- Glutamate-ammonia ligase (GLUL) catalyzes the syntheses of glutamine, as the antioxidant that has been shown to influence sperm quality in mammals. Research on the precise functions of the GLUL gene during spermatogenesis has been constrained by the structural complexity of the testis. In this study, we established a mouse model with postnatal, germ cell-specific deletion of GLUL. Conditional knockout (cKO) of GLUL led to reduced male fertility. Epididymal sperm from cKO mice exhibited acrosomal malformation, diminished acrosin activity, and redox imbalance. Moreover, GLUL deficiency was found to alter protein levels of Spam1 and Tssk3 in epididymal sperm. These functional deficits could be partially rescued by intraperitoneal glutathione (GSH) administration or by intracytoplasmic sperm injection (ICSI). Collectively, our results demonstrate that GLUL in germ cells is essential for combating oxidative stress during spermatogenesis in mice. These findings enhance the understanding of GLUL's role in male germ cell development and propose GSH supplementation as a potential therapeutic strategy for conditions associated with low acrosin activity. - Source: PubMed
Publication date: 2026/04/21
Lin MengyuanFeng YangkunZhang YunWang HonghuaWang YanFeng NinghanHe Qingwen - Hyaluronidases (HAase) increase tissue permeability by depolymerizing hyaluronan in the extracellular matrix. Consequently, the subcutaneous (SC) delivery of substantial volumes of fluids or biotherapeutics is facilitated. Recombinant human hyaluronidase PH20 (rHuPH20) has been developed to overcome the allergic and immunologic risks associated with animal-derived HAase. However, standalone rHuPH20 products remain unavailable in China despite increasing clinical demand. - Source: PubMed
Publication date: 2026/04/02
Ma HaipingLu XiaoyuXiu JianpingCao MengdieLi JuanQiao YunLiu YanjunWang ZhengZhang LuyaoQian XiaofengZhang HengyanTang HongtaiZhao NapingYu YanxiaZhang Li Aging is the primary risk factor for neurodegeneration. SIRT6, a key longevity regulator, is downregulated in aged brain tissue and linked to neurodegeneration. Thus, activating SIRT6 may delay brain aging. Based on this, the present study reveals the molecular mechanism by which the novel small-molecule positive allosteric modulator (SPAM1) antagonizes neuronal senescence through the PAC1-R/YY1/SIRT6 signaling axis, along with its highly efficient brain-targeting properties. In a naturally aging model of long-term cultured retinal ganglion cells (RGC-5), sustained administration of SPAM1 (1 μM) significantly ameliorates aging phenotypes, including upregulation of SIRT6 and Lamin B1 expressions and suppression of p16 accumulation. Dual luciferase reporter assays confirm that SPAM1 activates the SIRT6 promoter. Mechanistically, SPAM1 induces nuclear translocation of PAC1-R and releases its 24-kDa C-terminal fragment, which forms a complex with the transcription factor YY1 within the nucleus. ChIP-qPCR confirms that SPAM1 enhances YY1 enrichment on the SIRT6 promoter, while YY1 knockdown inhibits SPAM1-mediated SIRT6 activation, establishing YY1's pivotal role. Pharmacokinetics and in vivo imaging demonstrate that SPAM1 possesses rapid and persistent brain targeting capabilities: the drug is detectable in the brain within 10 min after intraperitoneal injection; following tail vein administration, brain fluorescence signals appear within 10 min, peak at 1 h, and persist for over 12 h. This study elucidates SPAM1's anti-neurogerontogenic mechanism through a complete signaling cascade: inducing PAC1-R nuclear translocation, recruiting YY1, and activating SIRT6 transcription. Its well-defined mechanism and unique brain targeting establish a pharmacological foundation for developing innovative drugs to intervene in age-related central nervous system decline.
. - Source: PubMed
Publication date: 2026/03/16
Su WanlinXiao LinTang SuxiangZheng XiaojingZhang YuYu Rongjie- The oncolytic adenovirus Ad5-delta-24-RGD (Ad5Δ24RGD) exhibits suboptimal therapeutic efficacy in high-grade glioma. Here, we show that combining two specific potency-enhancing mutations in and (designated 19K-iL) markedly increases the cytolytic efficiency and the size of vital dye-stained plaques. Unexpectedly, these mutations do not enhance actual spread efficiency, measured as the size of fluorescent plaques, in most tested cell lines. In contrast, the type of fiber modification (F5RGD4C, F5/3, or F5/35) strongly influences actual spread efficiency, with F5RGD4C generally conferring the greatest enhancement. In some cell lines, the fiber modification F5RGD10(2C) or verapamil treatment further improves actual spread efficiency. Nelfinavir inhibits spread and plaque formation of oncolytic adenoviruses with the 19K-iL modifications, irrespective of adenovirus death protein (ADP) expression. Expression of the reporter transgenes and or the human hyaluronidase PH20/ from the E1B-55K region or downstream of the L3-23K or L5-Fiber region differentially affects the oncolytic potency of Ad5-delta-24-RGD-19K-iL. We identified an insertion site downstream of the L3-23K region that supports relatively high hPH20 activity while preserving the enhanced oncolytic potency of the virus. Combining 19K-iL with hPH20 expression may potentially improve therapeutic benefit in glioma. - Source: PubMed
Publication date: 2026/01/23
Stepanenko Aleksei ASosnovtseva Anastasiia OVasiukova Anastasiia AValikhov Marat PChernysheva Anastasia AYusubalieva Gaukhar MChekhonin Vladimir P - Subcutaneous administration is an increasingly patient-preferred, alternative route of administration for monoclonal antibodies (mAb). To overcome the dose-volume restriction with subcutaneous administration and enable the large mAb doses typically required for immunotherapy, recombinant human hyaluronidase PH20 is co-dosed to transiently depolymerize hyaluronan at the injection site. Despite increasing clinical approvals and clinical trials of combination products with PH20, the potential impact of PH20 in facilitating intravenous-to-subcutaneous dose switching is largely unknown. In this study, we investigated whether increased lymphatic drainage via subcutaneous administration with PH20 co-dosing could improve the efficacy of anti-CTLA4 (αCTLA4) by increasing mAb access to the site of antitumor immunomodulation at the tumor-draining lymph node (TDLN). We showed that subcutaneous administration with PH20 significantly enhanced TDLN exposure of αCTLA4. In murine tumor models (CT26/HAS or MC38/OVA), this translated to improved tumor control compared with intravenous, and was either more efficacious or noninferior to subcutaneous alone. Greater efficacy occurred concomitantly with increased cytotoxic effector CD8+ T cells in the tumor and CD62L+ stem-like CD8+ T cells in the TDLN. This was due to increased mAb access to CTLA4+ T-cell populations at the TDLN and was only preserved at a lower mAb dose after subcutaneous administration with PH20. The efficacy advantage of subcutaneous administration with PH20 was primarily apparent for TDLN-targeted mAb (αCTLA4), as combination therapy with a non-TDLN-targeted mAb (αTIM3) was similarly efficacious regardless of dose routes. Overall, our study highlights the potential utility of PH20 to improve TDLN-targeted immunotherapy. - Source: PubMed
Gracia GraciaCao EnyuanYuen DanielFerreira Vilena D MChen Moore ZSenyschyn DanielleMintern Justine DJohnston Angus P RKang David WFeeney Orlagh MPorter Christopher J H