Search Results (314)

Esophageal squamous cell carcinoma (ESCC) represents a major therapeutic challenge due to the rapid development of resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Recent evidence highlights that this resistance is driven not only by genetic mutations but also by spatial heterogeneity of tumor microenvironments and compensatory signaling mechanisms. In this review, we propose a “spatial-signaling-intervention” framework with a particular focus on the NTRK2/MAPK signaling axis, which plays dual roles in signaling compensation and immune evasion. By integrating spatial multi-omics, proteomics, and AI-assisted topological modeling, three resistant niches are identified: (1) cancer stemness-enriched zones, (2) MAPK hyperactive islands, and (3) immune-cold regions. Based on this atlas, we design precision nanotherapeutic platforms, including responsive, dual-target, and feedback-loop nanocarriers, to selectively modulate resistant spatial niches. Preclinical validation in patient-derived xenografts and organoid models further demonstrates the translational potential of these strategies. This work provides a conceptual and technological roadmap for overcoming EGFR-TKI resistance in ESCC. Atlas-guided nanocarrier systems offer a promising avenue for spatially targeted and feedback-responsive therapy, highlighting the role of pharmaceutics in advancing precision oncology. Full article

Climate change reshapes crop–weed interactions and challenges the cultivation of oilseed rape (Brassica napus L.). Common ragweed (Ambrosia artemisiifolia L.) strongly suppresses early crop development, increases stress sensitivity and leads to yield loss. The stress–physiological responses of oilseed rape to ragweed competition were investigated using a combination of conventional and non-invasive methods. A pot experiment was conducted with increasing ragweed densities (0, 1, 3, 5 and 10 plants). Plant height and biomass were evaluated via non-destructive indicators (SPAD, NDVI) and different stages (1–15 and 16–30 min) of delayed fluorescence (DF) alongside ferric reducing antioxidant power (FRAP). Increasing ragweed density caused changes in growth, altered DF magnitude and decay kinetics, indicating photosynthetic imbalance. Moderate weed competition (1–5) induced an adaptive, eustress-like response characterised by enhanced non-enzymatic antioxidant capacity, whereas higher ragweed densities overwhelmed this compensatory mechanism, resulting in oxidative stress-like responses. Among all measured traits, DF₁–₁₅ proved to be the earliest and most sensitive indicator of the transition from adaptive to disruptive stress: T1: 0 ragweed: 213.07 ± 10.36 cps/mm² and 92.66 ± 6.67 cps/mm². These results demonstrate that delayed fluorescence, combined with conventional physiological and antioxidant-based parameters, enables the early detection of competitive stress in oilseed rape well before visible symptoms appear. Full article

Grassland degradation, exacerbated by climate change and anthropogenic disturbances, poses a substantial barrier to ecological restoration, largely due to the invasion of toxic weeds. In the degraded grasslands of the Ili River Valley, Xinjiang, Sophora alopecuroides has emerged as the dominant toxic species; yet, its expansion mechanisms and sensitivity to management interventions remain poorly understood. This study utilized a three-year (2023–2025) field experiment to evaluate the impacts of nitrogen addition (N), mowing (M), and their combination (NM) on the stoichiometric characteristics and homeostasis of the plant–soil system. The results demonstrated that while M suppressed aboveground biomass, it facilitated the accumulation of root carbon (RC) and phosphorus (RP). Nitrogen enrichment significantly lowered soil C:N and C:P ratios, thereby alleviating phosphorus limitation. Crucially, the NM treatment effectively counteracted N-induced weed proliferation and mitigated M-induced biomass reductions. Analysis of stoichiometric homeostasis revealed that NM optimized plant adaptive strategies, maintaining strict homeostasis for RC and RP (H > 4) while preserving the sensitivity of the root N:P ratio of S. alopecuroides (RN:P). Structural equation modeling further indicated that soil C:P and N:P indirectly regulated total biomass by modulating the root C:P ratio of S. alopecuroides (RC:P). Consequently, stoichiometric coupling within the plant–soil system is essential for maintaining ecosystem functions. Integrated management (NM) optimizes soil nutrient balance and harnesses compensatory growth to suppress weed expansion, providing a robust scientific framework for the restoration of S. alopecuroides-invaded grasslands. Full article

Acetaminophen (APAP) overdose is a major cause of acute liver failure and can be fatal, often without early symptoms. Protein deficiency, arising from illness or inadequate diet, impairs growth, immunity, and tissue repair. Both conditions can harm the kidneys, yet the impact of energy imbalance on renal physiology remains unclear. In this study, APAP toxicity and a low-protein diet induced behavioral suppression and tissue damage, as evidenced by reduced whole-body, liver, and kidney weights in rats. In kidney mitochondria of rats exposed to only toxic APAP doses, ATP levels declined sharply while ADP and AMP increased. AMP deaminase and ATPases’ activities rose about twofold and 1.5-fold, respectively, whereas cytosolic 5′-nucleotidase activity fell nearly threefold, suggesting compensatory responses to disrupted energy balance. The strongest reductions in ATP and the greatest increases in AMP and ATPase activity occurred in APAP-intoxicated rats fed a low-protein diet. This combination also intensified lipid peroxidation and oxidative protein damage, evidenced by elevated TBARS, reduced protein SH-groups, and increased protein carbonyls. Overall, APAP intoxication with protein deficiency disrupts renal energy metabolism, leading to mitochondrial dysfunction and structural kidney injury. Nutritional status therefore critically influences drug-induced nephrotoxicity, and antioxidant strategies may help prevent damage under metabolic stress. Full article

Introduction: Human breast milk (HBM) is a critical source of nourishment for newborns, containing bioactive compounds that influence infant growth and metabolic programming. Among these compounds, leptin—a hormone primarily produced by adipocytes but also synthesized in the mammary gland—has gathered attention for its potential role in regulating energy balance and body weight. This study investigates the influence of maternal factors on HBM leptin concentrations and explores their associations with neonatal growth parameters. Material and Methods: 262 HBM samples were collected from healthy lactating mothers through Spanish Biobanks during the first six months postpartum. Data on maternal characteristics (body mass index (BMI), age, physical activity, parity, and delivery type) and neonatal measurements (weight, length, and head circumference) were collected. Leptin concentrations in skimmed HBM were measured using the ELISA technique (R&D Systems™, Minneapolis, MN, USA). Statistical analyses were conducted using R version 4.3.1 and MATLAB R2023a, with significance set at p < 0.05. Results: Leptin levels were highest in and declined over time, reaching a stable level after the first month of lactation. Preterm deliveries exhibited significantly higher leptin concentrations than term deliveries (0.42 vs. 0.07 ng/mL). Higher leptin levels were also observed in younger and primiparous mothers. Maternal BMI was positively associated with leptin concentration, with mothers who had elevated BMI showing higher levels than those with optimal BMI (0.36 vs. 0.05 ng/mL). Maternal physical activity was not associated with leptin concentrations in univariate analyses; although greater self-reported physical activity appeared associated with lower leptin concentrations in regression models, this finding should be interpreted cautiously and should not be considered evidence of an independent or consistent effect. Neonatal growth parameters (weight, length, and head circumference) were negatively correlated with HBM leptin concentrations. Conclusions: Our findings indicate that leptin levels in breast milk reflect both maternal metabolic status and neonatal characteristics and may represent a compensatory mechanism in preterm infants. HBM leptin levels are modulated by maternal BMI, age, parity, and delivery type, and are associated with neonatal growth parameters. Full article

Betaphycus gelatinus, a member of the Eucheumatoideae, serves as the primary source for carrageenan extraction and has significant economic value. The growth and reproduction of B. gelatinus are significantly impacted by seasonal fluctuations in seawater temperature. To explore its adaptive mechanisms under temperature stress, we cultured the algae at 15 °C (Low temperature, LT), 27 °C (Medium temperature, MT), and 36 °C (High temperature, HT) for 2 h and conducted subsequent physiological, transcriptomics, and metabolomics analyses. The photosynthetic performance of B. gelatinus significantly declined under both LT and HT stress conditions. Carotenoid content increased significantly under LT conditions, while chlorophyll a showed no significant change. Phycocyanin and phycoerythrin decreased significantly under LT conditions, but there was no significant difference under HT conditions. Under LT stress, glutathione (GSH) levels, ascorbate peroxidase (APX) activity, and catalase (CAT) activity all increased significantly. Under HT stress, APX and CAT activities increased significantly, while superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels remained unchanged. Transcriptomics and metabolomics analyses suggested that photosynthesis, carbohydrate metabolism, amino acid biosynthesis, porphyrin metabolism, and vitamin B6 metabolism are involved in the acute temperature stress response of B. gelatinus. Under both HT and LT, most genes in the targeted metabolic pathways were significantly downregulated (p < 0.05), while only a few were upregulated. Specifically, in carbohydrate metabolism, only nine genes were upregulated, while all others were downregulated. Moreover, all the genes involved in photosynthesis, photosynthetic carbon fixation, arginine biosynthesis, and porphyrin metabolism were downregulated. In contrast, only four genes involved in GSH metabolism, alanine, aspartate, and glutamate metabolism, and glycine, serine, and threonine metabolism were upregulated. These results suggest that temperature stress markedly suppresses the transcription of key genes in these pathways and that the few upregulated genes in these pathways may contribute to compensatory mechanisms or regulatory network reprogramming during stress responses. These findings help clarify how B. gelatinus adapts to different temperature stresses and provide a basis for developing improved germplasm to support stable production under climate variability. Full article

Amid the intensifying global mandate for sustainable aquafeed strategies, this study investigates the functional efficacy and biochemical implications of black soldier fly larvae oil (BLO), extracted via recently approved patent method depending on cold-aqueous process, as a substitute for conventional fish oil (FO) in zebrafish (Danio rerio) diets. The refined extraction technique, representing an advancement over traditional aqueous methodologies, was engineered to selectively preserve bioactive lipid fractions while minimizing environmental footprint and processing residues. Over a 28-day feeding period, adult zebrafish were allocated into triplicate groups and fed diets comprising 0%, 50%, and 100% substitution of FO with BLO and growth, lipid composition, and dietary fatty acid profiles of both diets and flesh were rigorously evaluated. Zebrafish fed the BLO₁₀₀ diet exhibited the most pronounced somatic growth (2.47 ± 0.01 g), significantly elevated specific growth rates (3.88 ± 0.82% day⁻¹), and the most efficient feed conversion, without compromising survival. Flesh lipid analysis revealed a substantial enrichment in saturated fatty acids—most notably lauric acid (C12:0)—corresponding to increasing dietary BLO levels. Although dietary EPA and DHA levels were reduced, DHA concentrations in fish tissues remained comparable to those of the control group, indicating a compensatory capacity mediated by endogenous elongation and desaturation pathways. These findings substantiate the dual potential of BLO as both a nutritionally viable lipid source and a vector for enhancing aquafeed sustainability. The cold-aqueous extraction method demonstrated here underscores a pivotal advancement in green lipid processing, aligning oil quality with ecological stewardship. This integrative approach not only reinforces BLO’s candidacy as a strategic fish oil substitute but also delineates a pathway toward scalable, species-adapted feed innovation. Future investigations should prioritize the modulation of fatty acid profiles through dietary and extraction optimization to fully realize the translational potential of insect-derived lipids in aquaculture. Full article

Metabolic reprogramming allows cancer cells to proliferate rapidly, survive nutrient limitation, and resist stress, making tumor metabolism an important therapeutic target. However, pharmacological inhibition of metabolic enzymes often causes systemic toxicity and compensatory pathway activation. To overcome these limitations, recent studies have highlighted an alternative host-centered strategy based on increasing systemic energy expenditure. Recent studies highlight an alternative strategy in which the host increases energy expenditure through uncoupling protein 1 (UCP1) dependent thermogenesis, thereby lowering systemic glucose, fatty acid, and nucleotide availability for tumors. Engineered beige adipocytes overexpressing UCP1, PR domain-containing protein 16 (PRDM16), or peroxisome proliferator–activated receptor gamma coactivator 1 alpha (PPARGC1A/PGC1A) suppress tumor growth through nutrient competition, suggesting that activating endogenous UCP1 may provide a non-genetic and physiologically aligned anticancer approach. Building on this concept, natural products such as polyphenols, terpenoids, alkaloids, and carotenoids have emerged as promising UCP1 activators that stimulate beige and brown adipocyte thermogenesis through pathways involving AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), PGC1A, PRDM16, and mitochondrial biogenesis. In parallel, computational studies further indicate that several plant-derived compounds bind directly to the central cavity of UCP1 with high affinity, offering structural support for their thermogenic action. Importantly, many of these compounds also inhibit cancer cell intrinsic metabolism by reducing glycolysis, oxidative phosphorylation, lipid synthesis, and amino acid dependent anaplerosis. This review integrates UCP1 biology, natural product mediated thermogenesis, molecular docking evidence, and tumor metabolic suppression, proposing a unified framework in which natural compounds impose coordinated metabolic pressure on cancer through both adipocyte-driven nutrient competition and direct inhibition of tumor metabolism. Full article

Background: Genetic studies have found that a germline BRCA1 gene mutation is the origin of highly increased cancer risk. Clinical studies have suggested that increased cancer risk in type-2 diabetes may be attributed to unhealthy lifestyle factors and bad habits. Purpose: Patients with either BRCA1 gene mutation or type-2 diabetes similarly exhibit increased cancer risk, insulin resistance, and fertility disorders. It was suggested that these three alterations derive from a common genomic failure, and its recognition may shed light on the unsolved secret of cancer. Results: (1) Germline mutations on ESR1, BRCA1, and CYP19A genes encoding estrogen receptor alpha (ERα), genome safeguarding BRCA1 protein, and CYP19 aromatase enzyme cause genomic instability. BRCA1 and ESR1 gene mutations specifically cause breast cancer, while error in the CYP19A gene leads to cancers in the endometrium, ovaries, and thyroid. (2) ERα, BRCA1, and CYP19 aromatase proteins are transcription factors creating the crucial DNA stabilizer circuit driven by estrogen regulation. Liganded ERα drives a second regulatory circuit to also control cell proliferation, in partnership with various growth factors. In a third regulatory circuit, liganded ERα drives cellular glucose supply in close interplay with insulin, IGF-1, and glucose transporters. (3) Impaired expression or activation of each transcription factor of the triad leads to defective estrogen signaling and endangers regular cell proliferation, insulin sensitivity, and fertility. (4) Impaired estrogen signaling caused by either genetic or lifestyle factors alarms the hypothalamus, which issues neural and hormonal commands throughout the body to restore estrogen signaling. (5) When the compensatory actions cannot restore estrogen signaling, the breakdown of genomic regulation leads to cancer initiation. (6) Lifestyle factors that upregulate estrogen signaling decrease cancer risk, while downregulating estrogen signaling increases it. Conclusions: Increased cancer risk, insulin resistance, and infertility all originate from defective estrogen signaling. Full article

The mitogen-activated protein kinase (MAPK) signaling cascade is fundamental in regulating cellular proliferation and differentiation, cell survival and cell death via apoptosis. Disruption of the MAPK signaling cascade at any point can lead to the evasion of apoptosis and unchecked cell growth and proliferation, leading to oncogenesis. This narrative review describes MAPK pathway dysregulation, its therapeutic targets, and resistance mechanisms. The therapeutic targeting of the MAPK pathway is complex due to the dual context-dependent roles of several kinases in the signaling cascade. Despite the therapeutic effectiveness of MAPK inhibitors, cancer cells develop chemoresistance that needs to be targeted via bypassing (c-Jun N-terminal kinases) JNK, protein kinase AKT and (mammalian target of rapamycin) mTOR signaling cascades, pairing MAPK inhibitors with multiple immune agents and targeting the MAPK pathway downstream of (extracellular signal-regulated kinase) ERK to prevent its reactivation mechanisms using combination therapies, downstream signaling regulators and (Proteolysis Targeting Chimeras) PROTACs. Additionally, MAPK-mediated regulation of ferroptosis is a novel oncological therapeutic targeting strategy for controlling tumor progression. The inhibition of the RAF/MAPK pathway results in alteration of several key regulators of ferroptosis, including SLCA11, GSH, GPX4 and NCO4A, hence affecting lipid cellular iron concentration and lipid peroxidation. Emerging therapies targeting the MAPK pathway should be designed considering crosstalk, compensatory signaling mechanism activation, the role of ferroptosis and the impact of the tumor microenvironment. Full article

Argininosuccinate synthetase 1 (ASS1) expression and arginine availability are key metabolic determinants that influence tumor fitness and regulate immune interactions within the tumor microenvironment (TME). Using an orthotopic triple-negative breast cancer (TNBC) model, we demonstrate that arginine deprivation heightens tumor dependence on the TME for survival. Mechanistically, fibroblasts sustain tumor viability by supplying arginine, whereas macrophages cooperate with stromal cues to activate Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling, thereby enhancing tumor survival. Concordantly, a JAK-STAT gene-expression signature correlates with ASS1 levels in human TNBC datasets. Translationally, combined pharmacological inhibition of JAK signaling with arginine deprivation markedly suppresses tumor growth. Together, these findings reveal a TME-driven, targetable stromal–immune circuit that enables tumors to withstand arginine deficiency-induced metabolic stress. Broadly, our work highlights that mapping and strategically inducing metabolic dependencies can reveal actionable compensatory pathways, offering opportunities to improve cancer therapy. Full article

Common wheat (Triticum aestivum ssp. vulgare) is one of the three basic cereal crops worldwide that plays a key role in global food security. A key factor affecting the yield and traits of common wheat is an adequate nitrogen supply. Improving the efficiency of soil nitrogen use can be achieved through the application of appropriate mineral fertilizers and the proper selection of cultivars. The aim of this study was to determine the impact of residual nitrogen (N_res) after maize cultivation (the preceding crop) on the yield and chemical composition of winter and spring wheat grain. It was shown that both the variety selection and the type of nitrogen carrier had a significant impact on the characteristics related to wheat yield and grain quality. The most stable effect of the type of nitrogen, regardless of the type of corn variety, was recorded for ammonium nitrate with N-Lock. The average yield was approximately 6.1 t ha⁻¹. With the exception of the variant with N-Lock, the most progressive reaction to the type of fertilizer occurred in the stand with a three-line corn hybrid (TC, stay green). The advantage of this corn variety as a winter wheat forecrop results from the value of the site in a site without nitrogen. In the nitrogen control, the increase in yield compared to the single corn hybrid (SC) was 14%. However, in the U + N-Lock variant, it was 17%, and SG Stabilo as much as 32%. The increase in the weight of 1000 wheat grains in the stands after the SC and TC hybrid compared to stay green + roots power indicates a compensatory mechanism that became visible in the grain filling phase. Current challenges in agriculture caused by population growth and the need to ensure sufficient food production require greater awareness and knowledge regarding improved nitrogen management, including recognizing the role of residual nitrogen remaining in the soil after the preceding crop. A major advantage of slow-release fertilizers is that the nutrient (N) is released in response to the dynamic demand of the crop. This, on the one hand, increases grain yield and, on the other, does not negatively impact the agrosystem (eutrophication). Full article

The objective of this study is to evaluate the effects of crude protein (CP) levels and antibiotics in feed on the growth performance, body composition, nutrient digestion and absorption, gut health, and microbiota of weaned piglets. A total of 100 piglets (Duroc × Landrace × Yorkshire, weaned at day 21) with an initial weight of 6.39 ± 0.03 kg were randomly assigned to four treatments and fed with 18% CP antibiotic-free diets, 18% CP with antibiotics diets, 24% CP antibiotic-free diets, and 24% CP with antibiotics diets for 0–14 d (S1). Furthermore, the piglets were fed with an identical diet (19% CP and without antibiotics) starting day 15 until they reached 25 kg (S2). Results indicated that the average daily gain (ADG) and gain feed ratio (G:F) during the S1 phase as well as BW at day 14, were significantly decreased (p < 0.05) in the 18% CP group compared with the 24% CP group. Similarly, piglets in the 18% CP group showed a significantly decreased body protein content and body water, protein deposition rates at the S1 phase, and significantly improved the body lipid content and deposition rate but not (p > 0.05) at the S2 phase. The 18% CP group demonstrated significantly increased (p < 0.05) serum concentrations of Threonine, Valine, Isoleucine, and Lysine in weaned piglets during the S1 phase, while Glycine concentration significantly decreased, and no significant (p > 0.05) effects were observed in the S2 phase. Furthermore, dietary antibiotic supplementation had no effect on (p > 0.05) piglet growth performance, body composition, nutrient digestion, and metabolism throughout the entire trial period. In the absence of antibiotics, compared to the 24% CP diet group, the piglets fed with an 18% CP diet significantly increased the relative abundance of Lactobacillus in the colon of weaned piglets upon reaching 25 kg BW (p < 0.05). Compared to the diet without added antibiotics, the addition of antibiotics to the diet significantly decreased the relative abundance of Pseudoramibacter in the colon of weaned piglets on day 14. No significant (p > 0.05) difference was observed in intestinal morphology or gastrointestinal pH among the groups. In conclusion, lower dietary protein levels in the early post-weaning period reduced growth performance and promoted gut microbiota balance, and compensatory growth occurred after returning to higher protein levels two weeks after weaning. Full article

Nintedanib is an anti-fibrotic medication endowed with a multi-kinase inhibitor profile and approved for the treatment of Idiopathic Pulmonary Fibrosis (IPF). Nintedanib is believed to inhibit mainly Vascular Endothelial Growth Factor (VEGF), Platelet-Derived Growth Factor (PDGF), and Fibroblast Growth Factor (FGF) receptor kinases. The main objective was to identify potential tissue and/or circulating biomarkers to demonstrate Nintedanib’s target engagement and support its in vivo pharmacodynamic activity, consistent with its proposed mechanism(s) of action. In four independent experiments of bleomycin (BLM)-induced lung fibrosis model in rats, animals received Nintedanib (oral, 100 mg/kg/day) from day 7 post-BLM for 3 weeks. As expected, Nintedanib significantly reduced lung weight, the levels of lung fibrotic markers, and fibrotic areas. Moreover, Nintedanib-treated animals expressed lower levels of FGF2 in lung homogenates and higher plasma and lung levels of VEGF (≥3-fold, p < 0.05) compared to control animals. Lung proteomic analysis revealed the inhibition of receptor tyrosine kinases signaling in Nintedanib-treated animals. Circulating and lung levels of Nintedanib confirmed an optimal tissue distribution in the rat, consistent with the data reported for humans. Although VEGF ligand levels are elevated in the lungs of Nintedanib-treated animals, the VEGF signaling pathway remained functionally downregulated, strongly suggesting compensatory VEGF feedback delivery to its receptor blockade by Nintedanib. In summary, based on the present experimental findings in rats and supporting clinical preliminary evidence, increased VEGF levels can be reasonably considered an indicator of target engagement for Nintedanib and potentially for other VEGF modulators. Full article

Insulin resistance develops when skeletal muscle (SM), adipose tissue (AT), and the liver fail to respond adequately to insulin, a dysfunction closely intertwined with chronic low-grade inflammation. This combination leads to compensatory hyperinsulinemia, dysglycemia, and metabolic stress, driving major disorders such as type 2 diabetes, metabolic syndrome, metabolic dysfunction-associated steatotic liver disease (MASLD), and cardiovascular disease. Both adipokines and myokines are central modulators of this metabolic–inflammatory axis. In obesity, diabetes, MASLD, and thyroid dysfunction, alterations in myokines such as myostatin, irisin, fibroblast growth factor 21 (FGF-21), apelin, brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), and interleukin-15 (IL-15) influence glucose uptake, lipid oxidation, mitochondrial function, and systemic inflammation. Exercise-induced myokines exert insulin-sensitizing and anti-inflammatory effects, whereas myostatin and tumor necrosis factor-alpha (TNF-α) promote metabolic impairment. These pathways reveal extensive crosstalk between SM and key metabolic organs—including the liver, pancreas, AT, intestine, heart, and thyroid gland. In metabolic disease, inflammation-driven changes in deiodinase activity and triiodothyronine (T3) availability further link muscle dysfunction with thyroid imbalance. The aim of this narrative review was to elucidate the complex interplay between myokines, adipokines, inflammation, and insulin resistance, and to clarify their clinical relevance in metabolic and thyroid disorders. Given this integrative role of SM, sarcopenia should be recognized as a clinical marker of metabolic or thyroid dysregulation, and preserving muscle mass through structured physical activity should be a core therapeutic target. Full article