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: BACKGROUND: Exosomes derived from adipose-derived stem cells (ADSCs) have garnered significant attention for their therapeutic potential in various diseases. These vesicles are capable of transporting bioactive molecules such as noncoding RNAs and proteins. Among these noncoding RNAs, circular RNAs (circRNAs) are characterized as end-to-end circular structures, which are notably enriched within exosomes. OBJECTIVE: This study aims to investigate the impact of the circHIPK3 delivered via ADSC-derived exosomes on ovarian aging. MATERIALS AND METHODS: ADSCs were isolated, and exosomes were obtained from a cell culture medium. The exosomes were labeled with PKH26, and uptake by primary granulosa cells (pGCs) was detected. ADSCs were transfected with circHIPK3 siRNAs, and the exosomes were isolated for the treatment of aging female mice. Ovary weight was recorded, and HE staining, Masson's trichrome, and TUNEL staining were performed to detect tissue morphology and apoptosis in ovary tissues. In addition, the senescence and apoptosis of pGCs were evaluated using the S-β-gal staining kit and Annexin V/PI detection kit. Further experiments included immunoprecipitation and RNA pulldown, determined the ubiquitination of p38 protein under circHIPK3 alteration. RESULTS: Results showed that ADSC-derived exosomes effectively delivered circHIPK3 to pGCs. Treatment with these exosomes significantly increased ovary weight and enhanced follicular development in aged mice. Conversely, the depletion of circHIPK3 reversed these effects, promoting cell apoptosis. ADSC-derived exosomes also mitigated senescence and apoptosis in pGCs, while circHIPK3 depletion hindered these benefits. CONCLUSION: Exosomal circHIPK3 modulated the ubiquitination of p38 in pGCs to improve ovarian function in aging mice and to promote pGC cell viability. Keywords: Adipose-derived stem cell, circular RNA HIPK3, exosome, ovary aging, p38, ubiquitination, Author(s): Wei Zhao [1,2]; Da Erhan [3]; Shujun Liu [4]; Liyan Zhang [1]; Caizhu Hai [1]; Yanan Zhang [5]; Haiyan Li [5]; Hongwu Wang (corresponding author) [6]; Caisheng Wang (corresponding [...]

Author(s): Marc L Hyer [1]; Michael A Milhollen (corresponding author) [1]; Jeff Ciavarri [1]; Paul Fleming [1]; Tary Traore [1]; Darshan Sappal [1]; Jessica Huck [1]; Judy Shi [1]; James [...], The ubiquitin-proteasome system (UPS) comprises a network of enzymes that is responsible for maintaining cellular protein homeostasis. The therapeutic potential of this pathway has been validated by the clinical successes of a number of UPS modulators, including proteasome inhibitors and immunomodulatory imide drugs (IMiDs). Here we identified TAK-243 (formerly known as MLN7243) as a potent, mechanism-based small-molecule inhibitor of the ubiquitin activating enzyme (UAE), the primary mammalian E1 enzyme that regulates the ubiquitin conjugation cascade. TAK-243 treatment caused depletion of cellular ubiquitin conjugates, resulting in disruption of signaling events, induction of proteotoxic stress, and impairment of cell cycle progression and DNA damage repair pathways. TAK-243 treatment caused death of cancer cells and, in primary human xenograft studies, demonstrated antitumor activity at tolerated doses. Due to its specificity and potency, TAK-243 allows for interrogation of ubiquitin biology and for assessment of UAE inhibition as a new approach for cancer treatment.

Author(s): Alexander F. Schubert [1]; Christina Gladkova [1]; Els Pardon [2, 3]; Jane L. Wagstaff [1]; Stefan M. V. Freund [1]; Jan Steyaert [2, 3]; Sarah L. Maslen [1]; David [...], Autosomal-recessive juvenile Parkinsonism (AR-JP) is caused by mutations in a number of PARK genes, in particular the genes encoding the E3 ubiquitin ligase Parkin (PARK2, also known as PRKN) and its upstream protein kinase PINK1 (also known as PARK6). PINK1 phosphorylates both ubiquitin and the ubiquitin-like domain of Parkin on structurally protected Ser65 residues, triggering mitophagy. Here we report a crystal structure of a nanobody-stabilized complex containing Pediculus humanus corporis (Ph)PINK1 bound to ubiquitin in the C-terminally retracted (Ub-CR) conformation. The structure reveals many peculiarities of PINK1, including the architecture of the C-terminal region, and reveals how the N lobe of PINK1 binds ubiquitin via a unique insertion. The flexible Ser65 loop in the Ub-CR conformation contacts the activation segment, facilitating placement of Ser65 in a phosphate-accepting position. The structure also explains how autophosphorylation in the N lobe stabilizes structurally and functionally important insertions, and reveals the molecular basis of AR-JP-causing mutations, some of which disrupt ubiquitin binding.

Author(s): Guang-Nian Zhao [1, 2, 3, 4, 5]; Peng Zhang [1, 2, 3, 4]; Jun Gong [2, 3, 4, 5]; Xiao-Jing Zhang [2, 3, 4, 6]; Pi-Xiao Wang [2, 3, [...], Non-alcoholic steatohepatitis (NASH) is an increasingly prevalent liver pathology that can progress from non-alcoholic fatty liver disease (NAFLD), and it is a leading cause of cirrhosis and hepatocellular carcinoma. There is currently no pharmacological therapy for NASH. Defective lysosome-mediated protein degradation is a key process that underlies steatohepatitis and a well-recognized drug target in a variety of diseases; however, whether it can serve as a therapeutic target for NAFLD and NASH remains unknown. Here we report that transmembrane BAX inhibitor motif-containing 1 (TMBIM1) is an effective suppressor of steatohepatitis and a previously unknown regulator of the multivesicular body (MVB)-lysosomal pathway. Tmbim1 expression in hepatocytes substantially inhibited high-fat diet-induced insulin resistance, hepatic steatosis and inflammation in mice. Mechanistically, Tmbim1 promoted the lysosomal degradation of toll-like receptor 4 by cooperating with the ESCRT endosomal sorting complex to facilitate MVB formation, and the ubiquitination of Tmbim1 by the E3 ubiquitin ligase Nedd4l was required for this process. We also found that overexpression of Tmbim1 in the liver effectively inhibited a severe form of NAFLD in mice and NASH progression in monkeys. Taken together, these findings could lead to the development of promising strategies to treat NASH by targeting MVB regulators to properly orchestrate the lysosome-mediated protein degradation of key mediators of the disease.

Background and Purpose: Aberrant expression of β-catenin is highly associated with progression of various cancers including head and neck cancer (HNC). Green tea is most commonly used beverage in the [...]

Thalidomide and its derivatives, lenalidomide and pomalidomide, are immune modulatory drugs (IMiDs) used in the treatment of haematologic malignancies (1,2). IMiDs bind CRBN, the substrate receptor of the CUL4-RBX1-DDB1-CRBN (also [...]