Search Results (1,098)

Background/Objectives: Prostate needle biopsy often underestimates tumor aggressiveness due to limited tissue sampling, leading to Gleason score upgrading after radical prostatectomy (RP). Phosphatase and Tensin Homolog (PTEN) loss is an established tissue-based marker of adverse prostate cancer biology. This study evaluated whether reduced or absent PTEN immunoreactivity in diagnostic biopsies is associated with subsequent Gleason score and International Society of Urological Pathology (ISUP) Grade Group upgrading in RP specimens. Methods: This retrospective study included 85 prostate cancer patients who underwent multiparametric magnetic resonance imaging (mpMRI)-guided biopsy and subsequent RP. PTEN expression on biopsy samples was assessed via immunohistochemistry. Patients were stratified into PTEN-preserved (PTEN+, n = 75) and PTEN-deficient (PTEN−, n = 10) groups. Results: Upgrading occurred in 70% (7/10) of PTEN-deficient cases compared with 20% (15/75) of PTEN-preserved cases. This difference was statistically significant (two-sided Fisher’s exact p = 0.0024), with PTEN-deficient patients showing a 3.50-fold higher relative risk of upgrading (RR = 3.50, 95% CI: 1.91–6.43). Preoperative PSA levels (p = 0.91) and Prostate Imaging Reporting and Data System (PI-RADS) scores (p = 0.73) did not differ significantly between the groups. Conclusions: Reduced PTEN protein expression, as assessed by immunohistochemistry in prostate needle biopsies, was significantly associated with Gleason score/ISUP Grade Group upgrading at radical prostatectomy. PTEN immunohistochemistry warrants further evaluation as a potentially complementary tissue-based marker of biopsy undergrading. However, the observed unadjusted association does not establish PTEN immunoreactivity as an independent predictor of upgrading. Full article

The study on the valorization of natural resources through cowpea cultivation represents a challenge to mitigate the negative effects of climate change on the environment and on the food security of the population in drought-affected areas globally, and specifically in the sandy soil area of Romania. Thus, the existence in Romania of an area of approximately 439,000 ha with sands and sandy soils, soils with low natural fertility (below 1.2% humus) and with deficient hydrophysical properties, implies finding solutions for their efficient valorization through ecological modeling of the species/varieties structure, depending on the adaptability of the plant in a given area. In this sense, given the economic importance of cowpea, given by the plant’s properties (drought resistance, source of increasing the organic matter content in sands, source of atmospheric nitrogen fixation, good precursor plant, source of protein for humans and animals), the cultivation of this species in a sustainable agricultural system is outlined, as an alternative solution to the cultivation of other leguminous plants. Considered a crop suitable for a climate change scenario, the conservation of genetic biodiversity and the establishment of technological inputs are essential objectives for promoting cowpea in a sustainable agricultural system, given the increasing drought in the world and the increasing need for protein. Full article

Introduction: Restrictive diets are increasingly encountered in pediatric practice and may be adopted voluntarily or prescribed for medical conditions. Although they can support normal growth when appropriately planned, exclusion of nutritionally important foods may increase the risk of nutrient inadequacy. This narrative review examined nutritional deficiencies and laboratory monitoring in children following plant-based, food-allergy elimination, gluten-free, ketogenic, and protein-restricted diets for inherited metabolic disorders. Methods: Targeted searches of PubMed, Scopus, and Web of Science were conducted through 30 June 2026 using pediatric, diet-specific, nutritional-status, and biomarker terms. Because this was a narrative review, the literature was selected and synthesized qualitatively rather than through a formal systematic-screening process; no fixed study count, duplicate independent screening, or formal risk-of-bias assessment was performed. Professional guidelines and position papers were prioritized when discussing monitoring considerations, while pediatric studies were used to describe dietary intake, biochemical findings, clinically manifest deficiency, and growth outcomes. Results: Nutritional risks differed according to the foods or nutrients restricted. Vitamin B12 and iron were major concerns in plant-based diets, whereas cow’s milk and multiple-food elimination increased the risk of inadequate calcium, vitamin D, iodine, protein, and energy intake. Gluten-free diets were commonly associated with low fiber, iron, folate, and B-vitamin intake, particularly when refined, non-fortified products predominated. Ketogenic dietary therapy required attention to selenium, vitamin D, bone-related minerals, carnitine in selected patients, and linear growth. In phenylketonuria and related disorders, nutritional adequacy depended strongly on protein-substitute adherence and appropriate provision of essential amino acids and micronutrients. Across all dietary patterns, laboratory results required interpretation in relation to dietary intake, growth, supplementation, inflammation, medication, and the underlying condition. Across dietary patterns, inadequate intake, biochemical abnormalities, clinically manifest deficiency, and impaired growth were considered related but distinct outcomes. Conclusions: Nutritional monitoring should be individualized and based on the actual dietary restriction and clinical risk. The principal contribution of this review is a practical, risk-based framework that links the specific dietary restriction and adequacy of replacement foods with growth, symptoms, supplementation, and targeted laboratory biomarkers. Full article

Cerebral ischemia–reperfusion injury is a key determinant of a poor outcome after stroke. The mitochondrial uncoupling protein 2 (UCP2) has been implicated in cerebral ischemia-reperfusion injury and in the outcome of ischemic stroke, although its role remains controversial. In C57BL/6J and B6.129S4-Ucp2^tm1Lowl/J (UCP2^−/−) mice, we analyzed cognitive function and lifespan. In an MCAO model induced for one hour, infarct volumes, neurological deficits, and gene expression patterns were determined after 24 h. The UCP2 inhibitor genipin was used in an oxygen-glucose deprivation (OGD) model to investigate synaptic transmission in the hippocampus. Compared to controls, UCP2^−/− mice exhibited a reduced lifespan and displayed impaired cognition. However, in 6-month-old UCP2^−/− mice, the infarct volume was reduced, primarily due to a smaller core size, but not in 18-month-old animals. In both strains, ischemia induced upregulation of antioxidant defense genes, including catalase and SOD1. In the ex vivo ODG model, synaptic transmission was depressed, but pretreatment with genipin prevented the tissue from this impairment. Our findings indicate an infarct-reducing effect of UCP2 deficiency, especially in young-adult mice, and, mechanistically, a neuroprotective effect by genipin in hippocampal slices. Full article

Neurodegenerative diseases represent a major and growing global health burden. Although these disorders are often clinically defined by symptoms and affected brain regions, many are mechanistically linked to abnormal protein accumulation, misfolding, impaired proteostasis, RNA dysregulation, mitochondrial dysfunction, and neuroinflammation. In this Perspective article, I discuss major neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington’s disease, prion diseases, spinocerebellar ataxias, and spinal muscular atrophy, through the lens of disease-associated proteins and experimental modeling. I argue that a protein-centered framework provides a useful approach for understanding disease mechanisms and selecting transgenic mouse models, while recognizing that aging, cellular context, neuroinflammation, mitochondrial dysfunction, vascular dysfunction, and other disease modifiers also shape neurodegeneration. Transgenic and genetically engineered mouse models have been essential for dissecting the pathogenic roles of amyloid-β, tau, α-synuclein, TDP-43, SOD1, FUS, C9ORF72-associated dipeptide repeat proteins, mutant huntingtin, prion protein, ataxins, and SMN deficiency. However, these models have important limitations, including artificial overexpression, familial mutation bias, species differences, and incomplete representation of aging-related sporadic diseases. Rather than seeking a single “best” model, a more productive strategy is to adopt model portfolios tailored to specific biological questions and to integrate mouse studies with human cellular models, postmortem tissue, omics approaches, and biomarker-based validation. Such an approach may improve mechanistic insight, strengthen translational relevance, and enhance the predictive value of preclinical neurodegenerative disease research. Full article

Some mutants of the green alga Chlamydomonas reinhardtii, including the cia3 mutant deficient in the carbonic anhydrase CAH3 in the thylakoid lumen, strongly require high CO₂ supplementation for survival, which is usually explained by disruption at some step(s) of the carbon-concentrating mechanism. This study aimed to determine whether CAH3 contributes to photosystem II (PSII) functional stability under low CO₂ conditions. Two wild-type C. reinhardtii strains and the cia3 mutant were compared for PSII photoinhibition sensitivity, D1 protein stability, pigment content, and PSII photoprotective responses before and after short-term acclimation to low CO₂ growth conditions. Compared with the two wild-type strains, the cia3 mutant exhibited greater PSII sensitivity to increased light intensity after acclimation to low CO₂. In addition, this was accompanied by more pronounced degradation of the D1 protein of PSII, indicating that the absence of CAH3 also affects the structural stability of PSII. At the same time, no differences in pigment content were observed between the strains, and a low contribution of PSII photoprotective mechanisms was detected, indicating that the growth light conditions used were non-stressful for the algal photosynthetic apparatus. The observed data indicate that CAH3 contributes to maintaining the functional and structural stability of PSII under low CO₂, even under non-stressful light growth conditions. Full article

The search for new regulators of the immune response is an important task of modern immunology. In this work, we have found that Mts1 binds with high specificity to the innate immunity receptor TREM-1 and forms a stable complex with it. The same complex was found on the cell surface of macrophages. The appearance of soluble sTREM-1 in a conditioned medium after Mts1 interaction is considered the starting point of receptor activation. PCR analysis indicates activation of proinflammatory genes IL6, IL1β, and TNF after Mts1 administration. Based on these results, Mts1 can be considered a novel TREM-1 ligand. Using limited trypsinolisis, we have identified the epitopes of Mts1 responsible for TREM-1 activation. Similar to the full-length protein Mts1, the 17aa М7 peptide (⁴¹ELPSFLGKRTDEAAFQK⁵⁷) of the Mts1 protein activates the TREM-1 receptor. Incubation of human lymphocytes with the Mts1 protein of its M7 peptide results in the appearance of cytotoxic subpopulations of NK cells and T lymphocytes, able to lyse HLA-deficient cancer cells via apoptosis or necroptosis. Activated lymphocytes induce apoptosis and necroptosis in HLA-negative tumor cells. The new regulatory peptide may be potentially used for the regulation of inflammatory processes and activation of antitumor immunity. Full article

Mitochondrial diseases have traditionally been viewed as energy deficiencies, but current evidence positions mitochondria as central regulators of multiple cell death pathways. This review systematically analyzes the molecular mechanisms of apoptosis and ferroptosis in the context of both primary mitochondrial diseases—caused by mutations in mtDNA or nuclear DNA directly affecting oxidative phosphorylation—and secondary mitochondrial dysfunction associated with broader pathological conditions. Apoptosis is an energy-dependent process characterized by mitochondrial outer membrane permeabilization, cytochrome c release, and caspase cascade activation, whereas ferroptosis involves iron-dependent lipid peroxidation, glutathione depletion, and inactivation of glutathione peroxidase 4 (GPX4), leading to accumulation of oxidized phospholipids predominantly in endoplasmic reticulum and plasma membranes; mitochondrial ultrastructural changes—including volume reduction and cristae loss—represent characteristic morphological features of ferroptosis rather than its primary site of initiation. Key findings reveal that reactive oxygen species overproduction, disruption of reducing equivalent metabolism, iron dyshomeostasis, and calcium overload simultaneously prime cells for both death pathways. Cytochrome c, p53, and BCL-2 family proteins serve as integration hubs, with cardiolipin peroxidation and phospholipid composition influencing pathway switching. Tissue specificity is pronounced in primary mitochondrial diseases: retinal ganglion cells in Leber’s hereditary optic neuropathy, cardiomyocytes in mtDNA-associated cardiomyopathies, and hepatocytes in mtDNA depletion syndromes exhibit distinct dominant death pathways. It should be noted, however, that for many conditions discussed, the evidence for ferroptosis involvement relies on indirect markers—such as lipid peroxidation products, decreased GPX4, and iron deposition—rather than on pharmacological rescue with ferrostatin-1 or liproxstatin-1 and rigorous exclusion of alternative death modalities; this limitation is discussed critically throughout the review. Diagnostic criteria combining morphological, biochemical, and pharmacological tools enable differentiation of death pathways. The review concludes that combined inhibition—using mitochondria-targeted antioxidants, GPX4 modulators, iron chelators, and mPTP blockers—together with personalized diagnostic algorithms offers the most promising therapeutic strategy. Understanding the apoptosis–ferroptosis crosstalk is essential for developing targeted interventions in mitochondrial diseases. Full article

Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT1), the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), provides the UDP-N-acetylglucosamine (UDP-GlcNAc) required for protein glycosylation. Biallelic mutations in GFPT1 cause congenital myasthenic syndromes (GFPT1-CMS), yet the molecular mechanisms linking impaired glycosylation to skeletal muscle dysfunction remain incompletely understood. Here, we combine cellular models of inducible Gfpt1 knockdown and a skeletal muscle-specific Gfpt1 knockout mouse (Gfpt1^Tm1d/Tm1d) with whole-cell proteomics, immunoblot studies and secretomics to define glycosylation-dependent defects in intracellular trafficking, ER stress signaling and autophagy. Global proteomic profiling of Gfpt1-deficient myoblasts revealed marked downregulation of protein trafficking pathways and impaired secretion of key muscle cargo proteins, including serglycin (Srgn). Loss of GFPT1 reduced both high-molecular-weight glycosylated serglycin and its core protein, accompanied by intracellular retention and decreased secretion. These trafficking defects coincide with robust activation of the unfolded protein response (UPR), evidenced by increased Xbp1 expression and accumulation of spliced Xbp1s across pharmacologic, cellular, and mouse models of GFPT1 deficiency. Converging evidence from proteomics, immunoblotting, and immunofluorescence demonstrated impaired autophagy, including increased LC3-II accumulation, elevated p62/Sqstm1 levels, and enhanced p62-positive puncta in both Gfpt1-deficient C2C12 myoblasts and skeletal muscle. Soluble/insoluble fractionation further confirmed p62 accumulation, indicating defective autophagic flux and buildup of aggregated cargo. Together, these findings identify a glycosylation-dependent failure in protein trafficking that triggers ER stress, UPR activation, and autophagy impairment in Gfpt1-deficient skeletal muscle. This mechanistic cascade provides a unifying explanation for muscle pathology in GFPT1-CMS and suggests that restoring glycosylation or improving proteostasis may represent viable therapeutic approaches. Full article

This current research is a narrative review that seeks to establish the occasions under which thrombophilia can result in complications regarding bleeding and thrombosis during pregnancy. Under such circumstances, the influence of vitamin K deficiency is considered, since vitamin K plays an important role in activating the coagulation system. This occurs directly, via the activation of coagulation factors, as well as indirectly, through the activation of proteins S and C. Both proteins play an important role in the hemostatic mechanism of thrombosis and bleeding. However, the risk associated with the relationship between thrombosis and bleeding changes during pregnancy and is heightened by the natural tendency towards hypercoagulability during pregnancy. This paper presents a narrative review of the literature concerning the links between vitamin K, protein C, and protein S in relation to thrombophilia from the perspectives of both biochemistry and medicine, with a special focus on pregnancy. The study examined factors that could be useful to define the balance between hemorrhagic and thrombotic tendency, comparing conventional methods of studying hemostasis with other possible tests that can help better understand the interplay between hemorrhage and thrombosis. Collectively, disorders within the processes associated with vitamin K-mediated blood clotting may have a considerable effect on the woman’s thrombotic risk, especially for women who suffer from thrombophilia. This study confirms the need for monitoring and personalized treatment options to avoid thrombotic and hemorrhagic complications during pregnancy. Full article

CLEC3B (C-type lectin domain family 3 member B), also known as tetranectin (TN), is a secreted trimeric protein containing a C-type lectin-like domain (CTLD). Located on chromosome 3p21.31. CLEC3B maintains organismal homeostasis through roles in immune regulation, angiogenesis, and musculoskeletal biology. Genetic studies demonstrate that CLEC3B deficiency impairs tissue repair, bone mineralization, and fibrinolytic balance. Altered CLEC3B expression is linked to cardiovascular disease progression, autoimmune susceptibility, and cancer prognosis. This review synthesizes CLEC3B’s biological functions and evaluates its translational potential: circulating CLEC3B as a prognostic and diagnostic biomarker; tissue-resident CLEC3B as a predictive marker for therapeutic response; and CLEC3B-related pathways as candidate therapeutic targets for potential amenable to replacement or inhibition strategies. We identify critical research gaps to guide future investigations, including limited structural data, ambiguous glycan specificity, incomplete proteolytic network mapping, and lack of validated disease models. Collectively, these gaps currently preclude definitive therapeutic claims. Full article

RPE65, an isomerohydrolase expressed in retinal pigment epithelium (RPE), is critical for the visual cycle. More than 115 missense variants of the RPE65 gene have been associated with Leber’s congenital amaurosis (LCA), a severe childhood retinal dystrophy. Due to high genetic heterogeneity, the variant-specific pathogenic mechanisms remain largely uncharacterized. In this study we focus on an LCA patient carrying compound heterozygous RPE65 variants (c.200T > G, c.430T > C), aiming to dissect the mechanistic/functional basis of mutated protein-driven retinal degeneration and evaluate gene therapy-mediated restoration using patient-specific hiPSCs-RPE (iRPE). Transient overexpression of wild-type/mutant RPE65 in HEK293T cells showed both variants markedly destabilize the RPE65 protein through the autophagosome–lysosome degradation pathway and its isomerohydrolase activity required for the retinoid visual cycle. We further established a patient-specific iRPE platform suitable for enzymatic activity analysis. Characterization of patient-specific iRPE cells revealed those compound heterozygous variants did not compromise iRPE morphology, most gene expression, or core canonical physiological features of iRPE. However, they significantly downregulate endogenous RPE65 protein abundance and dampen enzymatic function. Subsequently, we delivered RPE65 via adeno-associated viral (AAV) vectors driven by either the ubiquitous CMV promoter or RPE-specific VMD2 promoter into patient iRPE to validate therapeutic potency, and verified that exogenous RPE65 supplementation effectively restores deficient isomerohydrolase activity in this disease model. Collectively, this work elucidates the variant-specific pathogenesis of RPE65-associated LCA and preliminarily assesses the efficacy of gene augmentation, providing preclinical experimental evidence to support the referral of this patient for clinical RPE65 gene replacement therapy. Full article

The Popeye domain-containing protein 1 (Popdc1), also known as Bves, plays a crucial role in maintaining skeletal muscle homeostasis, with its variants leading to limb–girdle muscular dystrophy type R25. Skeletal muscles of patients with the homozygous missense variant of Bves exhibit impaired membrane trafficking, while skeletal muscle fibers in bves^S191F homozygous mutant zebrafish are significantly reduced and disorganized. However, the mechanism by which the absence of bves induces skeletal muscle atrophy remains unclear. In this study, we discovered a novel mechanism whereby bves deficiency drives skeletal muscle atrophy by disrupting mitochondrial structure and function. Our findings indicate that bves knockout leads to a significant decrease in zebrafish’s ability to swim, atrophy of skeletal muscle tissue, loss of cell membrane localization signals, and abnormalities in mitochondrial structure and function. After an 8-week intervention of regular aerobic exercise, the symptoms of skeletal muscle atrophy in bves knockout zebrafish were significantly alleviated, and the expression levels of genes and proteins related to mitochondrial were effectively rescued. These findings establish a connection between bves deficiency-induced disruption of mitochondrial structure and function and the onset and progression of skeletal muscle tissue atrophy symptoms, thereby laying a molecular foundation for exercise rehabilitation strategies in atrophic myopathy. Full article

Background/Objectives: Signaling mediators of PPARγ influence pathways involved in adipogenesis, lipid storage, inflammation, energy-related processes, and glucose utilization. Recent research indicates that PPARγ coregulators, recruited or released during ligand binding, govern specific gene pathways. It was recently discovered that Gα_q, a heterotrimeric G protein subunit, also signals to PPARγ and may significantly affect adipogenesis and glucose sensitivity. Methods: To explore Gα_q’s role in adipocytes, we generated CRISPR-mediated Gα_q (Gnaq) knockout (Gnaq KO) and scramble control cells from 3T3-L1 preadipocytes. Results: The absence of Gα_q resulted in increased lipid accumulation and elevated serine 273 (but not serine 112) phosphorylation of PPARγ. Gα_q deficiency also decreased mitochondrial abundance and respiration in response to PPARγ ligands such as rosiglitazone, pioglitazone, and troglitazone. RNA sequencing comparing differentiated Gnaq KO and control adipocytes identified over 800 differentially expressed genes, including those associated with enhanced lipid metabolism and reduced inflammation. Corresponding PamGene kinome profiling showed increased serine/threonine kinase activity and decreased phosphotyrosine kinase signaling in Gnaq KO adipocytes. Conclusions: These findings support Gα_q as a regulator of adipocyte function, linking kinase signaling pathways to PPARγ-mediated transcription. This research provides mechanistic insights into targeting Gα_q as a potential treatment for individuals with obesity and metabolic disorders. Full article

We previously showed that TCEA1 deficiency in myeloid cells promotes proliferation, impairs differentiation and inhibits apoptosis, but its role and underlying mechanism in acute myeloid leukemia (AML) are unknown. Here, in NB-4 cells, an M3 subtype of AML, TCEA1 overexpression suppressed proliferation (p < 0.001), induced S-phase arrest (from 35.35% to 19.47%, p < 0.001), increased apoptosis (from 10.37% to 23.5%, p < 0.001), and promoted differentiation. Mechanistically, TCEA1 overexpression upregulated C/EBPε and IRF8 at the mRNA and protein levels; conversely, TCEA1 knockdown downregulated both. Rescue experiments in TCEA1 knockdown 32Dcl3 cells showed that ectopic C/EBPε or IRF8 reversed the uncontrolled proliferation, blocked apoptosis, and impaired differentiation. In xenograft mouse models, TCEA1 overexpression reduced leukemic infiltration in the bone marrow, spleen, and liver; extended overall survival; and elevated C/EBPε and IRF8 expression in vivo. Analysis of public APL datasets revealed that high TCEA1 expression is associated with a favorable prognosis (HR = 0.43, 95% CI: 0.2–0.93, logrank p = 0.028). Collectively, our findings demonstrate that TCEA1 suppresses proliferation, promotes apoptosis and differentiation, and attenuates disease progression by upregulating C/EBPε and IRF8, positioning this regulatory mechanism as a potential therapeutic target and prognostic biomarker for this disease. Full article