Search Results (192)

The transition toward sustainable food systems requires innovative approaches to managing perishable products, where inefficient inventory practices contribute significantly to global food loss and environmental degradation. This study develops a circular-economy-oriented inventory optimisation framework for dairy supply chains that integrates environmental externalities and waste valorisation pathways into operational decision-making. Departing from traditional linear “produce–consume–dispose” models, this study embeds three core sustainability mechanisms into a stochastic dynamic-programming framework: (1) progressive environmental cost internalisation aligned with EU Emissions-Trading System carbon pricing, capturing both waste-related emissions and cold-chain energy footprints; (2) circular-economy value-recovery channels that redirect near-expiry products to secondary applications (animal feed, biogas production, industrial processing) rather than disposal; and (3) deterioration-aware demand management that minimises resource throughput while maintaining service levels. Empirical calibration using Ukrainian dairy industry data demonstrates that sustainability-integrated inventory policies reduce waste generation by 4.8–10% relative to conventional approaches, with high-deterioration products showing the greatest potential for improvement. The authors identify a critical threshold in the circular economy: when salvage recovery rates exceed 35%, waste becomes an economic and ecological asset, fundamentally altering the sustainability calculus of inventory decisions. Environmental costs account for 4.6% of total operating expenses at current carbon prices, a share projected to increase substantially as climate regulations tighten. The findings provide actionable guidance for dairy supply chain stakeholders pursuing the Sustainable Development Goals (SDGs 2, 12, 13): processors should establish circular-economy partnerships that achieve salvage rates above 35%, implement product-specific policies for high-deterioration items, and proactively integrate carbon pricing into inventory optimisation. The framework bridges sustainable operations theory and circular economy practice, offering a replicable model for transitioning perishable food supply chains toward closed-loop, low-waste configurations that simultaneously reduce environmental impact and enhance economic performance. Full article

Background/Objectives: Melanoma is the deadliest form of skin cancer. Resistance to alkylating agents such as Temozolomide (TMZ) and Dacarbazine (DTIC) limits their clinical benefit, as these drugs remain palliative options when immunotherapies and targeted treatments fail. CSA/ERCC8 is a key component of transcription-coupled nucleotide excision repair (TC-NER), a pathway responsible for removing UV-induced DNA lesions. In principle, loss of a DNA repair factor would be expected to increase carcinogenesis. However, although CSA loss-of-function causes Cockayne Syndrome (CS), affected patients do not exhibit increased skin cancer incidence, suggesting that CSA impairment promotes apoptosis rather than tumor development. This paradox raises the possibility that CSA inhibition may selectively target melanoma cell survival pathways. Methods: The expression of CSA/ERCC8 was analyzed by qRT-PCR and Western blot. ERCC8 was silenced using antisense oligonucleotides. Cell viability, apoptosis, cell cycle progression, drug sensitivity, and DNA damage were assessed by functional assays, including IC50 determination and Bliss analysis for drug interactions. Results: We identified CSA/ERCC8 as a driver of melanoma chemoresistance. CSA was markedly overexpressed in primary and metastatic melanoma cells. ERCC8 silencing reduced proliferation, induced apoptosis, and significantly enhanced sensitivity to low doses of TMZ and DTIC while sparing normal cells. Conclusions: CSA represents a promising therapeutic target to overcome chemoresistance in melanoma. Its inhibition enhances the efficacy and selectivity of alkylating agents, supporting its potential as a salvage strategy for refractory disease and warranting further preclinical and clinical investigation. Full article

Background/Objectives: Varicocele repair can improve semen parameters and pregnancy rates in appropriately selected men; however, persistence or recurrence remains a common cause of treatment failure with ongoing infertility or scrotal pain. Because mechanisms and definitions vary across studies, counseling and salvage selection can be challenging. This review synthesizes contemporary evidence on why varicocele recur and provides an anatomy-informed approach to evaluation and retreatment. Methods: A narrative evidence synthesis was performed using PubMed/MEDLINE, prioritizing clinical practice guidelines, systematic reviews, meta-analyses, and contemporary adult and adolescent clinical series addressing mechanisms of failure, diagnostic workup, and outcomes of salvage microsurgery and endovascular therapy. Results: Recurrence rates vary by technique and follow-up, with the lowest rates reported in contemporary microsurgical subinguinal series. The dominant drivers of failure are incomplete venous control and complex reflux pathways, including duplicated internal spermatic veins and missed collaterals such as cremasteric, external spermatic, gubernacular, and deferential veins. Clinical examination remains central; Doppler ultrasonography is most useful when pain persists or semen parameters and testicular growth do not improve. Venography can define culprit channels in complex or multiply treated cases and enables targeted embolization. Retreatment achieves high anatomic success with consistent improvements in semen parameters and meaningful pregnancy rates in available series, with modality-specific complication profiles. Conclusions: Recurrent varicocele should be managed with structured reassessment that links venous anatomy and the index procedure to the salvage option. Microsurgical redo is generally favored after non-microscopic repairs, whereas endovascular occlusion is often preferred after prior surgery or when venographic mapping is needed. Full article

Pressure-controlled intermittent coronary sinus occlusion (PICSO) was initially developed to salvage ischemic myocardium. However, recent evidence suggests a more profound role: reawakening embryonic molecular pathways that facilitate myocardial regeneration. This review examines the paradigm shift in PICSO’s mechanism—from its traditional focus on infarct size reduction to its emerging role as a catalyst for myocardial repair through the reactivation of embryonic signaling. Findings suggested that myocardial decay could be ameliorated beyond salvage, revealing that PICSO enhances vascular activation in the coronary venous system, thereby influencing the fate of endothelial and myocardial cells. The theorem “embryonic recall” posits that PICSO induces molecular signals reminiscent of early cardiac development, offering a novel approach to cardiac repair in myocardial jeopardy. Noncoding RNA serves as a universal signaling event, thereby supporting the hypothesis. Yet, conflicting clinical outcomes highlight the need to redefine PICSO’s objectives, optimize device settings, and realize interventional strategies. The evolution of PICSO demands a radical shift in scientific perspective. Beyond ischemic salvage, its true potential may lie in harnessing regenerative mechanisms within the failing heart. Modern cardiology must adopt this dual role, bridging mechanical intervention with molecular rejuvenation to ensure its continued viability as a therapeutic option. PICSO, like the phoenix, may yet rise anew as a transformative force in cardiovascular medicine. Full article

Ceramides are central to stratum corneum barrier organization and hydration. Beyond topical replenishment, ceramide-stimulating strategies increasingly aim to enhance endogenous ceramide biosynthesis, processing, and homeostatic remodeling in coordination with keratinocyte differentiation. In this review, we summarize the three major metabolic routes that shape epidermal ceramide output—de novo synthesis, salvage, and sphingomyelin hydrolysis—and organize representative bioactive ingredients by their primary molecular targets rather than by origin. Specifically, we map ingredients to tractable regulatory nodes, including transcriptional “liposensors” (PPAR/LXR), the induction of biosynthetic/elongation and processing enzymes (e.g., SPT, CerS3, ELOVL4), the provision of structural substrates and precursors (e.g., linoleate-rich lipids and glycosylceramides), salvage-pathway sphingoid bases that can reshape ceramide subclass output, and metabolic sensing/stress-response pathways centered on AMPK–mTOR–SIRT1/autophagy. Across these mechanisms, agents spanning botanical and fermented extracts, vitamins, sphingoid intermediates, lipid precursors, and pathway modulators (including autophagy-focused probes) have been reported to increase ceramide abundance and, in some contexts, favor barrier-relevant ultra-long-chain species and ω-O-acylceramides that support lamellar organization and the corneocyte lipid envelope. Translational and clinical studies in dry, sensitive, and aged skin generally associate such interventions with improved barrier function and reduced dryness. Aligning ingredient selection with defined biosynthetic and processing checkpoints—and verifying outcomes with lipidomics alongside clinical endpoints—may accelerate the development of evidence-based, ceramide-stimulating cosmetics. Full article

Bulleidia extructa strain PP_925, isolated from the periodontal pocket of a patient with periodontitis, is a Gram-positive Bacillota with an unusually compact genome of 1.38 Mb. Phylogenomic analyses place PP_925 within Erysipelotrichales and show close relatedness of Bulleidia to Solobacterium and Lactimicrobium, as well as the existence of previously undescribed related clades. The metabolic repertoire of PP_925 is strongly reduced: it retains glycolysis, the phosphotransacetylase–acetate kinase pathway, and arginine catabolism but lacks the tricarboxylic acid cycle and most de novo biosynthetic pathways for amino acids, nucleotides, fatty acids, cofactors, and vitamins, implying reliance on salvage and cross-feeding. Phylogenetic inference indicates independent peptidoglycan losses in multiple mycoplasma Erysipelotrichia-related lineages, while PP_925 has retained an ancestral Gram-positive cell wall despite extensive genomic reduction. The genome preserves systems crucial for host interaction and adaptability, including a horizontally acquired tad locus encoding type IV pili, a comG competence system, and several adherence-associated virulence factors. Defense mechanisms are diverse and include a CRISPR-Cas II-A system, a type II restriction–modification module adjacent to Gao_Qat-like genes, and the Wadjet system in a genome without prophages; CRISPR spacers indicate repeated encounters with Bacillota phages. Comparative genomics of PP_925 and related strains reveals a small core genome with lineage-specific adhesion and defense modules, indicating recent shared ancestry combined with adaptive flexibility under substantial genome reduction. Full article

Polydeoxyribonucleotide (PDRN), a DNA fragment mixture, exerts biological effects via adenosine A2A receptor and salvage pathway activation. Here, Paeonia lactiflora-derived PDRN (Peony PDRN) is proposed as a plant-based alternative to salmon-derived PDRN. While P. lactiflora is known for its medicinal properties, the biological functions of Peony PDRN have not been characterized. To validate and optimize its efficacy, we systematically compared the biological activities of three molecular weight groups of Peony PDRN (high, medium, and low) using in vitro assays and clinical studies. The low-molecular-weight fraction (Low-Peony PDRN) markedly enhanced skin cell proliferation and migration, upregulated extracellular matrix-related genes (COL1A1, COL5A1, ELN, and FBN1), and promoted keratinocyte differentiation and epidermal barrier formation by increasing COL7A1, IVL, FLG, and OCLN expression. It also reduced reactive oxygen species levels and suppressed key inflammatory mediators. Clinically, topical application of Low-Peony PDRN for 2 weeks markedly reduced transepidermal water loss in a sodium lauryl sulfate-induced skin damage model, enhancing barrier recovery (n = 10). Periorbital skin elasticity improved after 4 weeks of treatment (Approval No. Intertek IRB-202505-HR(1)-0001, 20 June 2025). These results indicate that Low-Peony PDRN is a promising plant-derived biomaterial of pharmacological and cosmetic significance, with potential to address skin aging. Full article

Background: Ovarian cancer (OC) remains one of the most lethal gynecologic malignancies due to its often-late diagnosis and complex molecular heterogeneity. Understanding the metabolic alterations in OC can provide insights into its pathophysiology and potential therapeutic targets. This study aimed to explore serum metabolomic profiles and their correlation with clinical and pathological features in OC patients. Materials and Methods: Thirty serum samples were collected from patients diagnosed with ovarian tumors (OTs) (n = 24 malignant, n = 6 benign) and undergoing treatment at Careggi University Hospital. Additionally, 47 samples were obtained from age-matched healthy female donors. Serum samples underwent processing and analysis using an H-NMR (Nuclear Magnetic Resonance) platform to identify a panel of metabolites. Correlation analysis between the metabolomic data and clinical parameters was performed using R software (v.4.4.0). Results: Differential metabolomic profiling showed a significant upregulation of metabolites associated with the purine salvage pathway (i.e., hypoxanthine and inosine) and the ketone bodies axis (i.e., acetone, 3-hydroxybutyrate, and acetate) in samples from ovarian tumor (OT) patients compared to healthy donors. Within malignant OC samples, metabolomic profiles significantly correlated with BRCA1/2 mutation status (BRCA1/2-mutated vs. wild-type) and homologous recombination deficiency (HRD) status. Conclusions: The analysis revealed significant variation in specific metabolites such as betaine, creatinine, carnitine, glycerol, and mannose; notably, a downregulation of these metabolites was observed in HRD-positive patients. The study identifies significant metabolomic alterations in OC, implicating pathways such as purine salvage and ketone bodies. Intriguingly, consistent variation in specific metabolites across BRCA/HRD phenotypes underscores their potential as OC biomarkers. Further research is needed to validate these findings and explore their prognostic and therapeutic implications. Full article

The MTAP (methylthioadenosine phosphorylase) gene, located on chromosome 9p21, plays a crucial role in the methionine salvage pathway and is frequently co-deleted with CDKN2A in various malignancies. Loss of MTAP expression leads to the accumulation of methylthioadenosine (MTA), which selectively inhibits protein arginine methyltransferase 5 (PRMT5) and creates a unique metabolic vulnerability in MTAP-deficient tumors. These alterations have emerged as promising therapeutic targets in precision oncology. Recent advances highlight the potential of exploiting MTAP loss through synthetic lethality approaches using PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibitors. Preclinical and early clinical data indicate that targeting these pathways can selectively impair tumor growth while sparing MTAP-proficient cells. Moreover, MTAP deletion has been associated with specific molecular and immunologic profiles that may influence treatment response and tumor microenvironment characteristics. This review summarizes current knowledge on the biological functions of MTAP, the mechanisms linking its loss to oncogenesis, and the evolving landscape of therapeutic strategies targeting MTAP-deficient cancers. Understanding these molecular dependencies offers novel opportunities for the development of precision-based therapies across diverse tumor types. Full article

Homozygous deletion of the 9p21.3 genomic locus spanning the CDKN2A/B and MTAP genes is an event affecting 15% of cancers. While CDKN2A is a well-established tumor suppressor gene, the role of MTAP in tumorigenesis varies across cancer types. MTAP codes for methylthioadenosine phosphorylase, a key enzyme in the methionine salvage pathway, and its loss has been associated with several downstream synthetic vulnerabilities. Despite multiple efforts to exploit MTAP loss for targeted therapies, none of these efforts have yielded substantial results in clinical trials. In this review, we consolidate the existing literature along with our systematic analysis to provide an updated perspective on the incidence of MTAP loss in different cancers and elucidate its impact on metabolism, immune microenvironment, and tumor progression. In addition, we summarize the therapeutic strategies that have been investigated preclinically on MTAP-null tumors before and after the advent of functional genomic screening tools. We further assess the current landscape of clinical trials investigating MTAP-targeted inhibitors, evaluating their limitations and potential avenues for improvement. The insights gained from this review will inform future research directions beyond the promising PRMT5/MAT2A axis for rational combination therapies that would work synergistically to eradicate this devastating disease. Full article

Cardioprotection refers to the natural capacity of heart tissue to resist damage under conditions such as ischemia–reperfusion and various metabolic stresses. First identified in the phenomenon of ischemic preconditioning, the concept has since broadened to encompass other triggers of protective signaling, including hypoxia, temperature shifts, and a wide range of pharmacological compounds. This expansion indicates the presence of common molecular pathways and defense mechanisms. Known intracellular contributors to cardioprotection involve numerous factors, such as protein kinases, the reperfusion injury salvage kinase (RISK) cascade, the Survivor Activating Factor Enhancement (SAFE) pathway, hypoxia-inducible factor-1α (HIF1α), microRNAs, and Connexin 43, among others. These components are crucial in initiating downstream signaling, promoting the expression of protective genes, optimizing mitochondrial function, and regulating cytosolic and protein processes to maintain cardiac resilience. Key end-effectors include SUR2A, a regulatory subunit of sarcolemmal ATP-sensitive potassium (KATP) channels, autophagy, and mitochondria. Central mechanisms, such as modulation of the mitochondrial permeability transition pore and activation of KATP channels, play essential roles in the cardioprotective response. Although significant progress has been made in mapping these networks, many facets remain poorly understood. One of the most pressing challenges is to translate this knowledge into practical therapies and eventually create clinically applicable strategies to protect the heart. Full article

Nicotinamide adenine dinucleotide (NAD⁺) serves as a critical cofactor in redox reactions and metabolic transformations catalyzed by NAD-dependent enzymes and is essential for bacterial survival and virulence. The biosynthesis of NAD⁺ in the cariogenic pathogen Streptococcus Sobrinus (S. sobrinus), a pivotal participant in oral cavities of children and adolescents with a history of caries, has yet to be explored. Bioinformatics, genetics, and biochemical techniques were used to identify NAD⁺ biosynthesis pathways and corresponding regulator in S. Sobrinus. S. sobrinus lacks de novo NAD⁺ synthesis pathway but comprises NA and Nam salvage pathway I (PncA-PncB-NadD-NadE) and PnuC-NadR salvage pathway III. NiaY and PnuC were involved in the salvage pathways. N-terminal domain of SsNrtR regulator was identified as DNA-binding domain binding to the pnuC and pncB probe, and addition of ADP-ribose reversed the binding of SsNrtR to the target promoters to regulate NAD⁺ salvage pathways. C-terminal domain of SsNrtR was non-catalytic, consistent with loss of Nudix motif conservation. Furthermore, the abrogation of niaR compromised multiple pathogenic traits, including cellular proliferation, acidogenesis, and the architecture/mechanical integrity of biofilms. Consequently, this mutant exhibited attenuated virulence in a rat caries model. Our findings conclusively demonstrate that SsNrtR-mediated regulation of NAD⁺ homeostasis is a critical determinant of the cariogenic potential of S. sobrinus. This study identifies SsNrtR as a previously uncharacterized NAD⁺-responsive regulator that integrates metabolic homeostasis with the control of virulence in Streptococcus sobrinus. These findings elucidate a novel metabolic–virulence regulatory axis in this species and position SsNrtR as a promising target for the development of anti-caries interventions. Full article

Background: Endoscopic Electroporation (EE) is an innovative minimally invasive therapy that utilises short electrical pulses combined with intratumoural (IT) calcium or IT/intravenous (IV) chemotherapy to induce tumour cell death in colorectal cancer (CRC). Based on electrochemotherapy protocols developed for the treatment of skin cancers, EE has shown promising results in salvage therapy, local tumour control, and symptom palliation, particularly in patients who are unsuitable for surgery or standard treatments. Objective: To establish, for the first time, a comprehensive and standardised protocol for setting up a Salvage Endoscopic Electroporation (SEE) service in CRC clinical practice, covering multidisciplinary patient selection, procedural steps, equipment needs, and follow-up care. Methods: Drawing from the European Standard Operating Procedures of Electrochemotherapy (ESOPE) and emerging clinical evidence on EE from King’s College London, we detail infrastructure, treatment delivery, and monitoring for CRC. Key procedural elements, safety considerations, and patient management strategies are outlined. Electroporation pulses were delivered using the Conformité Européenne (CE) approved ePORE^® electroporation generator and single-use CE-marked EndoVE^® probe (Mirai Medical, Galway, Ireland). Results: Tumour assessment involves both clinical evaluation and endoscopic imaging, with radiological correlation. EE treatment has been safely carried out under sedation using specialised endoscopic probes, leading to effective local tumour response, symptomatic relief, and improved quality of life. Follow-up schedules allow for timely assessment of treatment response and enable repeat treatments if needed. Conclusions: This novel protocol provides a practical framework for centres aiming to implement SEE services, promoting consistency, safety, and better patient outcomes. Future prospective studies will refine indications and improve integration of this approach into colorectal cancer management pathways. Full article

Background and Objectives: Diabetic nephropathy (DN) is a major cause of end-stage renal disease, yet its molecular basis remains unclear. Nicotinamide adenine dinucleotide (NAD⁺) metabolism is crucial for energy regulation, redox balance, and inflammation. This study investigated the dysregulation of key NAD⁺ salvage enzymes (CD38, NAMPT, and SIRT1) across albuminuria stages in type 2 diabetes (T2D). Materials and Methods: A cross-sectional study was conducted on 225 participants: healthy controls (n = 45), T2D with normoalbuminuria (n = 60), microalbuminuria (n = 60), and macroalbuminuria (n = 60). Serum CD38, NAMPT, and SIRT1 were measured by ELISA, while CD38 and SIRT1 gene expression in peripheral blood mononuclear cells was analyzed by qPCR. Results: CD38 and NAMPT levels increased progressively with albuminuria, whereas SIRT1 levels declined significantly. CD38 and NAMPT correlated positively with HbA1c, creatinine, and urinary albumin-to-creatinine ratio (UACR), while SIRT1 showed inverse correlations and a positive association with eGFR. Regression analysis identified CD38 and NAMPT as independent positive predictors of albuminuria, and SIRT1 as a negative predictor. ROC analysis revealed strong diagnostic performance for CD38 (AUC = 0.89) and SIRT1 (AUC = 0.88). Conclusions: These findings highlight disrupted NAD⁺ salvage pathways in DN and suggest that restoring NAD⁺ balance, through CD38 inhibition, SIRT1 activation, or NAD⁺ precursor supplementation, may offer promising renoprotective strategies. Full article

Ferroptosis, a regulated cell death pathway driven by iron-dependent lipid peroxidation, is modulated by cellular antioxidant systems, particularly the glutathione (GSH)–glutathione peroxidase 4 (GPX4) axis. NAD kinase (NADK), the only enzyme converting NAD⁺ to NADP⁺ located in cytoplasm, fuels NADPH-dependent antioxidant defenses. However, its role in ferroptosis regulation remains not fully explored. Using ferroptosis-sensitive HT1080 cells, we employed pharmacological inhibition (thioNAM), siRNA-mediated knockdown, and plasmid-driven overexpression of NADK to dissect its impact on ferroptosis. Complementary interventions with nicotinamide mononucleotide (NMN), glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme 1 (ME1) were used to map metabolic interactions. Cell viability, redox metabolites (NADPH and GSH), oxidative stress markers (ROS, MDA), and protein expression were quantified. ThioNAM depleted NADP(H) and sensitized cells to RSL-3-induced ferroptosis, which was reversible with Ferrostatin-1. NADK knockdown produced similar results, reducing NADP(H) levels and amplifying lipid peroxidation. Conversely, NADK overexpression restored NADPH/GSH levels and rescued ferroptosis. NADK was essential for G6PD- and ME1-mediated NADPH production and ferroptosis resistance. Administration of ThioNAM or knockdown of NADK abolished the ferroptosis-rescuing effects of NMN, whereas NADK overexpression enhanced NMN’s ability to rescue ferroptosis by maintaining redox homeostasis. NADK is a metabolic hub in ferroptosis regulation, bridging NMN-driven NAD⁺ salvage to NADPH synthesis via G6PD/ME1. Targeting NADK offers novel strategies for diseases associated with ferroptosis. Full article