Review summarizes the mechanisms, existing therapeutic strategies, and potential therapeutic targets of myocardial IRI in diabetic states, which has very compelling clinical significance.

Breast cancer remains one of the most prevalent and challenging cancers to treat due to its complexity and heterogenicity. Cellular processes such as metabolic reprogramming and epithelial-to-mesenchymal transition (EMT) contribute to the complexity of breast cancer by driving uncontrolled cell division, metastasis, and resistance to therapies. Strategically targeting these intricate pathways can effectively impede breast cancer progression, thereby revealing significant potential for therapeutic interventions. Among various emerging therapeutic approaches, drug repurposing offers a promising avenue for enhancing clinical outcomes. In recent years, high-throughput screening, QSAR, and network pharmacology have been widely employed to identify promising repurposed drugs. As an outcome, several drugs, such as Metformin, Itraconazole, Pimozide, and Disulfiram, were repurposed to regulate metabolic and EMT pathways. Moreover, strategies such as combination therapy, targeted delivery, and personalized medicine were utilized to enhance the efficacy and specificity of the repurposed drugs. This review focuses on the potential of targeting altered metabolism and EMT in breast cancer through drug repurposing. It also highlights recent advancements in drug screening techniques, associated limitations, and strategies to overcome these challenges.

Breast cancer remains one of the most prevalent and challenging cancers to treat due to its complexity and heterogenicity. Cellular processes such as metabolic reprogramming and epithelial-to-mesenchymal transition (EMT) contribute to the complexity of breast cancer by driving uncontrolled cell division, metastasis, and resistance to therapies. Strategically targeting these intricate pathways can effectively impede breast cancer progression, thereby revealing significant potential for therapeutic interventions. Among various emerging therapeutic approaches, drug repurposing offers a promising avenue for enhancing clinical outcomes. In recent years, high-throughput screening, QSAR, and network pharmacology have been widely employed to identify promising repurposed drugs. As an outcome, several drugs, such as Metformin, Itraconazole, Pimozide, and Disulfiram, were repurposed to regulate metabolic and EMT pathways. Moreover, strategies such as combination therapy, targeted delivery, and personalized medicine were utilized to enhance the efficacy and specificity of the repurposed drugs. This review focuses on the potential of targeting altered metabolism and EMT in breast cancer through drug repurposing. It also highlights recent advancements in drug screening techniques, associated limitations, and strategies to overcome these challenges.

Betacoronaviruses encompass a spectrum of respiratory diseases, from common cold caused by the human coronavirus (HCoV)-OC43 to life-threatening severe acute respiratory syndrome (SARS)-CoV-2. Addressing the constant need for novel antiviral compounds, we turned to the exploration of 40 plant-specialized metabolites produced by the medicinal plant family Amaryllidaceae, known to produce lycorine, a strong antiviral alkaloid. The present screen included 35 alkaloids with representatives of 8 ring-type structures. Pancracine, crinamine, hemanthamine, and hemanthidine exhibited potency comparable to lycorine in blocking HCoV-OC43 replication, while amarbellisine demonstrated superior efficacy (SI = 60, EC₅₀ = 0.2 μM). Their anticoronaviral activity was confirmed using a SARS-CoV-2 replicon system. Time-of-drug-addition experiments established that a postentry step consistent with ribonucleic acid (RNA) replication or translation was targeted. Most antiviral Amaryllidaceae alkaloids selectively induced the expression of transcripts associated with the integrated stress response. Structure-activity relationship analyses elucidated key functional groups contributing to antiviral properties in the crinine- and lycorine-type. This study reveals that Amaryllidaceae produce a diverse repertoire of promising antiviral compounds in addition to lycorine, offering insights for developing new antiviral agents.