Huntington's disease (HD) is characterized by the accumulation of a pathogenic protein, Huntingtin (Htt), that contains an abnormal polyglutamine expansion. Here, we report that a pathogenic fragment of Htt (Httex1p) can be modified either by small ubiquitin-like modifier (SUMO)–1 or by ubiquitin on identical lysine residues. In cultured cells, SUMOylation stabilizes Httex1p, reduces its ability to form aggregates, and promotes its capacity to repress transcription. In a Drosophila model of HD, SUMOylation of Httex1p exacerbates neurodegeneration, whereas ubiquitination of Httex1p abrogates neurodegeneration. Lysine mutations that prevent both SUMOylation and ubiquitination of Httex1p reduce HD pathology, indicating that the contribution of SUMOylation to HD pathology extends beyond preventing Htt ubiquitination and degradation.
Lía Hoz Rodríguez, Maricela Santana Vázquez, Luis Fernando Ramírez González
et al.
Abstract A pentapeptide AVIFM (CAP‐p5) derived from the carboxy‐terminus end of cementum attachment protein was examined for its role on proliferation, differentiation, and mineralization of human periodontal ligament cells (HPLC), and for its potential to induce cementum deposition in vivo. CAP‐p5 capability to induce hydroxyapatite crystal formation on demineralized dentin blocks was characterized by scanning electron microscopy, μRAMAN, and high‐resolution transmission electron microscopy. The results revealed that CAP‐p5 promoted cell proliferation and cell differentiation and increases alkaline phosphatase activity of HPLC and mineralization at an optimal concentration of 10 μg/mL. It induced the expression of cementum molecular markers BSP, CAP, CEMP1, and ALP at the protein level. In a cell‐free system, human demineralized dentin blocks coated with CAP‐p5 induced the deposition of a homogeneous and continuous mineralized layer, intimately integrated with the underlying dentin indicating new cementum formation. Physicochemical characterization of this mineral layer showed that it is composed of hydroxyapatite crystals. Demineralized dentin blocks coated with CAP‐p5 implanted subcutaneously in BALB/cAnNCrl were analyzed histologically; the results disclosed that CAP‐p5 could induce the deposition of a cementum layer intimately integrated with the subjacent dentin with cementocytes embedded into the cementum matrix. Immunostaining showed the expression of cementum molecular markers; v.gr. BSP, CAP, CEMP1 and ALP, validating the molecular identity of the newly deposited cementum. We conclude that CAP‐p5 is a new biomolecule with the potential of therapeutic application to contribute to the regeneration of cementum and periodontal structures lost in periodontal disease.
Abstract Most patients with inflammatory bowel disease (IBD) develop anemia, which is attributed to the dysregulation of iron metabolism. Reciprocally, impaired iron homeostasis also aggravates inflammation. How this iron‐mediated, pathogenic anemia‐inflammation crosstalk is regulated in the gut remains elusive. Herein, it is for the first time revealed that anemic IBD patients exhibit impaired production of short‐chain fatty acids (SCFAs), particularly butyrate. Butyrate supplementation restores iron metabolism in multiple anemia models. Mechanistically, butyrate upregulates ferroportin (FPN) expression in macrophages by reducing the enrichment of histone deacetylase (HDAC) at the Slc40a1 promoter, thereby facilitating iron export. By preventing iron sequestration, butyrate not only mitigates colitis‐induced anemia but also reduces TNF‐α production in macrophages. Consistently, macrophage‐conditional FPN knockout mice exhibit more severe anemia and inflammation. Finally, it is revealed that macrophage iron overload impairs the therapeutic effectiveness of anti‐TNF‐α antibodies in colitis, which can be reversed by butyrate supplementation. Hence, this study uncovers the pivotal role of butyrate in preventing the pathogenic circuit between anemia and inflammation.
Meilinah Hidayat, Janice Natalia, Ardo Sanjaya
et al.
High sodium intake infuences the development of chronic kidney disease (CKD). Various factors can infuence sodium consumption, one of which is impaired taste perception. This study aims to evaluate factors infuencing taste disorders and the impact of high intake of sodium, saliva, and zinc, especially in CKD patients. The method used involved searching for articles using Google Scholar, PubMed, EBSCO, and ProQuest search engines. The inclusion, exclusion criteria, and journal selection method, using Problem/Population, Intervention, Comparison, Outcome form and Prisma Flow Diagram, focused on experimental studies in the last ten years (2013-2023) with specifc search keywords. A total of 28 suitable articles matched the criteria. The results revealed three sub-themes: (A) Factors afecting sodium intake: Taste disorder/dysgeusia in CKD, (B) Efect of zinc on sodium intake or CKD, and (C) Efect of sodium on CKD. This study discusses the three most signifcant factors that infuence taste distortion: salt intake, saliva quality, and zinc defciency, besides old age. Taste disorders due to old age can be overcome with education and behavior planning. The habit of high sodium intake and saliva quality can be improved by reducing sodium intake, while the management of zinc defciency is addressed through supplementation. In summary, tasting disorders in CKD are strongly infuenced by high intake of sodium, saliva, and zinc defciency.
Jorgen Thorup, Jorgen Thorup, Simone Hildorf
et al.
Cryptorchidism in males constitutes a notable risk factor for both infertility and testicular cancer. Infertility in adulthood is closely linked to the germ cell status in childhood. Furthermore, the significance of germ cell status is important as more than 95% of all reported testicular malignancies are germ cell tumors. The review aims to elucidate the pathogenesis of germ cells in cryptorchid testes concerning their association with infertility and testicular malignancies. Impaired germ cell numbers are evident in cryptorchid testes even during antenatal and neonatal stages. In cryptorchidism there is a rapid decline in germ cell number within the first year of life, partially attributed to physiologic gonocyte apoptosis. Additionally, germ cells fail to differentiate normally during mini-puberty leading to reduced germ cell proliferation and delayed clearance of gonocytes from the seminiferous epithelium. Absence of germ cells in testicular biopsies occurs already 10 months of age and germ cell deterioration progressively worsens with approximately 50% of persisting cryptorchid testes lacking germ cells during puberty. The deficient germ cell maturation and proliferation leads to later infertility. Elevated temperature in the cryptorchid testes and also hormonal deficiency contribute to this phenomenon. Germ cell neoplasia in situ (GCNIS) originating during fetal development may manifest in rare cases associated with disorders of sexual development, chromosomal abnormalities in boys, specific syndromes, and teratomas that include cryptorchidism. In adults, the presence of GCNIS predominantly represents a new histology pattern before invasive germ cell cancer is demonstrated and is neither congenital nor related to abnormal gonocyte transformation.
Diseases of the endocrine glands. Clinical endocrinology