Search Results (1,665)

Background and Objective: Intervertebral disc degeneration (IVDD) is a leading cause of lower back pain with limited regenerative treatments. Among emerging regenerative approaches, growth factor-based therapies, such as recombinant human transforming growth factor-beta (Rh-TGF-β), have shown potential for disc regeneration but are hindered by rapid degradation and uncontrolled release by direct administration. Additionally, mechanical stress elevates heat shock protein 90 (HSP-90), impairing cell function and extracellular matrix (ECM) production. This study aimed to investigate a dual self-cross-linked alginate di-aldehyde (ADA) hydrogel system for the sustained delivery of Rh-TGF-β and epigallocatechin gallate (EGCG) to enhance protein stability, regulate release, and promote disc regeneration by targeting both regenerative and stress-response pathways. Methods: ELISA and UV-Vis spectrophotometry assessed Rh-TGF-β and EGCG release profiles. A rat tail IVDD model was established with an Ilizarov-type external fixator for loading, followed by hydrogel treatment with or without bioactive agents. Disc height, tissue structure, and protein expression were evaluated via radiography, histological staining, immunohistochemistry, and Western blotting. Results: The hydrogel demonstrated a biphasic release profile with 100% Rh-TGF-β released over 60 days and complete EGCG release achieved within 15 days. Treated groups showed improved disc height, structural integrity, and proteoglycan retention revealed by histological analysis and elevated HSP-90 expression by immunohistochemistry. In contrast, Western blot analysis confirmed that EGCG effectively downregulated HSP-90 expression, suggesting a reduction in mechanical stress-induced degeneration. Conclusions: ADA hydrogel effectively delivers therapeutic agents, offering a promising strategy for IVDD treatment. Full article

Straw returning inhibits tillering at the early stage of rice growth and thus affects grain yield. Sulfur-coated urea (SCU) has been expected to increase nitrogen use efficiency (NUE) and yield, save labor input, and reduce environmental pollution in crop production. Nevertheless, the sulfur coatings of SCU are easy to break and then shorten the nutrient release cycle. Whether there was a complementary effect between straw returning and SCU in NUE and grain yield had remained elusive. To investigate the effects of straw returning combined with the application of SCU on NUE and rice yield, a two-year field experiment was conducted from 2022 to 2023 with three treatments (straw returning combined with conventional urea (SRU), no straw returning combined with SCU (NRS), straw returning combined with SCU (SRS)). We found that straw returning combined with the application of SCU increased rice yield and NUE significantly. Compared with SRU and NRS, SRS treatments significantly increased grain yield by 14.61–16.22%, and 4.14–7.35%, respectively. Higher effective panicle numbers per m² and grain numbers per panicle were recorded in NRS and SRS treatments than SRU. SRS treatment increased nitrogen recovery efficiency by 79.53% and 22.97%, nitrogen agronomic efficiency by 18.68% and 17.37%, and nitrogen partial factor productivity by 10.51% and 9.81% compared with SRU and NRS treatment, respectively. The enhanced NUE in SRS was driven by higher leaf area index, SPAD value, net photosynthetic rate, carbon metabolic enzyme (RuBP and SPS) activity, nitrogen metabolic enzyme (NR, GS, and GOGAT) activity, sucrose and nitrogen content in leaves, and nitrogen accumulation in plant during grain filling. Moreover, the improved yield in SRS was closely related to superior NUE. In conclusion, straw returning combined with application of SCU boosted grain yield and NUE via enhanced carbon–nitrogen metabolism during the late growth period in rice. Full article

Background: Astrocytes are not only structural cells but also play a pivotal role in neurogenesis and neuroprotection by secreting a variety of neurotrophic factors that support neuronal survival, growth, and repair. This study investigates the time-dependent responses of primary rat cortical astrocytes to oxygen–glucose deprivation (OGD) and evaluates the neuroprotective potential of astrocyte-conditioned medium (ACM). Methods: Primary rat cortical astrocytes and neurons were obtained from postnatal Sprague Dawley rat pups (P1–3) and embryos (E17–18), respectively. Astrocytes exposed to 6, 24, and 48 h of OGD (0.3% O₂) were assessed for viability, metabolic function, hypoxia-inducible factor 1 and its downstream genes expression. Results: While 6 h OGD upregulated protective genes such as Vegf, Glut1, and Pfkfb3 without cell loss, prolonged OGD, e.g., 24 or 48 h, led to significant astrocyte death and stress responses, including elevated LDH release, reduced mitochondrial activity, and increased expression of pro-apoptotic marker Bnip3. ACM from 6 h OGD-treated astrocytes significantly enhanced neuronal survival following 6 h OGD and 24 h reperfusion, preserving dendritic architecture, improving mitochondrial function, and reducing cell death. This protective effect was not observed with ACM from 24 h OGD astrocytes. Furthermore, 6 h OGD-ACM induced autophagy in neurons, as indicated by elevated LC3b-II and decreased p62 levels, suggesting autophagy as a key mechanism in ACM-mediated neuroprotection. Conclusions: These findings demonstrate that astrocytes exhibit adaptive, time-sensitive responses to ischemic stress and secrete soluble factors that can confer neuroprotection. This study highlights the therapeutic potential of targeting astrocyte-mediated signalling pathways to enhance neuronal survival following ischemic stroke. Full article

Diabetic retinopathy (DR), a leading cause of blindness in working-age adults, arises from chronic hyperglycemia-induced oxidative stress, inflammation, and vascular dysfunction. Current therapies such as laser photocoagulation, intravitreal anti-vascular endothelial growth factor (VEGF) agents, and steroids target advanced stages but fail to prevent early neuronal and microvascular damage. Emerging evidence highlights oxidative stress as a key driver of DR pathogenesis, disrupting the blood-retinal barrier (BRB), promoting neurodegeneration and angiogenesis. Advances in imaging, particularly optical coherence tomography angiography (OCTA), enable earlier detection of neurodegeneration and microvascular changes, underscoring DR as a neurovascular disorder. Polyphenols, such as resveratrol, curcumin, and pterostilbene, exhibit multitarget antioxidant, anti-inflammatory, and anti-angiogenic effects, showing promise in preclinical and limited clinical studies. However, their low bioavailability limits therapeutic efficacy. Nanotechnology-based delivery systems enhance drug stability, tissue targeting, and sustained release, offering potential for early intervention. Future strategies should integrate antioxidant therapies and precision diagnostics to prevent early irreversible retinal damage in diabetic patients. Full article

Creep and stress sensitivity can lead to the long-term conductivity degradation of fractures, and this influences the accuracy of long-term productivity predictions in ultra-deep carbonate reservoirs (UDCRs). However, the current models do not consider these two factors. For the long-term conductivity degradation of acid-etched symmetry fractures in UDCRs, a new fracture permeability evolution model incorporating creep and stress sensitivity effects was established. Building upon this, a numerical simulation model for UDCRs was developed for the first time to quantitatively analyze the impacts of creep, stress sensitivity, and production strategies on well productivity. The research revealed that the creep and stress sensitivity characteristics of acid-etched fractures had a significant impact on the well productivity for UDCRs. The larger the creep coefficient and stress sensitivity coefficient, the lower the oil well productivity. The larger the initial reservoir pressure and drawdown pressure, the higher the daily production and cumulative production of the oil well, but the cumulative production growth rate decreased. The cumulative production in the early stage of the released-pressure production was significantly higher than that of the pressure-controlled production, but with the increase in the pressure-controlled time, the cumulative production reversed. When the pressure was controlled for three years, the cumulative production increased by 5952 m³ (38.8%); as the creep coefficient increased, the cumulative production increased by greater than the pressure-released production. This shows that the larger the creep coefficient, the better the effect of controlling pressure production. The research results can provide a theoretical basis and technical support for the efficient development of UDCRs. Full article

Antibody–drug conjugates (ADCs) have revolutionized precision oncology by enabling targeted drug delivery with improved therapeutic indices. Among these, deruxtecan (DXd)-based ADCs have demonstrated remarkable efficacy across a range of cancers, particularly in tumors expressing human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 3 (HER3), and trophoblast cell surface antigen 2 (TROP2), including breast, lung, gastric, and other solid tumors. DXd, a potent topoisomerase I inhibitor, enhances the cytotoxic potential of ADCs through a cleavable and stable linker and a high drug-to-antibody ratio that ensures optimal drug release. The clinical success of trastuzumab DXd (Enhertu^®) and datopotamab DXd (Datroway^®), along with the ongoing development of patritumab DXd, has expanded the therapeutic potential of ADCs. However, challenges remain, including toxicity, resistance, and manufacturing scalability. This review discusses the mechanisms of action, clinical progress, and challenges of DXd-based ADCs, highlighting their transformative role in modern oncology and exploring future directions to optimize their efficacy and accessibility. Full article

4-Aminodiphenylamine (4-ADPA) is a common additive in rubber tires, known for its antioxidant properties. It plays a crucial role in enhancing tire durability by preventing issues such as drying, cracking, and degradation from prolonged exposure to environmental factors like heat, oxygen, and ozone. However, despite its advantages in extending tire lifespan, the use of 4-ADPA raises significant environmental concerns. As tires wear down, microscopic tire wear particles (TWPs) containing 4-ADPA are released into the environment with substantial leaching, contaminating the waterways. The 4-ADPA leachates pollute and pose a threat to aquatic ecosystems, affecting various forms of marine life. The current study investigates the ecotoxicological effects of 4-ADPA on the aquatic plant Lemna minor (L. minor), focusing on its impact on relative growth and physiological biomarkers. Several parameters were assessed to evaluate ecotoxicity, including frond morphology, fresh biomass, total frond number, chlorophyll content, and starch accumulation. L. minor was grown for 7 and 14 days under controlled laboratory conditions using Hoagland media with varying concentrations of 4-ADPA (10–100 μg/L), while a control group was maintained in media without 4-ADPA. The results indicate that exposure to 4-ADPA led to a dose-dependent reduction in fresh biomass, total frond number, and chlorophyll levels. Lugol’s staining revealed increased starch accumulation in the fronds after exposure to 4-ADPA. The biological effects observed in L. minor following exposure to 4-ADPA, even at environmentally relevant concentrations, demonstrate a significant ecotoxicological impact on aquatic ecosystems. Further research involving additional species and investigating the mechanisms behind 4-ADPA toxicity is recommended to better understand its long-term consequences. Full article

Dissolved arsenic in private bedrock drinking water wells is a problem in eastern Wisconsin. Previous studies have identified bedrock sources of arsenic as discrete intervals within the local Paleozoic sedimentary section and have also identified release mechanisms causing arsenic to enter well boreholes. However, widespread contamination modeling is hindered by a lack of 3-D knowledge constraining the depth of the arsenic-bearing units in the subsurface. The growth and improvement of 3-D geologic mapping provides an opportunity to improve predictive models. This study in eastern Wisconsin, USA, uses a multivariate binary logistic regression analysis combined with 3-D geologic mapping to both assess various geologic and well construction factors that impact arsenic occurrence, and improve the ability to predict contamination risk. We find well construction characteristics, the stratigraphic unit within the open interval of a well, and the proximity to fold axes/fault zones are all statistically significant variables that impact the probability of a well exceeding either 2 or 10 µg/L dissolved arsenic. We apply these results by using 3-D mapping to determine the geologic unit present within the open interval of thousands of untested wells and use the logistic regression results to calculate contamination probability. This allows arsenic risk to be rapidly estimated for thousands of individual groundwater wells, and models of potential casing regulations to be assessed. Full article

Plant diseases caused by Rhizoctonia solani present a significant challenge in agriculture. While chemical pesticides remain a common control strategy, their use leads to health and environmental problems. In contrast, endophytic bacteria with plant growth-promoting (PGP) activity offer a promising, sustainable alternative. In this context, a novel endophytic Priestia megaterium strain, KW16, originated from the bluegrass (Poa pratensis L.), demonstrated distinct biocontrol potential against R. solani. in vitro assays showed that KW16 inhibited R. solani growth by up to 58%, primarily by releasing volatile compounds. In planta experiments further highlighted KW16′s ability to colonize oilseed rape internal tissues, significantly enhancing its growth and development. In the presence of the pathogen, KW16 abolished the negative impact of R. solani and promoted plant growth, increasing shoot and root biomass by 216% and 1737%, respectively, when compared to the plants grown in fungal-infested soil. Biochemical and genome analyses confirmed the strain’s metabolic versatility, resistance to biotic and abiotic factors, and a whole spectrum of PGP and biocontrol traits such as biofilm formation, production of phytohormones, and synthesis of lytic enzymes, siderophores, and volatiles, alongside its ability to survive in the presence of autochthonous soil microflora. These findings position KW16 as a potent biological alternative to synthetic fungicides, with significant potential for sustainable crop protection. Full article

Seed germination is the initial step in a plant’s life cycle; it is precisely regulated by many factors at the molecular and biological levels. Reversible protein phosphorylation, which is regulated by protein kinases and protein phosphatases, plays a key role in hormone signal transduction, energy metabolism, stress response, and plant growth and development, including seed germination. This review provides a comprehensive elucidation of the coordinated regulatory mechanisms mediated by kinases and phosphatases during seed germination, with particular emphasis on their dynamic interplay and reciprocal modulation within biological signaling networks. Through the systematic integration of current research findings, we mechanistically dissect the sophisticated phosphorylation–dephosphorylation circuitry that governs metabolic activation, hormonal signaling transduction, and cellular homeostasis in germinating seeds. Furthermore, we propose a novel conceptual framework that delineates the spatiotemporal cooperation between these opposing enzymatic activities in regulating dormancy release and developmental transitions. The current challenges in the field of seed germination research are critically examined, and potential future investigative trajectories are outlined, aiming to establish a robust theoretical framework for elucidating the molecular mechanisms underlying seed dormancy regulation, as well as translating these findings into innovative agricultural production practices. Full article

Background/Objectives: To study the efficacy and pharmacological mechanism of the dual-target liposome complex AD808 in the treatment of Alzheimer’s disease. Methods: Using APP/PS1 mouse models, the therapeutic efficacy and pharmacological mechanism of AD808 on Alzheimer’s disease were studied through water maze tests, brain tissue staining, immunofluorescence, and ELISA for inflammatory and neurotrophic factors. Results: AD808 exhibited significant pharmacodynamic effects in improving behavioral and cognitive abilities (70% reduction in escape latency) and repairing damaged nerve cells (90% reduction in Aβ plaque) in Alzheimer’s disease mice. The efficacy of the liposome complex AD808 was significantly better than that of ST707 or gh625-Zn₇MT3 alone. AD808 significantly reduced brain inflammation (57.3% and 61.5% reductions in TNF-α and IL-1β, respectively) in AD (Alzheimer’s disease) mouse models and promoted the upregulation of neurotrophic factors and nerve growth factors (142.8% increase in BDNF, 275.9% in GDNF, and 111.3% in NGF-1) in brain homogenates. By activating the PI3K/AKT signaling pathway in brain microglia, AD808 upregulated TREM2 protein expression and removed Aβ amyloid plaques in the brain. Additionally, it promoted the transition of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, regulated the M1/M2 balance, released anti-inflammatory and neurotrophic factors, reduced chronic inflammation, and enhanced neurological repair. Based on these results, the potential pharmacological mechanism of AD808 against Alzheimer’s disease was proposed. Conclusions: As a dual-target liposome complex, AD808 has shown promising therapeutic potential in the treatment of Alzheimer’s disease, providing a new strategy for innovative drug development. Full article

Obesity, hypertension, and chronic kidney disease (CKD) constitute the deadly trinity of modern threats for populations of both developed and developing countries. These diseases (together with type 2 diabetes) are closely linked in their pathophysiology and result in increasing cardiovascular (CV) morbidity and premature death from CV causes. In this review, we focused on the kidney as the target of obesity-related disorders. Obesity-related glomerulosclerosis (ORG) represents a pattern of renal injury caused solely or predominantly by obesity; usually, it is superimposed on chronic kidney disease (CKD) from other causes, such as diabetic kidney disease, hypertensive kidney disease, type 2 cardiorenal syndrome, primary or secondary glomerulopathies, and others. Adipose tissue contributes to kidney injury in several ways: it releases proinflammatory cytokines and growth factors, leading to podocyte and mesangial cell injury and glomerulosclerosis. In particular, perirenal adipose tissue (PRAT), besides exerting paracrine and endocrine effects on the kidney, modifies its function via compression on renal parenchyma and vessels. The intrinsic ability of the kidneys in obesity to increase the reabsorption of sodium warrants intraglomerular hypertension and hyperfiltration, followed by progressive renal injury. Lifestyle interventions and pharmacological agents, as well as metabolic (bariatric) surgery resulting in weight reduction, may also be beneficial for the kidneys. Using GLP1 receptor agonists (with a special focus on subcutaneous semaglutide and tirzepatide) seems to be the most promising treatment strategy for preventing kidney injury in obese individuals. Full article

The role of abiotic factors in the allelopathic interactions between copepods and rotifers is poorly documented. Temperature has a marked effect on the metabolism of zooplankton. Therefore, the release of allelochemicals by copepods and the response of rotifers to them may change as temperatures increase. Here, we tested the effect of two temperatures (20 and 25 °C) on the population growth of Brachionus havanaensis cultured on a conditioned medium (CM) of Arctodiaptomus dorsalis and Eucyclops sp. The CM was obtained daily, separately, for the males and females of both copepod species at a density of 0.1 ind. mL⁻¹ for 24 h prior to experiments. In the controls and CM treatments, higher temperatures had a stimulatory effect on the population growth and the rate of population increase (r) of B. havanaensis. At 25 °C, the CM from the females and males of A. dorsalis caused >30% increase in r, but for the CM from Eucyclops sp., this effect was lower (<21%). At 20 °C, the r in the controls and CM treatments was not significantly different. The morphometry of B. havanaensis varied depending on the treatments. Compared to controls, longer loricae were recorded in the CM of male A. dorsalis at both temperatures. However, in the CM of female calanoids, longer rotifers were observed only at higher temperatures. At 20 °C, the CM from Eucyclops produced smaller loricae. The relationship between the lorica length and width of rotifers showed a linear relation but the slope differed among the treatments. Full article

Neurotrophins, such as brain-derived neurotrophic factor (BDNF) and neurosteroids, including allopregnanolone (ALLO), play critical roles in modulating neuronal activity in the brain. Levels of these compounds dynamically fluctuate in response to physiological and environmental conditions, particularly stress, suggesting complex regulatory interactions. This study aimed to explore the effects of acute stress and ALLO (individually and combined) on hippocampal expression of BDNF, its TrkB receptor, and other neurotrophins in sheep, a translational large animal model. Adult, luteal-phase sheep (n = 24), implanted with a guide cannula into the third brain ventricle, were divided into four experimental groups: (i) 3 days of Ringer–Locke solution (RL) infusion as the control; (ii) 3 days of RL infusion with 4 h acute stress on day three; (iii) 3 days of ALLO infusion (4 × 15 µg/60 µL/30 min) with 4 h acute stress on day three; and (iv) 3 days of ALLO infusion alone (n = 6 per group). Both acute stress and ALLO alone significantly reduced BDNF concentration and BDNF transcript abundance in the hippocampal CA1 and CA3 fields compared to the control group. The combined application of both stress and ALLO resulted in decreased levels of these parameters, except for BDNF concentration in the CA3 region. Additionally, TrkB mRNA expression in both hippocampal fields was significantly reduced in all treatment groups. Changes in mRNA levels for other neurotrophins, including nerve growth factor (NGF) and neurotrophin 3 (NT3) and 4 (NT4), varied under experimental conditions. While an inhibitory effect was predominant, NGF expression in the CA1 region remained unaffected by stress or ALLO. Interestingly, stress alone induced a significant increase in NT4 mRNA expression in the CA3 field compared to the control. In conclusion, the study demonstrated that a 4 h acute stress exposure inhibited the synthesis of BDNF, TrkB, and several other neurotrophins in the sheep hippocampus. Furthermore, ALLO, whose increased levels are highly correlated with the initial stress response, may serve as a mediator of this stress effect, temporarily preventing over-stimulation of hippocampal BDNF release and signaling. Full article

Skeletal muscle, traditionally recognized for its motor function, has emerged as a key endocrine organ involved in metabolic regulation and interorgan communication. This narrative review addresses the dual role of muscle as a target tissue for classical hormones—such as growth hormone (GH), insulin-like growth factor type 1 (IGF-1), thyroid hormones, and sex steroids—and as a source of myokines, bioactive peptides released in response to muscle contraction that exert autocrine, paracrine, and endocrine effects. Several relevant myokines are discussed, such as irisin and Metrnl-like myokines (Metrnl), which mediate exercise-associated metabolic benefits, including improved insulin sensitivity, induction of thermogenesis in adipose tissue, and immunometabolic modulations. It also examines how muscle endocrine dysfunction, caused by chronic inflammation, hormone resistance, or sedentary lifestyle, contributes to the development and progression of metabolic diseases such as obesity, type 2 diabetes, and sarcopenia, highlighting the importance of muscle mass in the prognosis of these pathologies. Finally, the therapeutic potential of interventions aimed at preserving or enhancing muscle function—through physical exercise, hormone therapy and anabolic agents—is highlighted, together with the growing research on myokines as biomarkers and pharmacological targets. This review expands the understanding of muscle in endocrinology, proposing an integrative approach that recognizes its central role in metabolic health and its potential to innovate the clinical management of endocrine–metabolic diseases. Full article