Pharmacological research最新文献_第5页

Response to Letter to the Editor: Letter by Ru and Zhang regarding article, “Plasma miR-150–5p as a biomarker for immunosuppressive therapy response in acetylcholine receptor positive myasthenia gravis: a long-term prospective longitudinal study” 回复编辑：Ru和Zhang关于“血浆miR-150-5p作为免疫抑制治疗反应的生物标志物在乙酰胆碱受体阳性重症肌无力：一项长期前瞻性纵向研究”这篇文章的来信。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-03-01 Epub Date: 2026-01-29 DOI: 10.1016/j.phrs.2026.108116

Nemanja Garai, Sanja Madic, Vukan Ivanovic, Aleksa Palibrk, Jovan Pesovic, Milos Brkusanin, Ivana Basta, Stojan Peric, Dusanka Savic-Pavicevic

引用次数: 0

Therapeutic use of cannabinoids in age-related pain: Current evidence and clinical perspectives 大麻素治疗与年龄相关的疼痛：目前的证据和临床观点。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-03-01 Epub Date: 2026-02-04 DOI: 10.1016/j.phrs.2026.108130

Sabina Pulone , Chantalle Moulton , Saverio Nucera , Sara Ilari , Carolina Muscoli , Ennio Tasciotti

Pain is a frequently reported long lasting symptom among older adults, often associated with age-related conditions such as osteoarthritis, neuropathies, and musculoskeletal degeneration. In a normal inflammatory condition, the release of pro-inflammatory mediators and the concomitant local vasodilation increases capillary permeability leading to the sensation of pain and hyperalgesia. In a physiologically balanced system, removal of the noxious stimulus allows gradual reduction in inflammation and pain. However, in ageing individuals, the inflammatory response is frequently dysregulated due to immunosenescence, leading to impaired resolution mechanisms, sustained production of pro-inflammatory mediators, and chronic low-grade inflammation—commonly referred to as “inflammaging.” This persistent inflammatory condition contributes to the development and maintenance of chronic pain states in the elderly. In this context, the present review explores the role of the endocannabinoid system (ECS) in modulating pain and inflammation during ageing. Particular attention is given to the therapeutic potential of phytocannabinoids derived from Cannabis sativa L., including Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), and their interactions with cannabinoid receptors. The synergistic effects of phytocannabinoids with other bioactive plant constituents, such as terpenes and flavonoids—commonly known as the “entourage effect”—are also discussed as a means to enhance analgesic efficacy. Furthermore, this review examines how advanced drug delivery platforms, particularly nano-carriers, can address the limitations of conventional cannabis-based formulations by improving bioavailability, pharmacokinetic stability, and targeted delivery, ultimately optimizing the therapeutic application of cannabinoids in managing age-related pain.

疼痛是老年人中经常报道的一种长期持续的症状，通常与年龄相关的疾病如骨关节炎、神经病变和肌肉骨骼变性有关。在正常的炎症状态下，促炎介质的释放和伴随的局部血管扩张增加毛细血管通透性，导致疼痛和痛觉过敏的感觉。在一个生理平衡的系统中，去除有害刺激会使炎症和疼痛逐渐减少。然而，在衰老个体中，由于免疫衰老，炎症反应经常失调，导致消退机制受损，促炎介质的持续产生和慢性低度炎症-通常被称为“炎症”。这种持续的炎症状况有助于老年人慢性疼痛状态的发展和维持。在此背景下，本综述探讨了内源性大麻素系统（ECS）在衰老过程中调节疼痛和炎症的作用。特别关注从大麻中提取的植物大麻素的治疗潜力，包括Δ -四氢大麻酚（THC）和大麻二酚（CBD），以及它们与大麻素受体的相互作用。植物大麻素与其他生物活性植物成分（如萜烯和类黄酮）的协同作用-通常称为“随行效应”-也被讨论为增强镇痛效果的一种手段。此外，本综述探讨了先进的药物传递平台，特别是纳米载体，如何通过提高生物利用度、药代动力学稳定性和靶向传递来解决传统大麻制剂的局限性，最终优化大麻素在治疗与年龄相关的疼痛方面的治疗应用。

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引用次数: 0

Gut-liver axis dysregulation in colitis underlies structure-dependent pharmacokinetics of a traditional Chinese medicine 结肠炎肠肝轴失调是中药结构依赖性药代动力学的基础。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-03-01 Epub Date: 2026-02-12 DOI: 10.1016/j.phrs.2026.108135

Ka Wing Cheng , Jingchun Shi , Mengyang Hou , Ziwan Ning , Mengbi Yang , Yujuan Zhou , Ping Zheng , Heung Lam Mok , Cheng Lyu , Chunhua Huang , Yiqi Xu , Wing Lam Wendy To , Jie Zhang , Jialing Zhang , Xuan Zhang , Chengyuan Lin , Hor Yue Tan , Min Ye , Lin Zhu , Zhaoxiang Bian

Pharmacokinetic (PK) variability under pathological conditions poses challenges for drug efficacy and safety. Although clinical data comparing PK in healthy individuals and patients is limited, evidence suggests that disease-induced variability is common and clinically significant. The liver and gut microbiota are key contributors to this variability, yet their individual and combined roles—particularly via the gut-liver axis—remain unclear, especially for complex herbal medicines. Ulcerative colitis (UC), characterized by immune dysregulation, gut microbiota dysbiosis, and hepatic inflammation, provides a relevant model to study these interactions. In this study, we investigated how UC-induced alterations in liver metabolism and gut microbiota affect the PK profiles of a multi-component herbal formula. Comparative analysis between healthy and colitis mice revealed structure-dependent PK shifts: iridoids and flavonoids exhibited reduced systemic exposure (e.g., 0.8-fold change in AUC for loganin), while saponins and polyphenols demonstrated altered colonic availability. Additionally, alkaloids showed delayed systemic elimination (e.g., 5.8-fold change in T_1/2 for berberine). Multi-omics profiling identified disruptions along the gut-liver axis, including downregulated hepatic enzymes (CYPs, UGTs) and microbial changes such as 125% increased glycoside hydrolases (GHs). Specific compounds—berberine, liquiritin, and glycyrrhizic acid—were influenced by both hepatic and microbial metabolism, while loganin and curcumin were primarily affected by gut processes. Dysfunction of GHs, particularly β-glucosidase and β-glucuronidase, was confirmed using human microbiome datasets and clinical samples, linking PK variability to disease activity. This study establishes a baseline of colitis-induced PK variability across various natural compounds, identifies key determinants, and proposes hypotheses for biomarker development.

病理条件下的药代动力学（PK）变异性对药物的有效性和安全性提出了挑战。虽然比较健康个体和患者PK的临床数据有限，但有证据表明，疾病引起的变异是常见的，并且具有临床意义。肝脏和肠道微生物群是造成这种变异的关键因素，但它们各自和共同的作用——特别是通过肠-肝轴——仍不清楚，特别是对于复杂的草药。溃疡性结肠炎（UC）以免疫失调、肠道菌群失调和肝脏炎症为特征，为研究这些相互作用提供了相关模型。在这项研究中，我们研究了uc诱导的肝脏代谢和肠道微生物群的改变如何影响多组分草药配方的PK谱。健康小鼠和结肠炎小鼠之间的比较分析揭示了结构依赖性的PK变化：环烯醚萜和类黄酮显示出系统性暴露减少（例如，马齿苋素的AUC变化0.82倍），而皂苷和多酚显示出结肠可用性改变。此外，生物碱表现出延迟的全身消除（例如，小檗碱T1/2变化5.81倍）。多组学分析确定了沿肠-肝轴的破坏，包括下调肝酶（CYPs, UGTs）和微生物变化，如糖苷水解酶（GHs）增加125%。特定化合物——小檗碱、甘草素和甘草酸——受到肝脏和微生物代谢的影响，而马鞭草素和姜黄素主要受到肠道过程的影响。利用人类微生物组数据集和临床样本证实了GHs功能障碍，特别是β-葡萄糖苷酶和β-葡萄糖醛酸酶，将PK变异性与疾病活动性联系起来。本研究建立了结肠炎诱导的各种天然化合物PK变异性的基线，确定了关键决定因素，并提出了生物标志物开发的假设。

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引用次数: 0

DCN-type NEDD8 E3 ligases: Structure, biological function and small-molecule inhibitor dcn型NEDD8 E3连接酶：结构、生物学功能及小分子抑制剂

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-03-01 Epub Date: 2026-02-21 DOI: 10.1016/j.phrs.2026.108151

Wenjuan Zhou , Chenhao Xu , Shengnan Zhang , Xiuying Chen , Tian Zhou , Tingting Liu , Xiaohang Song , Yongtao Duan , Ole Andreas Andreassen , Liying Ma

Defective in cullin neddylation 1–5 (DCN1–5) are critical E3 ligases of the neddylation pathway that participate in post-translational modification by selectively catalyzing cullin neddylation, thus mediating the activation of Cullin-RING Ligases (CRLs), and further modulating the activity of target proteins. Currently, DCN1–5 have been identified to play vital roles in cancer, fibrotic diseases, and several other human diseases. Inhibitors targeting DCN1 with various chemotypes had been developed and evaluted in cancer and many NRF2-related diseases. As described above, this review provides insights into the structure and biological functions of DCN1–5, emphasizes the medicinal chemistry advances in the development of DCN1–5 inhibitors, and discusses these five E3 enzymes as appealing therapeutic targets for the treatment of human diseases.

cullin neddylation 1-5 （DCN1-5）是类化修饰途径中关键的E3连接酶，通过选择性催化cullin类化修饰参与翻译后修饰，从而介导cullin - ring连接酶（CRLs）的激活，进而调控靶蛋白的活性。目前，DCN1-5已被确定在癌症、纤维化疾病和其他几种人类疾病中发挥重要作用。各种化学型靶向DCN1的抑制剂已经在癌症和许多nrf2相关疾病中被开发和评估。如上所述，本文综述了DCN1-5的结构和生物学功能，重点介绍了DCN1-5抑制剂的药物化学进展，并讨论了这5种E3酶作为治疗人类疾病的有吸引力的治疗靶点。

引用次数: 0

A gut-liver lipid flux checkpoint mediates FAHFA protection from MASLD 肠-肝脂质通量检查点介导fafa对MASLD的保护

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-02-01 Epub Date: 2026-01-02 DOI: 10.1016/j.phrs.2025.108085

Hao Xie , Hong Sheng Cheng , Jia Xun Jarryl Ng , Shuang Zhang , Joseph Han Sol Kim , Soon Heng Tan , Choon-Hong Tan , Nguan Soon Tan

Pharmacotherapies for metabolic dysfunction-associated steatotic liver disease (MASLD) remain limited. Although resmetirom and semaglutide have approvals for MASH, gut-liver axis options are still needed. Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) offer anti-inflammatory and metabolic benefits but are constrained by poor stability and synthesis complexity. We develop a modular, scalable chemistry platform that installs bioisosteric linkages to generate orally stable, gut-retentive FAHFAs. High-throughput screening identifies lead candidates (12-TAASA, 12-HDTZSA) that selectively inhibit intestinal lipid handling while sparing glucose absorption. In a diet-induced MASLD model, oral dosing reduces weight gain, lowers hepatic triglycerides, improves steatosis histology and liver injury markers, and enhances glycemic control, achieving efficacy comparable to semaglutide. Mechanistically, we identify an intestine-anchored dual-brake mechanism. First, 12-TAASA slows and diminishes gut-to-liver lipid flux in vivo, directly reducing the dietary lipid burden reaching the liver. Second, 12-TAASA and 12-HDTZSA remodel the gut microbiome toward short-chain fatty acid (SCFA)–producing consortia and increase circulating, bacterially derived SCFAs, providing a complementary, microbiota-mediated route to systemic metabolic benefit. Multi-omics integration further implicates a CD44-centered epithelial program, together with allied lipid-handling pathways, as a key intestinal target network governing flux control. These findings position stabilized FAHFAs as gut-localized agents that couple epithelial lipid-uptake restraint with microbiome-derived SCFA signals to reduce gut-to-liver lipid flux, establishing an orally active, dual-action strategy for MASLD.

代谢功能障碍相关脂肪变性肝病（MASLD）的药物治疗仍然有限。尽管雷司替龙和西马鲁肽已被批准用于MASH，但仍然需要肠肝轴治疗方案。羟基脂肪酸脂肪酸酯（FAHFAs）具有抗炎和代谢作用，但稳定性差，合成复杂。我们开发了一个模块化的，可扩展的化学平台，安装生物等构连接，以产生口服稳定的，保留肠道的fahfa。高通量筛选确定了主要候选药物（12-TAASA, 12-HDTZSA）选择性地抑制肠道脂质处理，同时保留葡萄糖吸收。在饮食诱导的MASLD模型中，口服剂量可减少体重增加，降低肝脏甘油三酯，改善脂肪变性组织学和肝损伤标志物，并增强血糖控制，达到与西马鲁肽相当的疗效。在机械上，我们确定了肠道锚定的双制动机制。首先，12-TAASA减缓并减少体内肠道到肝脏的脂质通量，直接减少到达肝脏的膳食脂质负担。其次，12-TAASA和12-HDTZSA将肠道微生物群重塑为产生短链脂肪酸（SCFA）的菌群，并增加循环的细菌来源的SCFA，为系统代谢益处提供了一种互补的微生物介导途径。多组学整合进一步暗示以cd44为中心的上皮程序，连同相关的脂质处理途径，作为控制通量控制的关键肠道靶点网络。这些研究结果表明，稳定的fahfa是肠道定位的药物，它将上皮脂质摄取抑制与微生物组来源的SCFA信号结合起来，减少肠道到肝脏的脂质通量，从而建立了一种口服活性的双作用策略。

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引用次数: 0

Fig-derived exosome-like nanoparticles attenuating bone metastasis of breast cancer through establishing an anti-tumor microenvironment 无花果衍生的外泌体样纳米颗粒通过建立抗肿瘤微环境减弱乳腺癌骨转移。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-02-01 Epub Date: 2026-01-05 DOI: 10.1016/j.phrs.2026.108088

Dan-dan Wang , Jin Qian , Hui-zhen Zou , Hao Tian , Jia Cai , Cui-cui Hao , Xiao-wen Huang , Ming Li , Yan Dai , Min Zhang , Gao-ming Li , Song-tao Wang , Meng-meng Yang , Ruo-hong Liu , Ce-shi Chen , Xia Kang , Xiao-wei Qi

Plant-derived exosomes-like nanoparticles (ELNs) have been proven to be utilized as a promising therapy for varieties of diseases and conditions with ideal biocompatibility and biosecurity. Fig (Ficus carica) was reported to exert an anti-tumor effect, however, the active components and the underlying mechanism are still unclear. Herein, we isolated and characterized Fig-releasing ELNs (Fig-ELNs). Then, we found Fig-ELNs can prevent the growth of both human and murine breast cancer (BC) cells and induce M1 polarization of macrophages in bone metastasis murine model of BC. Mechanically, peu-miR-2916-p3 was identified as the important component in Fig-ELNs to inhibit the progression of bone metastasis of BC. Peu-miR-2916-p3 can promote the degradation of RN7SL1 and induce the apoptosis of BC cells. On the other hand, it also directly targeted Stab1 and promote the activation of non-canonical NF-κB pathway to facilitate M1 polarization. Our study demonstrated that Fig-ELNs can be a promising therapeutical target of bone metastasis of BC through directly inhibiting the growth of BC cells and remodeling tumor microenvironment, implying as safe and effective adjuvant therapy.

植物源性外泌体样纳米颗粒（ELNs）已被证明具有理想的生物相容性和生物安全性，是一种有前景的治疗多种疾病和病症的方法。据报道，无花果（Ficus carica）具有抗肿瘤作用，但其有效成分及其作用机制尚不清楚。在此，我们分离并表征了Fig-ELNs （Fig-ELNs）。然后，我们发现Fig-ELNs可以抑制人和小鼠乳腺癌（BC）细胞的生长，并在乳腺癌骨转移小鼠模型中诱导巨噬细胞M1极化。机械地，peu-miR-2916-p3被认为是fig - eln中抑制BC骨转移进展的重要成分。Peu-miR-2916-p3可促进RN7SL1降解，诱导BC细胞凋亡。另一方面，它也直接靶向Stab1，促进非典型NF-κB通路的激活，促进M1极化。我们的研究表明Fig-ELNs可以通过直接抑制BC细胞的生长和重塑肿瘤微环境，成为BC骨转移的治疗靶点，是一种安全有效的辅助治疗方法。

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引用次数: 0

Differential toll-like receptor 2 activation by Akkermansia muciniphila and Bacteroides thetaiotaomicron mediates the beneficial effects of Fu brick tea polysaccharide against colitis 嗜粘杆菌和拟杆菌对toll样受体2的差异激活介导茯茯茶多糖对结肠炎的有益作用

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-02-01 Epub Date: 2026-01-14 DOI: 10.1016/j.phrs.2026.108100

Gaolong Zuo , Feifei Chang , Xinyi Yuan , Yujie Shen , Xiaoli Guo , Bo Tang , Jian-an Huang , Zhonghua Liu , Yong Lin

Fu Brick Tea Polysaccharide (FBTP) ameliorates dextran sulfate sodium (DSS)-induced colitis in mice. However, the key intestinal bacterial strains and downstream molecular mechanisms mediating these protective effects remain unclear. In this study, FBTP ameliorated colitis and concurrent liver injury in a microbiota-dependent manner, primarily by enriching Akkermansia muciniphila (A. muciniphila) and depleting Bacteroides thetaiotaomicron (B. thetaiotaomicron). The essential role of the microbiota was confirmed through fecal microbiota transplantation. Mechanistically, A. muciniphila synergistically employed both its microbe-associated molecular patterns (MAMPs) and metabolic activity to activate the toll-like receptor 2 (TLR2)-Akt anti-inflammatory signaling pathway, favorably modulating Treg/Th17 immune homeostasis. However, challenging its established status as a beneficial commensal, B. thetaiotaomicron was found to activate the TLR2-NF-κB pro-inflammatory pathway driven primarily by its MAMPs, significantly exacerbating colitis, bacterial translocation, and liver injury. The pivotal role of TLR2 in mediating these divergent bacterial outcomes was confirmed through gene knockdown experiments. In conclusion, this study reveals that FBTP restores immune homeostasis by orchestrating a complex, TLR2-dependent interplay between beneficial (A. muciniphila) and pathobiontic (B. thetaiotaomicron) bacteria. This discovery not only clarifies the therapeutic mechanism of FBTP but also highlights the context-dependent risk of key commensals, offering critical insights for developing more precise microbiota-targeted interventions.

茯砖茶多糖（FBTP）可改善硫酸葡聚糖钠（DSS）诱导的小鼠结肠炎。然而，介导这些保护作用的关键肠道细菌菌株和下游分子机制尚不清楚。在这项研究中，FBTP以微生物依赖的方式改善了结肠炎和并发肝损伤，主要是通过富集嗜粘杆菌（a.m uiniphila）和消耗嗜粘杆菌（b.t taiotaomicron）。通过粪便微生物群移植证实了微生物群的重要作用。在机制上，嗜muciniphila协同利用其微生物相关分子模式（MAMPs）和代谢活性激活toll样受体2 (TLR2)-Akt抗炎信号通路，有利于调节Treg/Th17免疫稳态。然而，挑战其作为有益共生菌的既定地位，发现B. thetaiotaomicron激活主要由其MAMPs驱动的TLR2-NF-κB促炎途径，显著加剧结肠炎、细菌易位和肝损伤。通过基因敲低实验证实了TLR2在介导这些不同细菌结果中的关键作用。总之，本研究表明，FBTP通过协调有益细菌（嗜粘杆菌）和致病细菌（嗜粘杆菌）之间复杂的tlr2依赖性相互作用来恢复免疫稳态。这一发现不仅阐明了FBTP的治疗机制，还强调了关键共生菌的环境依赖性风险，为开发更精确的针对微生物群的干预措施提供了重要见解。

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引用次数: 0

A CARM1-targeted therapeutic peptide suppresses breast cancer progression both in vitro and in vivo 一种靶向carm1的治疗肽在体内和体外均可抑制乳腺癌的进展。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-02-01 Epub Date: 2026-01-16 DOI: 10.1016/j.phrs.2026.108105

Bing-ling Peng , Jun Hong , Zi-rui Wang , Zao-zao Zheng , Jian-cheng Ding , Jia-ying Zhou , Ting Ran , Wen Liu

Coactivator-associated arginine methyltransferase 1 (CARM1/PRMT4) is well-known for its essential physiological functions and its pivotal role in the development and progression of various cancers. Targeted inhibition of CARM1 activity has emerged as a promising strategy for cancer treatment. Herein, we report a peptide inhibitor of CARM1 designated as Pi-CARM1, which demonstrates high selectivity for CARM1. The cell-permeable variant, Pi-CARM1 modified with Trans-Activator of Transcription sequence (Pi-CARM1-TAT), effectively inhibits breast cancer cell proliferation in vitro and significantly reduces tumor growth in mouse models of breast cancer. Mechanistically, Pi-CARM1-TAT recapitulates the impact of CARM1 on the expression of oncogenic estrogen/ERα-target genes, as well as type I interferon (IFN) and IFN-induced genes (ISGs) in breast cancer cells. Notably, the combination of Pi-CARM1-TAT with endocrine therapy drugs or etoposide shows synergistic effects in inhibiting breast tumorigenesis. Furthermore, Pi-CARM1-TAT effectively overcomes endocrine therapy resistance in ER-positive breast cancer cells. In conclusion, we present a novel peptide inhibitor of CARM1, which provides valuable insights and may offer therapeutic potential for the development of CARM1-targeted treatments in breast cancer.

Coactivator-associated arginine methyltransferase 1 （CARM1/PRMT4）因其重要的生理功能和在各种癌症的发生和进展中的关键作用而闻名。靶向抑制CARM1活性已成为一种很有前途的癌症治疗策略。在此，我们报道了一种CARM1的肽抑制剂Pi-CARM1，它对CARM1具有高选择性。细胞渗透性变体Pi-CARM1经转录反式激活子序列修饰（Pi-CARM1- tat），在体外有效抑制乳腺癌细胞增殖，并显著降低乳腺癌小鼠模型中的肿瘤生长。在机制上，Pi-CARM1-TAT概括了CARM1对乳腺癌细胞中致癌雌激素/ er α靶基因以及I型干扰素（IFN）和IFN诱导基因（ISGs）表达的影响。值得注意的是，Pi-CARM1-TAT与内分泌治疗药物或依托泊苷联用在抑制乳腺肿瘤发生方面具有协同作用。此外，Pi-CARM1-TAT可有效克服er阳性乳腺癌细胞的内分泌治疗耐药。总之，我们提出了一种新的CARM1肽抑制剂，这为乳腺癌CARM1靶向治疗的发展提供了有价值的见解，并可能提供治疗潜力。

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引用次数: 0

Gene modification: Exploring the potential in treating kidney diseases 基因修饰：探索治疗肾脏疾病的潜力。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-02-01 Epub Date: 2026-01-17 DOI: 10.1016/j.phrs.2026.108104

Ubong S. Ekperikpe, Serena Zhao, Ilse S. Daehn

Chronic kidney disease (CKD) is a leading cause of death worldwide. Currently available drugs slow but do not cure or prevent progression to end-stage kidney disease. Unfortunately, dialysis and kidney transplant not only pose severe lifestyle constraints and healthcare costs on patients but are also associated with side effects such as electrolyte abnormalities and increased susceptibility to infections. It is imperative to research new therapeutic strategies for the management of CKD. Technological advances in genetics and genomics in recent years have revealed the role that genetics plays in CKD pathophysiology, suggesting that gene therapies may be a viable therapeutic strategy for the management of CKD. Over the years, there has been an increase in new gene therapies approved for various indications; however, none are currently approved for kidney diseases. As our understanding of the genetics of kidney diseases grows, together with emerging gene modifying technologies and delivery tools improve, there is hope that a new generation of gene therapies may become available in the future. In this review, we describe the mechanisms of action and delivery strategies of recent gene editing technologies, after which we explore the potential of gene therapies for kidney diseases. We also discuss noteworthy adverse effects associated with gene therapies and explore the use of emerging artificial intelligence and machine learning in opening new avenues for precision editing towards treatment of kidney diseases. We conclude by discussing the challenges that may impact the development of gene therapies, along with a perspective on how the current landscape may influence the adoption of these strategies for kidney diseases.

慢性肾脏疾病（CKD）是世界范围内导致死亡的主要原因。目前可用的药物减缓但不能治愈或防止进展到终末期肾脏疾病。不幸的是，透析和肾移植不仅给患者带来了严重的生活方式限制和医疗保健费用，而且还与电解质异常和感染易感性增加等副作用有关。研究新的CKD治疗策略势在必行。近年来遗传学和基因组学的技术进步揭示了遗传学在CKD病理生理中的作用，提示基因治疗可能是CKD管理的可行治疗策略。多年来，针对各种适应症批准的新基因疗法有所增加；然而，目前没有一种药物被批准用于肾脏疾病。随着我们对肾脏疾病遗传学的理解不断加深，加上新兴的基因修饰技术和传递工具的改进，新一代的基因疗法有望在未来成为可能。在这篇综述中，我们描述了最近基因编辑技术的作用机制和传递策略，然后我们探索了肾脏疾病基因治疗的潜力。我们还讨论了与基因疗法相关的值得注意的不良反应，并探索了新兴的人工智能和机器学习的使用，为精确编辑治疗肾脏疾病开辟了新的途径。最后，我们讨论了可能影响基因治疗发展的挑战，以及当前形势如何影响这些策略在肾脏疾病中的应用。

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引用次数: 0

Purinosomes and mitochondria: Dynamic interactomes at the crossroads of metabolism, cell structure, and disease 嘌呤小体和线粒体：代谢、细胞结构和疾病十字路口的动态相互作用组。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-02-01 Epub Date: 2026-01-10 DOI: 10.1016/j.phrs.2026.108096

Andrea Mancini , Elisabetta Betterini , Matteo Bordi , Francesco Cecconi

Mitochondria are central hubs of cellular metabolism, integrating nutrient catabolism, ATP production, redox balance, and biosynthetic precursor supply. Recent work has revealed that their influence extends beyond canonical bioenergetics to include intimate connections with cytosolic multi-enzyme assemblies. Among these, the purinosome, the complex dedicated to de novo purine biosynthesis, has emerged as a paradigmatic example of how metabolic pathways achieve efficiency through spatial and functional coupling. This Review highlights the dynamic interplay between purinosomes and mitochondria. We describe how mitochondrial metabolism supplies key substrates, including aspartate, glycine, and formate, while oxidative phosphorylation provides the ATP required for nucleotide synthesis. We discuss how purinosomes assemble through liquid–liquid phase separation, position near mitochondria in response to energetic stress, and act as adaptive metabolic hubs that sense and integrate growth and nutrient signals. Finally, we examine how disruption of this mitochondrion–purinosome axis contributes to disease, from rare neurodevelopmental disorders to cancer and neurodegeneration.

线粒体是细胞代谢的中心枢纽，整合营养分解代谢、ATP生产、氧化还原平衡和生物合成前体供应。最近的研究表明，它们的影响超出了典型的生物能量学，包括与细胞质多酶组合的密切联系。其中，嘌呤酶体，一种致力于从头合成嘌呤的复合物，已经成为代谢途径如何通过空间和功能耦合实现效率的范例。本文综述了嘌呤小体和线粒体之间的动态相互作用。我们描述了线粒体代谢如何提供关键底物，包括天冬氨酸、甘氨酸和甲酸，而氧化磷酸化提供核苷酸合成所需的ATP。我们讨论了嘌呤小体如何通过液-液相分离组装，如何在线粒体附近定位以响应能量应激，以及如何作为适应性代谢中心感知和整合生长和营养信号。最后，我们研究了线粒体-嘌呤酶体轴的破坏如何导致疾病，从罕见的神经发育障碍到癌症和神经变性。

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引用次数: 0