Pharmacological research最新文献

{"title":"Nanoparticles Encapsulating Phosphatidylinositol Derivatives Promote Neuroprotection and Functional Improvement via a long-lasting activation of TRPML1 lysosomal channel in Preclinical Models of ALS.","authors":"Valentina Tedeschi, Valeria Nele, Valeria Valsecchi, Serenella Anzilotti, Antonio Vinciguerra, Laura Zuccaro, Maria Josè Sisalli, Chiara Cassiano, Nunzia De Iesu, Giuseppe Pignataro, Lorella Maria Teresa Canzoniero, Anna Pannaccione, Giuseppe De Rosa, Agnese Secondo","doi":"10.1016/j.phrs.2024.107491","DOIUrl":"https://doi.org/10.1016/j.phrs.2024.107491","url":null,"abstract":"<p><strong>Background and purpose: </strong>Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease currently incurable, in which motor neuron degeneration leads to voluntary skeletal muscle atrophy. Molecularly, ALS is characterized by protein aggregation, synaptic and organellar dysfunction, and Ca²⁺ dyshomeostasis. Of interest, autophagy dysfunction is emerging as one of the main putative targets of ALS therapy. A tune regulation of this cleansing process is affordable by a proper stimulation of TRPML1, one of the main lysosomal channels. However, TRPML1 activation by PI(3,5)P₂ has low open probability to remain in an active conformation. To overcome this drawback we developed a lipid-based formulation of PI(3,5)P₂ whose putative therapeutic potential has been tested in in vitro and in vivo ALS models.</p><p><strong>Experimental approach: </strong>Pharmacodynamic properties of PI(3,5)P₂ lipid-based formulations (F1 and F2) on TRPML1 activity have been characterized by means of patch-clamp electrophysiology and Fura-2AM video-imaging in motor neuronal cells. Once selected for the ability to stabilize TRPML1 activity, the most effective preparation F1 was studied in vivo to measure neuromuscular function and survival of SOD1^G93A ALS mice, thereby establishing its therapeutic profile. Key Results F1, but not PI(3,5)P₂ alone_, stabilized the open state of the lysosomal channel TRPML1 and increased the persistence of intracellular calcium concentration ([Ca²⁺]_i). Then, F1 was effective in delaying motor neuron loss, improving innervated endplants and muscle performance in SOD1^G93A mice, extending overall lifespan by an average of 10 days. Of note F1 prevented gliosis and autophagy dysfunction in ALS mice by restoring PI(3,5)P₂ level.</p><p><strong>Conclusion and implications: </strong>Our novel self-assembling lipidic formulation for PI(3,5)P₂ delivery exerts a neuroprotective effect in preclinical models of ALS mainly regulating dysfunctional autophagy through TRPML1 activity stabilization.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immobilized Protein Strategies Based on Cell Membrane Chromatography and its Application in Discovering Active and Toxic Substances in Traditional Chinese Medicine.","authors":"Yi Shan, Jiayu Lu, Hua Qian, Zhaomin Xia, Xiaoxue Mo, Meidi An, Wen Yang, Siqi Wang, Delu Che, Cheng Wang, Huaizhen He","doi":"10.1016/j.phrs.2024.107492","DOIUrl":"https://doi.org/10.1016/j.phrs.2024.107492","url":null,"abstract":"<p><p>Traditional Chinese medicine (TCM) contributes significantly to human health. Owing to the complexity of the ingredients in TCM, it is necessary to conduct basic research on effective substances and identify toxic substances to control the safety of medication. Cell membrane chromatography (CMC) is an important method for identifying target components in complex systems. The cell membrane stationary phase (CMSP) is the core component and key factor in determining the effectiveness of CMC. This review summarizes the development of CMSP with different membrane protein immobilization strategies and the application of CMC in the discovery of active and toxic substances in TCM, with the aim of providing an effective means for the discovery of active ingredients and quality control of TCM.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New avenues of combating antibiotic resistance by targeting cryptic pockets.","authors":"Yangyang Gao, Huimin Chen, Weicheng Yang, Shuang Wang, Daohong Gong, Xiao Zhang, Yuanqin Huang, Vinit Kumar, Qiuqian Huang, W M W W Kandegama, Gefei Hao","doi":"10.1016/j.phrs.2024.107495","DOIUrl":"https://doi.org/10.1016/j.phrs.2024.107495","url":null,"abstract":"<p><p>Antibiotic resistance is a global health concern that is rapidly spreading among human and animal pathogens. Developing novel antibiotics is one of the most significant approaches to surmount antibiotic resistance. Given the difficult in identifying novel targets, cryptic binding sites provide new pockets for compounds design to combat antibiotic resistance. However, there exists a lack of comprehensive analysis and discussion on the successful utilization of cryptic pockets in overcoming antibiotic resistance. Here, we systematically analyze the crucial role of cryptic pockets in neutralizing antibiotic resistance. First, antibiotic resistance development and associated resistance mechanisms are summarized. Then, the advantages and mechanisms of cryptic pockets for overcoming antibiotic resistance were discussed. Specific cryptic pockets in resistant proteins and successful case studies of designed inhibitors are exemplified. This review provides insight into the discovery of cryptic pockets for drug design as an approach to overcome antibiotic resistance.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of the Histone Deacetylase Family in Lipid Metabolism: Structural Specificity and Functional Diversity.","authors":"Yunxia Li, Qi Han, Yuxin Liu, Jie Yin, Jie Ma","doi":"10.1016/j.phrs.2024.107493","DOIUrl":"https://doi.org/10.1016/j.phrs.2024.107493","url":null,"abstract":"<p><p>Lipids play crucial roles in signal transduction. Lipid metabolism is associated with several transcriptional regulators, including peroxisome proliferator activated receptor γ, sterol regulatory element-binding protein 1, and acetyl-CoA carboxylase. In recent years, increasing evidence has suggested that members of the histone deacetylase (HDAC) family play key roles in lipid metabolism. However, the mechanisms by which each member of this family regulates lipid metabolism remain unclear. This review discusses the latest research on the roles played by HDACs in fat metabolism. The role of HDACs in obesity, diabetes, and atherosclerosis has also been discussed. In addition, the interaction of HDACs with the gut microbiome and circadian rhythm has been reviewed, and the future development trend in HDACs has been predicted, which may potentiate therapeutic application of targeted HDACs in related metabolic diseases.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trends of drug licensing in China: from bring-in to go-global","authors":"","doi":"10.1016/j.phrs.2024.107488","DOIUrl":"10.1016/j.phrs.2024.107488","url":null,"abstract":"<div><h3>Summary</h3><div>Global medicine R&amp;D has shown a stabilized trend after fleeting prosperity lately. Despite of discouraging whole picture, the role of China in cross-border out-licensing activities of medical therapeutics keeps rising, which started since 2020 and further boosted in 2023. A holistic analysis of drug and technology licensing, involving Chinese enterprises from 2019 to 2023, revealed 807 license-in deals and 401 license-out deals. In-licensing showed a decreasing trend, while out-licensing was the opposite. Increasing ingenuity of Chinese products has led to a shift from an import-oriented to an export-oriented situation, such as antibody-drug-conjugates, and cell/gene therapies. With supportive policies of Chinese government, southeast Asia is becoming an important downstream market for out-licensed drugs. Biotech innovators are emerging as a dominant force with core innovation capacity. China is embracing international collaboration by showing favorable markets and high-level innovative products.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ESC-sEVs alleviate non-early-stage osteoarthritis progression by rejuvenating senescent chondrocytes via FOXO1A-autophagy axis but not inducing apoptosis","authors":"","doi":"10.1016/j.phrs.2024.107474","DOIUrl":"10.1016/j.phrs.2024.107474","url":null,"abstract":"<div><div>Osteoarthritis (OA) is a common joint degenerative disease which currently lacks satisfactory disease-modifying treatments. Oxidative stress-mediated senescent chondrocytes accumulation is closely associated with OA progression, which abrogates cartilage metabolism homeostasis by secreting senescence-associated secretory phenotype (SASP) factors. Numerous studies suggested mesenchymal stem cells-derived small extracellular vesicles (MSC-sEVs) have been regarded as promising candidates for OA therapy. However, MSC-sEVs were applied before the occurrence of cartilage degeneration or at early-stage OA, while in clinical practice, most OA patients who present with pain are already in non-early-stage. Recently, embryonic stem cells-derived sEVs (ESC-sEVs) have been reported to possess powerful anti-aging effects. However, whether ESC-sEVs could attenuate non-early-stage OA progression remains unknown. In this study, we demonstrated ESC-sEVs ameliorated senescent phenotype and cartilage destruction in both mechanical stress-induced non-early-stage posttraumatic OA and naturally aged mice. More importantly, we found ESC-sEVs alleviated senescent phenotype by rejuvenating aged chondrocytes but not inducing apoptosis. We also provided evidence that the FOXO1A-autophagy axis played an important role in the anti-aging effects of ESC-sEVs. To promote clinical translation, we confirmed ESC-sEVs reversed senescent phenotype in <em>ex-vivo</em> cultured human end-stage OA cartilage explants. Collectively, our findings reveal that ESC-sEVs-based therapy is of high translational value in non-early-stage OA treatment.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbiota-driven metabolic alterations reveal the distinct pathogenicity of chemotherapy-induced cachexia in gastric cancer","authors":"","doi":"10.1016/j.phrs.2024.107476","DOIUrl":"10.1016/j.phrs.2024.107476","url":null,"abstract":"<div><div>Cachexia affects approximately 50–80 % of advanced cancer patients, particularly those with gastric cancer (GC). Therefore, early detection of cachexia is essential to prevent its progression. Targeting the gut microbiota may be a promising approach for preventing and treating cachexia in patients with GC. Chemotherapy significantly reduced gut microbiota diversity in GC patients. Specifically, the abundance of bacterial genera such as <em>Bacteroides</em>, <em>Streptococcus</em>, and <em>Prevotella</em> was increased in the gut of patients postchemotherapy, which was closely associated with the development of cachexia. Serum metabolic analysis revealed a strong link between specific microbes and metabolite in patients with chemotherapy-induced GC cachexia. We further constructed a random forest model based on the top 6 genera in terms of abundance for the prediction of chemotherapy-related GC cachexia development; this model had an area under the receiver operating characteristic curve (AUC) of 93.5 % [95 % confidence interval (CI), 86.6 %-100 %], with a specificity and accuracy above 75 %. Additionally, we identified <em>Enterotoxin Bacteroides fragilis</em> (ETBF) as a key factor in chemotherapy-induced GC cachexia. In an <em>in vivo</em> GC model, the colonization of ETBF in the intestines of mice significantly accelerated the muscle and adipose tissue consumption induced by chemotherapy, resulting in cachexia symptoms. Furthermore, ETBF damaged the intestinal mucosal barrier by disrupting cell connections and attracting M1 macrophages, which advances GC cachexia. In conclusion, our findings indicate that gut microbiota imbalance is crucial in GC cachexia development, suggesting potential biomarkers for early diagnosis. Clinical trial registration: <span><span>http://www.chictr.org.cn</span><svg><path></path></svg></span>, Identification No: ChiCTR2200064547</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142552222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New insights in the mechanisms of opioid analgesia and tolerance: Ultramicronized palmitoylethanolamide down-modulates vascular endothelial growth factor-A in the nervous system","authors":"","doi":"10.1016/j.phrs.2024.107472","DOIUrl":"10.1016/j.phrs.2024.107472","url":null,"abstract":"<div><div>Growing evidence suggests that opioid analgesics modulate angiogenesis during pathophysiological processes. Vascular endothelial growth factor-A (VEGF-A) was recently proposed to be involved in pain development. To date, no anti-angiogenic drug is used for pain management. When administered in a bioavailable formulation, (i.e., ultramicronized) N-palmitoylethanolamine (PEA) delays the onset of morphine tolerance, improves morphine analgesic activity and reduces angiogenesis in <em>in vivo</em> models. This study aimed at investigating whether VEGF-A is involved in PEA-induced delay of morphine tolerance. The anti-VEGF-A monoclonal antibody bevacizumab was used as a reference drug. Preemptive and concomitant treatment with ultramicronized PEA delayed morphine tolerance and potentiated the analgesic effect of morphine, while counteracting morphine-induced increase of VEGF-A in the nervous system. Similar results were obtained when bevacizumab was administered together with morphine. Of note, bevacizumab showed an analgesic effect <em>per se</em>. In equianalgesic treatment regimens (obtained through increasing morphine doses and associating PEA), PEA resulted in lower expression of VEGF-A in dorsal root ganglia (DRG) and spinal cord compared to morphine alone. Similar results were observed for plasma levels of the soluble VEGF receptor 1 (sFLT-1). Moreover, in morphine-treated animals, two pain-related genes (i.e., <em>Serpina3n</em> and <em>Eaat2</em>) showed a more than 3-fold increase in their expression at spinal cord and DRG level, with the increase being significantly counteracted by PEA treatment. This study supports the hypothesis that the effects of PEA on morphine analgesia and tolerance may be mediated by the down-modulation of VEGF-A and sFLT-1 in the nervous system and plasma, respectively.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142505696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simultaneously blocking ANGPTL3 and CD47 prevents the progression of atherosclerosis through regulating lipid metabolism, macrophagic efferocytosis and lipid peroxidation","authors":"","doi":"10.1016/j.phrs.2024.107486","DOIUrl":"10.1016/j.phrs.2024.107486","url":null,"abstract":"<div><div>Atherosclerosis (AS) ultimately cause major adverse cardiovascular events (MACEs). While traditional strategies by lipid-reducing have reduced MACEs, many patients continue to face significant risks. It might attribute to the upregulation of CD47 expression in AS lesions, that mediated anti-efferocytosis of macrophages. Therefore, we propose simultaneously blocking ANGPTL3, a vital regulator of lipid metabolism, and CD47 might be a potential approach for AS therapy. Firstly, we investigate the role of a novel anti-ANGPTL3 nanobody-Fc (FD03) in AS. We found that FD03 treatment significantly decreased circulating lipids, plaque size, and lipid deposition in apoE^-/- mice compared to control Ab, but there was a twofold increase in plaque formation in comparison to baseline. However, immunofluorescence indicated the upregulation of CD47 expression in the plaques even after FD03 treatment compared to normal vascular tissue. Next, a bifunctional protein containing signal regulatory protein alpha (SIRPα) and FD03 (SIRPαD1-FD03) was constructed to block CD47 and ANGPTL3 concurrently, which had high purity, robust stability, and high affinity to CD47 and ANGPTL3 with biological activity <em>in vitro</em>. Furthermore, SIRPαD1-FD03 fusion protein exhibited the enhanced therapeutic effect on AS compared with SIRPαD1-Fc or FD03, regressing plaque contents and the necrotic core equal to baseline. Mechanistically, SIRPαD1-FD03 reduced serum lipids, augmented the efferocytosis rate and macrophage M2 polarization, and decreased the reactive oxygen species (ROS) and lipid peroxidation level in atherosclerotic plaques. Collectively, our project suggests an effective approach for AS by simultaneously blocking ANGPTL3 and CD47 to regulate lipid metabolism, macrophage activity and lipid peroxidation.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Global and Chinese trends in oligonucleotide drug clinical development: A comparative analysis","authors":"","doi":"10.1016/j.phrs.2024.107487","DOIUrl":"10.1016/j.phrs.2024.107487","url":null,"abstract":"<div><div>Oligonucleotide drugs are anticipated to mark the new wave of pharmaceutical innovation, succeeding the eras of small molecule drugs and monoclonal antibodies. This review assessed a decade of global and Chinese clinical advancements in this field. Since 2013, there has been a notable surge in the development of oligonucleotide drugs, although a considerable majority of these candidates are still in the nascent stages of clinical trials. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) represent two pivotal classes both on global scale and within China. Rare diseases have been the main therapeutic target for oligonucleotide drugs, with a less pronounced focus in China's pipeline relative to the global trend. Concurrently, these drugs are broadening their scope to encompass a variety of indications, potentially revolutionizing treatment approaches for chronic conditions. While China's clinical development in this sector is in its infancy compared to the global stage, technological progress and favorable policies are expected to foster a new landscape of oligonucleotide drug development in the future.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}