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Nutrients Jun 2024Patients with chronic kidney disease (CKD) suffer disproportionately from a high burden of cardiovascular disease, which, despite recent scientific advances, remains... (Review)
Review
Patients with chronic kidney disease (CKD) suffer disproportionately from a high burden of cardiovascular disease, which, despite recent scientific advances, remains partly understood. Vascular calcification (VC) is the result of an ongoing process of misplaced calcium in the inner and medial layers of the arteries, which has emerged as a critical contributor to cardiovascular events in CKD. Beyond its established role in blood clotting and bone health, vitamin K appears crucial in regulating VC via vitamin K-dependent proteins (VKDPs). Among these, the matrix Gla protein (MGP) serves as both a potent inhibitor of VC and a valuable biomarker (in its inactive form) for reflecting circulating vitamin K levels. CKD patients, especially in advanced stages, often present with vitamin K deficiency due to dietary restrictions, medications, and impaired intestinal absorption in the uremic environment. Epidemiological studies confirm a strong association between vitamin K levels, inactive MGP, and increased CVD risk across CKD stages. Based on the promising results of pre-clinical data, an increasing number of clinical trials have investigated the potential benefits of vitamin K supplementation to prevent, delay, or even reverse VC, but the results have remained inconsistent.
Topics: Humans; Vascular Calcification; Vitamin K; Renal Insufficiency, Chronic; Matrix Gla Protein; Vitamin K Deficiency; Extracellular Matrix Proteins; Calcium-Binding Proteins; Dietary Supplements; Cardiovascular Diseases; Biomarkers
PubMed: 38931153
DOI: 10.3390/nu16121798 -
Journal of Clinical Medicine Jun 2024In observational studies, high levels of desphospho-uncarboxylated matrix gla protein (dp-ucMGP) that result from vitamin K deficiency were consistently associated with...
In observational studies, high levels of desphospho-uncarboxylated matrix gla protein (dp-ucMGP) that result from vitamin K deficiency were consistently associated with poor clinical outcomes during COVID-19. Vitamin K-activated matrix gla protein (MGP) is required to protect against elastic fibre degradation, and a deficiency may contribute to pathology. However, intervention trials assessing the effects of vitamin K supplementation in COVID-19 are lacking. This is a single-centre, phase 2, double-blind, randomised, placebo-controlled trial investigating the effects of vitamin K2 supplementation in 40 hospitalised COVID-19 patients requiring supplemental oxygen. Individuals were randomly assigned in a 1:1 ratio to receive 999 mcg of vitamin K2-menaquinone-7 (MK-7)-or a placebo daily until discharge or for a maximum of 14 days. Dp-ucMGP, the rate of elastic fibre degradation quantified by desmosine, and hepatic vitamin K status quantified by PIVKA-II were measured. Grade 3 and 4 adverse events were collected daily. As an exploratory objective, circulating vitamin K2 levels were measured. Vitamin K2 was well tolerated and did not increase the number of adverse events. A linear mixed model analysis showed that dp-ucMGP and PIVKA-II decreased significantly in subjects that received supplementation compared to the controls ( = 0.008 and = 0.0017, respectively), reflecting improved vitamin K status. The decrease in dp-ucMGP correlated with higher plasma MK-7 levels ( = 0.015). No significant effect on desmosine was found ( = 0.545). These results demonstrate that vitamin K2 supplementation during COVID-19 is safe and decreases dp-ucMGP. However, the current dose of vitamin K2 failed to show a protective effect against elastic fibre degradation.
PubMed: 38930004
DOI: 10.3390/jcm13123476 -
Journal of Personalized Medicine May 2024The intestinal wound healing process is a complex event of three overlapping phases: exudative, proliferative, and remodeling. Although some mechanisms have been... (Review)
Review
BACKGROUND
The intestinal wound healing process is a complex event of three overlapping phases: exudative, proliferative, and remodeling. Although some mechanisms have been extensively described, the intestinal healing process is still not fully understood. There are some similarities but also some differences compared to other tissues. The aim of this systematic review was to summarize all studies with knockout (KO) experimental models in bowel anastomoses, underline any recent knowledge, and clarify further the cellular and molecular mechanisms of the intestinal healing process. A systematic review protocol was performed.
MATERIALS AND METHODS
Medline, EMBASE, and Scopus were comprehensively searched.
RESULTS
a total of eight studies were included. The silenced genes included interleukin-10, the four-and-one-half LIM domain-containing protein 2 (FHL2), cyclooxygenase-2 (COX-2), annexin A1 (ANXA-1), thrombin-activatable fibrinolysis inhibitor (TAFI), and heparin-binding epidermal growth factor (HB-EGF) gene. Surgically, an end-to-end bowel anastomosis was performed in the majority of the studies. Increased inflammatory cell infiltration in the anastomotic site was found in IL-10-, annexin-A1-, and TAFI-deficient mice compared to controls. COX-1 deficiency showed decreased angiogenesis at the anastomotic site. Administration of prostaglandin E2 in COX-2-deficient mice partially improved anastomotic leak rates, while treatment of ANXA1 KO mice with Ac2-26 nanoparticles reduced colitis activity and increased weight recovery following surgery.
CONCLUSIONS
our findings provide new insights into improving intestinal wound healing by amplifying the aforementioned genes using appropriate gene therapies. Further research is required to clarify further the cellular and micromolecular mechanisms of intestinal healing.
PubMed: 38929776
DOI: 10.3390/jpm14060553 -
Medicina (Kaunas, Lithuania) May 2024: Clear cell sarcoma (CCS) is an extremely rare form of sarcoma representing less than 1% of all soft-tissue sarcomas. It has morphological, structural, and... (Review)
Review
: Clear cell sarcoma (CCS) is an extremely rare form of sarcoma representing less than 1% of all soft-tissue sarcomas. It has morphological, structural, and immunohistochemical similarities to malignant melanoma, affecting young adults and equally affecting both sexes, and is usually located in the tendinous sheaths and aponeuroses of the limbs. Gastrointestinal localization is exceptional, with less than 100 cases reported thus far. The gene fusion of activating transcription factor 1 (ATF1) and the Ewing sarcoma breakpoint region 1 (EWSR1) are pathognomonic for clear cell sarcoma, representing the key to the diagnosis. CCS is an extremely aggressive tumor, with >30% having distant or lymphatic metastasis at the time of diagnostic, and it has a high recurrence rate of over 80% in the first year after diagnosis and a high tendency for metastatic dissemination. Given the rarity of this tumor, there is no standardized treatment. Early diagnosis and radical surgery are essential in the treatment of CCS both for the primary tumor and for recurrence or metastasis. Chemo-radiotherapy has very little effect and is rarely indicated, and the role of targeted therapies is still under investigation. : We present an extremely rare case of intestinal CSS in a 44-year-old Caucasian female. The patient, asymptomatic, first presented for a routine checkup and was diagnosed with mild iron-deficiency anemia. Given her family history of multiple digestive cancers, additional investigations were requested (gastroscopy, colonoscopy, tumoral markers and imaging) and the results were all within normal limits. In the subsequent period, the patient experienced mild diffuse recurrent abdominal pain, which occurred every 2-3 months. Two years later, the patient presented with symptoms of intestinal obstruction and underwent an emergency laparotomy followed by segmental enterectomy and regional lymphadenectomy for stenotic tumor of the jejunum. Histology, immunohistochemistry, and genetic testing established the diagnosis of CCS. No adjuvant therapy was indicated. Initially, no signs of recurrence or metastasis were detected, but after 30 and 46 months, respectively, from the primary treatment, the patient developed liver metastasis and pericolic peritoneal implants treated by atypical hepatic resections and right hemicolectomy. The patient remains under observation.
Topics: Humans; Sarcoma, Clear Cell; Adult; Female; Intestinal Neoplasms; Male
PubMed: 38929464
DOI: 10.3390/medicina60060847 -
Antioxidants (Basel, Switzerland) May 2024Our previous studies have shown that scorpion venom heat-resistant synthesized peptide (SVHRSP) induces a significant extension in lifespan and improvements in...
BACKGROUND
Our previous studies have shown that scorpion venom heat-resistant synthesized peptide (SVHRSP) induces a significant extension in lifespan and improvements in age-related physiological functions in worms. However, the mechanism underlying the potential anti-aging effects of SVHRSP in mammals remains elusive.
METHODS
Following SVHRSP treatment in senescence-accelerated mouse resistant 1 (SAMR1) or senescence-accelerated mouse prone 8 (SAMP8) mice, behavioral tests were conducted and brain tissues were collected for morphological analysis, electrophysiology experiments, flow cytometry, and protein or gene expression. The human neuroblastoma cell line (SH-SY5Y) was subjected to HO treatment in cell experiments, aiming to establish a cytotoxic model that mimics cellular senescence. This model was utilized to investigate the regulatory mechanisms underlying oxidative stress and neuroinflammation associated with age-related cognitive impairment mediated by SVHRSP.
RESULTS
SVHRSP significantly ameliorated age-related cognitive decline, enhanced long-term potentiation, restored synaptic loss, and upregulated the expression of synaptic proteins, therefore indicating an improvement in synaptic plasticity. Moreover, SVHRSP demonstrated a decline in senescent markers, including SA-β-gal enzyme activity, P16, P21, SIRT1, and cell cycle arrest. The underlying mechanisms involve an upregulation of antioxidant enzyme activity and a reduction in oxidative stress-induced damage. Furthermore, SVHRSP regulated the nucleoplasmic distribution of NRF2 through the SIRT1-P53 pathway. Further investigation indicated a reduction in the expression of proinflammatory factors in the brain after SVHRSP treatment. SVHRSP attenuated neuroinflammation by regulating the NF-κB nucleoplasmic distribution and inhibiting microglial and astrocytic activation through the SIRT1-NF-κB pathway. Additionally, SVHRSP significantly augmented Nissl body count while suppressing neuronal loss.
CONCLUSION
SVHRSP could remarkably improve cognitive deficiency by inhibiting oxidative stress and neuroinflammation, thus representing an effective strategy to improve brain health.
PubMed: 38929067
DOI: 10.3390/antiox13060628 -
International Journal of Molecular... Jun 2024A homozygous mutation of the gene causes autosomal recessive familial type 19 of Parkinson's disease (PARK19). To test the hypothesis that PARK19 DNAJC6 mutations...
A homozygous mutation of the gene causes autosomal recessive familial type 19 of Parkinson's disease (PARK19). To test the hypothesis that PARK19 DNAJC6 mutations induce the neurodegeneration of dopaminergic cells by reducing the protein expression of functional DNAJC6 and causing DNAJC6 paucity, an in vitro PARK19 model was constructed by using shRNA-mediated gene silencing of endogenous DANJC6 in differentiated human SH-SY5Y dopaminergic neurons. shRNA targeting DNAJC6 induced the neurodegeneration of dopaminergic cells. DNAJC6 paucity reduced the level of cytosolic clathrin heavy chain and the number of lysosomes in dopaminergic neurons. A DNAJC6 paucity-induced reduction in the lysosomal number downregulated the protein level of lysosomal protease cathepsin D and impaired macroautophagy, resulting in the upregulation of pathologic α-synuclein or phospho-α-synuclein in the endoplasmic reticulum (ER) and mitochondria. The expression of α-synuclein shRNA or cathepsin D blocked the DNAJC6 deficiency-evoked degeneration of dopaminergic cells. An increase in ER α-synuclein or phospho-α-synuclein caused by DNAJC6 paucity activated ER stress, the unfolded protein response and ER stress-triggered apoptotic signaling. The lack of DNAJC6-induced upregulation of mitochondrial α-synuclein depolarized the mitochondrial membrane potential and elevated the mitochondrial level of superoxide. The DNAJC6 paucity-evoked ER stress-related apoptotic cascade, mitochondrial malfunction and oxidative stress induced the degeneration of dopaminergic neurons via activating mitochondrial pro-apoptotic signaling. In contrast with the neuroprotective function of WT DNAJC6, the PARK19 DNAJC6 mutants (Q789X or R927G) failed to attenuate the tunicamycin- or rotenone-induced upregulation of pathologic α-synuclein and stimulation of apoptotic signaling. Our data suggest that PARK19 mutation-induced DNAJC6 paucity causes the degeneration of dopaminergic neurons via downregulating protease cathepsin D and upregulating neurotoxic α-synuclein. Our results also indicate that PARK19 mutation (Q789X or R927G) impairs the DNAJC6-mediated neuroprotective function.
Topics: Cathepsin D; Dopaminergic Neurons; Humans; alpha-Synuclein; HSP40 Heat-Shock Proteins; Endoplasmic Reticulum Stress; Up-Regulation; Parkinson Disease; Mitochondria; Lysosomes; Down-Regulation; Apoptosis; Cell Line, Tumor
PubMed: 38928416
DOI: 10.3390/ijms25126711 -
International Journal of Molecular... Jun 2024Lung cancer has an unfavorable prognosis with a rate of low overall survival, caused by the difficulty of diagnosis in the early stages and resistance to therapy. In... (Review)
Review
Lung cancer has an unfavorable prognosis with a rate of low overall survival, caused by the difficulty of diagnosis in the early stages and resistance to therapy. In recent years, there have been new therapies that use specific molecular targets and are effective in increasing the survival chances of advanced cancer. Therefore, it is necessary to find more specific biomarkers that can identify early changes in carcinogenesis and allow the earliest possible treatment. Vitamin D (VD) plays an important role in immunity and carcinogenesis. Furthermore, the vitamin D receptor (VDR) regulates the expression of various genes involved in the physiological functions of the human organism. The genes encoding the VDR are extremely polymorphic and vary greatly between human populations. To date, there are significant associations between VDR polymorphism and several types of cancer, but the data on the involvement of VDR polymorphism in lung cancer are still conflicting. Therefore, in this review, our aim was to investigate the relationship between VDR single-nucleotide polymorphisms in humans and the degree of risk for developing lung cancer. The studies showcased different gene polymorphisms to be associated with an increased risk of lung cancer: , , , , and . In addition, there is a strong positive correlation between VD deficiency and lung cancer development. Still, due to a lack of awareness, the assessment of VD status and VDR polymorphism is rarely considered for the prediction of lung cancer evolution and their clinical applicability, despite the fact that studies have shown the highest risk for lung cancer given by TaqI gene polymorphisms and that VDR polymorphisms are associated with more aggressive cancer evolution.
Topics: Humans; Receptors, Calcitriol; Lung Neoplasms; Vitamin D; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease; Risk Factors
PubMed: 38928369
DOI: 10.3390/ijms25126664 -
International Journal of Molecular... Jun 2024Glucocerebrosidase (GCase) is a lysosomal enzyme that catalyzes the breakdown of glucosylceramide in the presence of its activator saposin C (SapC). SapC arises from the...
Glucocerebrosidase (GCase) is a lysosomal enzyme that catalyzes the breakdown of glucosylceramide in the presence of its activator saposin C (SapC). SapC arises from the proteolytical cleavage of prosaposin (encoded by gene), which gives rise to four saposins. GCase is targeted to the lysosomes by LIMP-2, encoded by gene. GCase deficiency causes Gaucher Disease (GD), which is mainly due to biallelic pathogenetic variants in the GCase-encoding gene, . However, impairment of GCase activity can be rarely caused by SapC or LIMP-2 deficiencies. We report a new case of LIMP-2 deficiency and a new case of SapC deficiency (missing all four saposins, PSAP deficiency), and measured common biomarkers of GD and GCase activity. Glucosylsphingosine and chitotriosidase activity in plasma were increased in GCase deficiencies caused by and mutations, whereas -linked deficiency showed only Glucosylsphingosine elevation. GCase activity was reduced in fibroblasts and leukocytes: the decrease was sharper in - and -mutant fibroblasts than -mutant ones; LIMP-2-deficient leukocytes displayed higher residual GCase activity than -mutant ones. Finally, we demonstrated that GCase mainly undergoes proteasomal degradation in LIMP-2-deficient fibroblasts and lysosomal degradation in PSAP-deficient fibroblasts. Thus, we analyzed the differential biochemical profile of GCase deficiencies due to the ultra-rare and biallelic pathogenic variants in comparison with the profile observed in -linked GCase deficiency.
Topics: Glucosylceramidase; Humans; Gaucher Disease; Saposins; Lysosomal Membrane Proteins; Receptors, Scavenger; Fibroblasts; Mutation; Lysosomes; Hexosaminidases; Male; Female
PubMed: 38928321
DOI: 10.3390/ijms25126615 -
International Journal of Molecular... Jun 2024Absent in melanoma 2 (AIM2), a key component of the IFI20X/IFI16 (PYHIN) protein family, is characterized as a DNA sensor to detect cytosolic bacteria and DNA viruses....
Absent in melanoma 2 (AIM2), a key component of the IFI20X/IFI16 (PYHIN) protein family, is characterized as a DNA sensor to detect cytosolic bacteria and DNA viruses. However, little is known about its immunological role during pathogenic (. ) infection, an extracellular bacterial pathogen. In a pathogenic . gas gangrene model, mice are more susceptible to pathogenic . soft tissue infection, revealing the importance of AIM2 in host protection. Notably, deficiency leads to a defect in bacterial killing and clearance. Our in vivo and in vitro findings further establish that inflammasome signaling is impaired in the absence of in response to pathogenic . . Mechanistically, inflammasome signaling downstream of active AIM2 promotes pathogen control. Importantly, pathogenic . -derived genomic DNA triggers inflammasome signaling activation in an AIM2-dependent manner. Thus, these observations uncover a central role for AIM2 in host defense and triggering innate immunity to combat pathogenic . infections.
Topics: Inflammasomes; Animals; Clostridium perfringens; Mice; Signal Transduction; DNA-Binding Proteins; Mice, Knockout; Immunity, Innate; Mice, Inbred C57BL; Gas Gangrene; Disease Models, Animal; Clostridium Infections; Humans
PubMed: 38928277
DOI: 10.3390/ijms25126571 -
International Journal of Molecular... Jun 2024NF2-related schwannomatosis (NF2) is a genetic syndrome characterized by the growth of benign tumors in the nervous system, particularly bilateral vestibular... (Review)
Review
NF2-related schwannomatosis (NF2) is a genetic syndrome characterized by the growth of benign tumors in the nervous system, particularly bilateral vestibular schwannomas, meningiomas, and ependymomas. This review consolidates the current knowledge on NF2 syndrome, emphasizing the molecular pathology associated with the mutations in the gene of the same name, the gene, and the subsequent dysfunction of its product, the Merlin protein. Merlin, a tumor suppressor, integrates multiple signaling pathways that regulate cell contact, proliferation, and motility, thereby influencing tumor growth. The loss of Merlin disrupts these pathways, leading to tumorigenesis. We discuss the roles of another two proteins potentially associated with deficiency as well as Merlin: Yes-associated protein 1 (YAP), which may promote tumor growth, and Raf kinase inhibitory protein (RKIP), which appears to suppress tumor development. Additionally, this review discusses the efficacy of various treatments, such as molecular therapies that target specific pathways or inhibit neomorphic protein-protein interaction caused by deficiency. This overview not only expands on the fundamental understanding of NF2 pathophysiology but also explores the potential of novel therapeutic targets that affect the clinical approach to NF2 syndrome.
Topics: Humans; Neurofibromatoses; Neurofibromin 2; Neurilemmoma; Skin Neoplasms; Animals; Neurofibromatosis 2; Mutation; Signal Transduction; Molecular Targeted Therapy
PubMed: 38928264
DOI: 10.3390/ijms25126558