Pharmacological research最新文献

{"title":"Trends of drug licensing in China: from bring-in to go-global","authors":"Yale Jiang ,&nbsp;Guo Zhao ,&nbsp;Linlin Jia ,&nbsp;Cheng Li ,&nbsp;Xin Wang ,&nbsp;Jing Cai ,&nbsp;Huiyao Huang ,&nbsp;Shuhang Wang ,&nbsp;Ning Li","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":"210 ","pages":"Article 107488"},"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":"IUPHAR editorial: Emerging targets for the treatment of pain: Moving towards non-addicting therapeutics and new preclinical directions","authors":"James E. Barrett,&nbsp;Alvin V. Terry","doi":"10.1016/j.phrs.2024.107339","DOIUrl":"10.1016/j.phrs.2024.107339","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107339"},"PeriodicalIF":9.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897969","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":"An in-depth look at the relationship between anti-diabetic drugs and Alzheimer’s disease","authors":"Shiyi Huang,&nbsp;Hangyu Liu","doi":"10.1016/j.phrs.2024.107397","DOIUrl":"10.1016/j.phrs.2024.107397","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107397"},"PeriodicalIF":9.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146124","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":"Jian Wu ,&nbsp;Ruijuan Zhang ,&nbsp;Zhonghua Yin ,&nbsp;Xu Chen ,&nbsp;Runwen Mao ,&nbsp;Xiaoxia Zheng ,&nbsp;Mengyun Yuan ,&nbsp;Huaizhi Li ,&nbsp;Yujia Lu ,&nbsp;Shenlin Liu ,&nbsp;Xuejiao Gao ,&nbsp;Qingmin Sun","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":"209 ","pages":"Article 107476"},"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":"ESC-sEVs alleviate non-early-stage osteoarthritis progression by rejuvenating senescent chondrocytes via FOXO1A-autophagy axis but not inducing apoptosis","authors":"Kai Feng ,&nbsp;Teng Ye ,&nbsp;Xuetao Xie ,&nbsp;Jiashuo Liu ,&nbsp;Liangzhi Gong ,&nbsp;Zhengsheng Chen ,&nbsp;Juntao Zhang ,&nbsp;Haiyan Li ,&nbsp;Qing Li ,&nbsp;Yang Wang","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":"209 ","pages":"Article 107474"},"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":"Corrigendum to “Dynamic regulation of phosphorylation of NMDA receptor GluN2B subunit tyrosine residues mediates ketamine rapid antidepressant effects” [Pharmacol. Res. 205(2024)107236]","authors":"Ke Wang ,&nbsp;Xuan Tan ,&nbsp;Kai-Mo Ding ,&nbsp;Xue-Zhu Feng ,&nbsp;Yu-Yu Zhao ,&nbsp;Wei-Li Zhu ,&nbsp;Guo-Hai Li ,&nbsp;Su-Xia Li","doi":"10.1016/j.phrs.2024.107451","DOIUrl":"10.1016/j.phrs.2024.107451","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107451"},"PeriodicalIF":9.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392391","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":"Laura Micheli,&nbsp;Stefania Nobili,&nbsp;Elena Lucarini,&nbsp;Alessandra Toti,&nbsp;Francesco Margiotta,&nbsp;Clara Ciampi,&nbsp;Daniel Venturi,&nbsp;Lorenzo Di Cesare Mannelli,&nbsp;Carla Ghelardini","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":"209 ","pages":"Article 107472"},"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":"Xiaozhi Hu ,&nbsp;Yanyang Nan ,&nbsp;Yuting Zhang ,&nbsp;Jiajun Fan ,&nbsp;Hanqi Wang ,&nbsp;Yu Bai ,&nbsp;Yuanzhen Zhang ,&nbsp;Xuyao Zhang ,&nbsp;Zeguo Zhu ,&nbsp;Zhonglian Cao ,&nbsp;Xiaomiao Ye ,&nbsp;Tao Wu ,&nbsp;Shuwen Xu ,&nbsp;Zhengyu Wu ,&nbsp;Wei Hu ,&nbsp;Dianwen Ju","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":"210 ","pages":"Article 107486"},"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":"Xiaofei Wu ,&nbsp;Shupeng Liu ,&nbsp;Dan Liu ,&nbsp;Xiuqi Li ,&nbsp;Hongyun Wang ,&nbsp;Xiaohong Han","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":"210 ","pages":"Article 107487"},"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}

{"title":"The mysteries of LETM1 pleiotropy","authors":"Sami E.M. Mohammed,&nbsp;Karin Nowikovsky","doi":"10.1016/j.phrs.2024.107485","DOIUrl":"10.1016/j.phrs.2024.107485","url":null,"abstract":"<div><div>LETM1 is a nuclear-encoded protein located in the inner mitochondrial membrane, playing a critical role in regulating mitochondrial cation and volume homeostasis. However, numerous studies on functional features, molecular interactions, and disease-associated effects of LETM1 revealed that LETM1 is also involved in other metabolic functions including glucose utilization, mitochondrial DNA and ribosome organization, cristae architecture and respiratory complex stability. Undisputedly, osmoregulatory processes are essential for mitochondrial functionality, but the pleiotropic aspects of LETM1 challenges us to understand the core function of LETM1, which still remains elusive. In this review, we provide an overview of the current knowledge and latest developments regarding the activities involving LETM1. We highlight various findings that offer different functional perspectives and ideas on the core function of LETM1. Specifically, we emphasize data supporting LETM1's role as a mitochondrial translational factor, K⁺/H⁺ exchanger, or Ca²⁺/H⁺ exchanger, along with recent findings on its interaction with ATAD3A and TMBIM5. We also present the severe clinical implications of LETM1 deficiency. Finally, we discuss emerging questions raised by the different views on LETM1, which need to be addressed to guide future research directions and ultimately resolve the function of this essential protein and develop targeted therapeutic strategies.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"210 ","pages":"Article 107485"},"PeriodicalIF":9.1,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558459","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}