Heat stress is an increasing global health concern associated with high mortality and multi-organ dysfunction. The brain is particularly vulnerable to heat stress, which can lead to behavioral impairments. At the molecular level, heat stress disrupts proteins involved in synaptic communication, mitochondrial function, and cellular homeostasis. Current treatments are mainly symptomatic, highlighting the need for targeted neuroprotective strategies. Edaravone, a potent free-radical scavenger with anti-inflammatory properties, has demonstrated neuroprotective effects in various neurological conditions. This study aimed to evaluate the neuroprotective effects of edaravone against heat stress–induced behavioral dysfunction and to investigate the underlying molecular mechanisms using proteomic analysis. Male Wistar rats (n = 54) were assigned to four groups: control, heat stress (HS), edaravone (Edv), and heat stress plus edaravone (HS + Edv). Heat stress exposure and edaravone treatment were administered for 12 weeks. Behavioral assessments, including radial arm water maze (RAWM), open field test (OFT), elevated plus maze (EPM), and tail suspension test (TST), were conducted. Proteomic analysis of the cortex, hippocampus, and cerebellum was performed using LC–MS/MS with a nanoElute-QTOF-MS system. Heat stress impaired memory retention and increased anxiety-like behavior, while evidence for depressive-like behavior was modest. Proteomic analysis revealed region-specific alterations, with the hippocampus showing the largest number of significantly altered proteins, while the cortex showed the strongest multivariate separation between groups. The HS + Edv group showed partial normalization of behavioral outcomes and modulation of key proteomic pathways, including improved mitochondrial function, reduced oxidative stress, and preservation of synaptic and cytoskeletal integrity. These findings suggest that edaravone attenuates heat stress–induced brain dysfunction by promoting adaptive proteomic remodeling rather than complete restoration.

Heat stress (HS) is an escalating global health concern driven by climate change. Despite increasing epidemiologic recognition, the molecular mechanisms underlying HS pathophysiology remains poorly defined. This review systematically synthesizes metabolomic and proteomic findings to elucidate these mechanisms and identify molecular targets for intervention. Current management remains limited to symptomatic relief, with no targeted therapies available to prevent or reverse HS-induced injury. To address this gap, metabolomics and proteomics offer powerful approaches for elucidating the molecular and cellular mechanisms underlying HS responses. Metabolomic studies demonstrate that HS disrupts central energy metabolism, promotes lipid remodeling, elevates oxidative stress, alters amino acid and sulfur metabolism, disrupts hormone regulation, and induces hepatic stress. Complementary proteomics studies reveal significant upregulation of heat shock proteins (HSPs), particularly HSP70 and HSP90, as well as remodeling of inflammatory mediators, cytoskeletal proteins, and signaling pathways. Together, these omics-based findings highlight a coordinated reprogramming of metabolic pathways and proteomic signatures that underpins both susceptibility and adaptation to HS. This review explores recent metabolomic and proteomic investigations into HS, underscoring how integrative multiomics approaches provide a coherent view of its molecular complexity. By bridging metabolite-protein crosstalk with therapeutic exploration, the review highlights how these insights advance the identification of biomarkers and molecular targets, ultimately guiding the development of more precise interventions for HS.

Colorectal cancer (CRC) remains a major global health burden, necessitating innovative therapeutic approaches with improved selectivity and reduced toxicity. DNA minor groove binders (MGBs) represent a promising class of agents that modulate DNA-associated processes without inducing permanent DNA damage. In this study, two previously reported distamycin-like DNA minor groove binders, MGB30 and MGB32, were investigated to elucidate their molecular mechanisms of action in HCT-116 human colorectal cancer cells. An integrated multiomics approach combining metabolomics and proteomics was employed using TIMS-QTOF-UHPLC-MS. Four biological replicates were used for each treatment condition. Following MGB30 treatment, 12 metabolites and 187 proteins were significantly dysregulated, whereas MGB32 treatment resulted in alterations of 41 metabolites and 409 proteins using a Student’s t-test with q-value <0.05. Pathway enrichment analysis revealed that both compounds significantly disrupted purine metabolism, while MGB32 additionally affected beta-alanine metabolism, glutathione metabolism, and spermidine and spermine biosynthesis. Proteomic analysis further demonstrated deactivation of RNA processing, translation, and ribosome biogenesis, leading to impaired protein synthesis and reduced cancer cell proliferation. This study provides mechanistic insights into the downstream molecular effects of MGB30 and MGB32 that disrupt key mechanisms underlying tumor growth, offering new avenues for CRC treatment.

Background: Obesity is a complex and prevalent global health issue strongly associated with chronic diseases. Early diagnosis and precise monitoring remain challenging due to the complex metabolic dysregulation underlying obesity. Metabolomics provides a powerful tool to investigate biochemical changes and discover novel diagnostic biomarkers. Objectives: This study used untargeted metabolomics of human plasma samples to identify distinct plasma metabolite profiles and altered metabolic pathways in overweight and obese individuals. The ultimate goal is to improve obesity management through early diagnosis and personalized treatments. Methods: A total of 74 Jordanian participants were recruited and categorized into normal-weight (n=29), overweight (n=17), and obese (n=28) groups based on BMI and metabolic parameters. Plasma samples were analyzed using ultra-high-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESI-QTOF-MS). Data processing and statistical analysis were performed using MetaboScape and MetaboAnalyst 5.0. Group comparisons were evaluated using t-tests, ANOVA, and multivariate models, and pathway enrichment analysis was conducted to determine altered metabolic pathways. Results: A total of 82 metabolites were identified, with 26 showing significant differences between groups. In the overweight group, pantothenic acid and L-proline were elevated, while phenylacetaldehyde and glycerophosphocholine were decreased. The obese group exhibited increased levels of L-leucine, L-tryptophan, phenylalanine, and tyrosine, and reduced levels of 2,3-diaminopropionic acid and phenylacetaldehyde. Key altered pathways included pantothenate and CoA biosynthesis, beta-alanine metabolism, phenylalanine and tyrosine metabolism, and beta-oxidation of long-chain fatty acids. Conclusions: The study revealed significant novel metabolic disturbances associated with overweight and obesity, highlighting potential diagnostic biomarkers and perturbed metabolic pathways. These findings provide valuable insights into the molecular underpinnings of obesity, underscore the potential of metabolomics in advancing personalized approaches for managing obesity, and warrant further validation in larger, diverse populations to assess their diagnostic and clinical relevance.

[This corrects the article DOI: 10.1371/journal.pone.0240156.].

ETHNOPHARMACOLOGICAL RELEVANCE:Ziziphus spina-christi is a medicinal plant native to arid regions of the UAE and has been used in folk medicine to treat respiratory diseases, but its efficacy in asthma triggered by allergens remains to be confirmed. AIM OF THE STUDY:To investigate the therapeutic potential of Z. spina-christi in modulating immune responses in allergic asthma and to confirm the systemic bioavailability of its major phytochemicals. METHODS:The major flavonoids in Z. spina-christi were identified using an untargeted metabolite profiling, followed by pharmacokinetic analysis in rats to evaluate their systemic bioavailability. The anti-asthmatic effect was assessed in an HDM-induced asthma model in BALB/c mice (n = 8 per group). FlexiVent was used to assess airway hyperresponsiveness (AHR), and H&E staining was used to evaluate lung inflammation. Flow cytometry was used to quantify eosinophils in bronchoalveolar lavage fluid (BALF). Cytokine expression in lung homogenates and cytokine levels in BALF were measured by qPCR and ELISA, respectively. NF- κB pathway activation was assessed by western blotting. RESULTS:Quercetin, kaempferol, myricetin, and luteolin were identified by metabolic profiling. A pharmacokinetic study confirmed the systemic absorption of these flavonoids. Treatment with Ziziphus spina-christi reduced AHR, inflammatory cell infiltration in the lungs, and eosinophil counts. It also significantly reduced the levels of IL-17A, IFN-γ, IL-4, IL-5, and IL-13. Treatment with Z. spina-christi reduced p-IkB expression and consequently inhibited the NF-κB pathway. CONCLUSION:These findings show that Z. spina-christi suppresses allergic airway inflammation by modulating Th2/Th17 immune responses and inhibiting NF-κB-mediated inflammatory pathways. These findings are consistent with the systemic availability of major flavonoid constituents of the extract. This integrated approach linking phytochemical characterisation, pharmacokinetics and mechanistic in vivo assessments highlights the therapeutic potential of Z. spina-christi derived flavonoids as natural modulators of allergic airway inflammation.

Chemobrain (CMB) is a common complication that affects the majority of cancer patients and can persist for years following chemotherapy. Common symptoms are deficits in memory, attention, and affective regulation, yet they are mainly diagnosed through patient-reported symptoms. Additionally, the molecular mechanisms underlying CMB remain poorly understood, limiting the development of effective neuroprotective strategies for cancer patients. Using a rat model of CMB, this study investigates the molecular impact of doxorubicin (DOX) and temozolomide (TMZ), administered individually and in combination in comparison with a control group (n = 10/group). Untargeted metabolomic profiling was performed on the cortex, cerebellum, and hippocampus tissues after performing the neurobehavioural tests. Behavioural assessments revealed impaired spatial learning and memory, particularly in the combination-treated group, together with alterations in anxiety-related behaviour. The metabolites were extracted from their respective tissues using a two-in-one extraction protocol and were analysed by TIMS-QTOF-MS/MS. DOX treatment was associated with relatively modest region-specific metabolic alterations, with patterns consistent with possible oxidative stress-related and membrane-associated responses. TMZ treatment was associated with metabolic changes involving nucleotide metabolism and energy-related pathways, particularly in the hippocampus. The combination treatment showed a distinct metabolic profile with partial qualitative overlap with TMZ-associated alterations. Overall, these findings suggest that chemotherapy exposure is associated with region-specific metabolic alterations that co-occur with behavioural changes relevant to a CMB-like phenotype. The present results should be interpreted as exploratory and hypothesis-generating, pending targeted metabolite validation and orthogonal mechanistic confirmation. Ultimately, understanding these responses can provide critical insights into CMB pathophysiology and may lay the groundwork for the development of targeted diagnostic, monitoring, and neuroprotective strategies.

Background:EORTC thresholds for clinical importance on the QLQ-C30 have been proposed to improve the interpretability of patient-reported outcomes (PROs), but their clinical relevance remains underexplored in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Objectives:This study aimed to evaluate the frequency of clinically important baseline PRO domains and their associations with survival and adverse events in patients with CLL/SLL. Design:This was a pooled retrospective analysis of individual patient data from three randomized clinical trials of ibrutinib-based therapy. Methods:Data were pooled from RESONATE, RESONATE-2, and HELIOS. EORTC thresholds for clinical importance were applied to baseline QLQ-C30 scores to identify clinically important PRO domains. Cox proportional hazards models were used to examine associations between the number of clinically important PRO domains and overall survival (OS), progression-free survival (PFS), and grade ≥3 adverse events. Results:Among 1,238 patients, 920 (74%) reported at least one clinically important PRO domain and 395 (32%) reported five or more. Each additional clinically important domain was independently associated with worse OS (adjusted HR [95% CI]: 1.07 [1.04-1.11]; P < 0.001), worse PFS (1.03 [1.00-1.06]; P = 0.047), and increased risk of grade ≥3 adverse events (1.03 [1.01-1.06]; P = 0.006). Compared with patients reporting no clinically important PRO domains, those with ≥5 domains had worse OS (2.04 [1.42-2.94]; P < 0.001) and higher risk of grade ≥3 adverse events (1.47 [1.17-1.85]; P < 0.001). Physical function was the strongest individual prognostic domain for OS (C-index = 0.63). Conclusion:Clinically important PRO domains were common among patients with CLL/SLL initiating ibrutinib-based therapy and were independently associated with survival and toxicity outcomes. These findings support the clinical utility of EORTC QLQ-C30 thresholds for identifying patients with higher baseline PRO burden who may benefit from enhanced risk stratification, supportive care, and individualized treatment planning.

Chemotherapy-induced cognitive impairment, widely known as chemobrain, has emerged as a pressing concern as cancer incidence and treatment success continue to rise worldwide. Patients frequently report persistent deficits in memory, attention, affective regulation, and executive function, which significantly diminish quality of life. While early explanations emphasized psychological causes, evidence now supports a biological basis involving oxidative stress, neuroinflammation, synaptic alterations, and blood-brain barrier disruption. Yet, the precise molecular mechanisms remain incompletely understood, in part due to methodological limitations of conventional neuroscience approaches. Recent advances in multi-omics technologies have opened new avenues to dissect the complexity of chemobrain at genomic, transcriptomic, proteomic, metabolomic, and lipidomic levels. Studies employing both untargeted discovery workflows and targeted validation strategies have revealed convergent disruptions in mitochondrial function, neurotransmitter pathways, and inflammatory signaling, despite differences across chemotherapeutic agents. Integrative analyses further highlight how these molecular perturbations align with behavioural deficits observed in preclinical and clinical settings. This review synthesizes current multi-omics evidence, emphasizing not only the shared downstream neurotoxic pathways across diverse chemotherapies but also the variability introduced by experimental design, tissue selection, and validation practices. Importantly, multi-omics profiling underscores the need for combination neuroprotective strategies, as chemotherapy-induced cognitive impairment arises from intertwined molecular insults rather than a single pathway. By consolidating mechanistic insights from multi-omics, this review aims to inform biomarker discovery, therapeutic innovation, and ultimately the development of precision strategies to mitigate the burden of chemobrain in cancer survivors.

BACKGROUND AND OBJECTIVES:Multiple myeloma (MM) is characterized by substantial clinical heterogeneity, leading to wide variability in treatment response and toxicity. Although numerous prognostic tools exist, relatively few models estimate outcomes conditional on a specific therapeutic regimen. Treatment-specific prediction models are an important step toward individualized therapy selection. This review synthesizes the current landscape of treatment-specific clinical prediction models in MM. METHODS:A structured search of PubMed and Embase/Scopus identified multivariable clinical prediction models developed within a static treatment framework, evaluating treatment-specific therapeutic or toxicity-related outcomes in MM. Information was extracted on treatment regimens, predictors, modeling methods, validation strategies, and reporting of clinical utility. RESULTS:Thirteen models were identified, evaluating therapeutic (n = 10) or toxicity-related (n = 3) outcomes across regimens including bortezomib-based induction, daratumumab-containing combinations, ixazomib-based triplets, and CAR-T therapy. Predictors were mainly routine clinical and laboratory variables, with limited integration of cytogenetics or patient-reported outcomes. Most models used traditional regression methods; calibration was inconsistently reported, and external validation was performed in seven studies. Decision curve analysis was included in only two models. CONCLUSIONS:Methodological and translational gaps remain, including limited transparency, scarce external validation, and lack of patient-reported or longitudinal predictors. None of the models have been implemented as online calculators or integrated into electronic decision-support systems, limiting real-world uptake. Addressing these gaps is essential for developing clinically meaningful prediction tools to support personalized treatment in MM.

The worldwide impact of colorectal cancer (CRC) as a primary cause of cancer-related morbidity and mortality demonstrates the urgent need for better early detection methods and personalized treatment approaches. While colonoscopy and fecal tests have contributed to reduced mortality rates from CRC, they encounter important limitations stemming from their invasive procedures and insufficient sensitivity plus patient adherence issues. Consequently, the latest progress in molecular biology and omics technologies has enabled researchers to identify new biomarkers which present effective solutions for early detection and risk assessment while monitoring treatment efficacy. Therefore, this review explores new developments in CRC biomarker research through the lens of emerging liquid biopsy methods like circulating tumor DNA (ctDNA) and microRNAs (miRNAs) as well as genomic, epigenomic, gut microbiome, metabolomic, and proteomic markers. The usage of biomarker-based methods demonstrates transformative potential for CRC treatment by boosting survival rates and lessening global impact through precision medicine development in oncology.

Multiple sclerosis (MS) is a neurological condition characterized by recurrent inflammation, demyelination, axonal injury, and functional impairment. MS has a diverse array of clinical manifestations, with the progressive variants leading to neurological impairment. Sensitive and accurate biomarkers are required to diagnose, predict disease progression, and guide MS management. Here, we utilized liquid chromatography-mass spectrometry-based proteomics (LC-MS/MS) to find biomarkers in serum from patients with MS. The study examined protein expression in healthy individuals (n = 20) and MS groups (n = 60), comprising 20 patients in each disease course (relapsing-remitting (RRMS), primary progressive (PPMS), and secondary progressive (SPMS)). An enzyme-linked immunosorbent assay (ELISA) was used to verify a candidate protein in serum samples from patients with MS (n = 18) and healthy controls (HC) (n = 15) (validation cohort). Our findings showed 12 differentially expressed proteins (DEPs). Among the discovered proteins, some have been previously documented in MS, while others constitute novel findings. We found two proteins, junction plakoglobin (JUP) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), that were downregulated and upregulated in patients with MS relative to HCs, respectively. ELISA validations were consistent with those from LC-MS/MS. Identification of these proteins may help elucidate pathogenic processes and support novel therapeutic methods for MS.

Filter-Aided Sample Preparation (FASP) is a well-established method in proteomics, yet its potential for the parallel recovery of metabolites remains largely unexplored. Herein, we evaluate the performance of FASP as a straightforward workflow for the simultaneous isolation of protein and corresponding metabolite fractions from a single urine sample. The FASP-based LC-MS/MS approach for both proteomics and metabolomics analysis identified 3,163 nonredundant peptides corresponding to 957 unique protein groups. The metabolomic profile comparison of three urine fractions, specifically FASP-concentrated, FASP flow-through, and raw samples, resulted in the identification of 176 common metabolites. Next, as a proof-of-concept, the FASP protocol was applied to compare the metabolomic profiles of clinical urine samples from healthy individuals (n = 13) and patients with Ta bladder cancer (n = 12). The metabolomic modulation was consistent with previously reported findings, highlighting perturbations in phenylacetate, purine, and tryptophan metabolism, as reflected by changes in metabolites such as adenosine monophosphate (AMP), phenylacetic acid, glutamine, cytosine, and l-tryptophan. FASP protocol can be effectively adapted for the concurrent profiling of both proteomic and metabolomic fractions from urine samples. Thus, FASP-based workflow represents a viable alternative for single-step sample preparation, facilitating subsequent quantitative multiomics data integration.

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor. Despite combined treatments, including surgical removal followed by radiation and chemotherapy, the prognosis remains poor. Even with temozolomide, the current standard for GBM treatment, the disease is still incurable because of GBM's highly invasive nature and resistance to therapy. This review examines the contributions of key DNA repair pathways, including O6-methylguanine-DNA methyltransferase, base excision repair, and homologous recombination, to the resolution of DNA lesions induced by therapy. It also highlights emerging molecular therapeutic targets that exploit synthetic lethality to enhance treatment efficacy. In addition, the review explores other determinants of GBM resistance, such as oncogenic genetic mutations, the tumorigenic glioma stem cells (GSCs), metabolic reprogramming within the tumor microenvironment that promotes immune evasion, and the restrictive nature of the blood-brain barrier, which limits effective drug intratumoral concentrations. Finally, we discuss patient-specific immunotherapeutic strategies, including chimeric antigen receptor T (CAR-T) cell therapy and personalized cancer vaccines, which hold promise for improving survival outcomes across different GBM subtypes. Advances in multi-omics profiling and machine learning are reshaping opportunities for personalized therapy in GBM. Integrating WES, RNA-seq, and HLA typing enables tailored immunotherapies, while AI-driven antibody design accelerates the development of GSC-targeting candidates. Yet translation remains hindered by GBM's heterogeneity, limited patient availability, and disparities in trial participation. Progress will require combining mechanistic tumor profiling with computational design approaches within more inclusive clinical trials to advance truly personalized and effective GBM treatment.

Patients with multiple myeloma (MM) often use cardiovascular medications due to their increased risk of cardiovascular diseases. This study investigated the associations of baseline use of these drugs with survival and adverse events in MM patients initiating daratumumab, lenalidomide, or bortezomib combination treatments. Data from Phase III trials (CASTOR, MAIA, and POLLUX) were analysed, focusing on beta-blockers, calcium channel blockers, ACE inhibitors (ACEI), angiotensin II receptor blockers (ARBs), diuretics, and statins. Cox proportional hazard analysis and logistic regression were used to assess associations with survival and grade ≥ 3 adverse events. Among 1804 patients, ACEI/ARBs were most common (31%), followed by beta-blockers (23%), statins (21%), calcium channel blockers (17%), and diuretics (16%). ACEI/ARBs was associated with better progression-free survival (adjusted hazard ratio (aHR) [95% CI] = 0.84 [0.71-0.99], P = 0.034) but also higher odds of grade ≥ 3 adverse events (adjusted odds ratio (aOR) = 1.45 [1.06-1.97], P = 0.019). Diuretics were similarly associated with grade ≥ 3 adverse events (aOR = 1.53 [1.01-2.34], P = 0.047). Other cardiovascular drugs showed no significant associations. While ACEI/ARBs may improve progression-free survival, they pose safety concerns. It is reassuring that other cardiovascular drugs were not significantly associated with MM treatment outcomes. Further research is essential to fully understand the implications of these medications.

Background: Glioblastoma (GBM) is a highly aggressive brain malignancy with limited treatment options due to recurrence, therapy resistance, and invasiveness. Chemotherapy, though essential, is often hindered by severe side effects and chemoresistance. This highlights the need for alternative therapies with reduced cytotoxicity. Recent studies suggest that calcium channel blockers, such as amlodipine, may exhibit anticancer properties across various malignancies. Objectives: This study aimed to investigate the molecular changes induced by amlodipine in U87 and U373 GBM cell lines using quantitative proteomics to assess its potential as a repurposed therapeutic agent. Methods: Quantitative proteomic analysis was performed using UHPLCESI-QTOF-MS on U87 and U373 GBM cell lines treated with amlodipine. Statistical analysis was conducted using a Student's t-test with a q-value < 0.05 to identify significantly dysregulated proteins. Results: A total of 1,820 proteins in U87 and 2,250 proteins in U373 were identified. Statistical analysis revealed 77 significantly dysregulated proteins in U87 and 14 in U373. Functional enrichment analysis demonstrated distinct pathway alterations between the two cell lines following amlodipine treatment. In U87 cells, mitochondrial oxidative phosphorylation pathways were deactivated, including NADH dehydrogenase and mitochondrial respiratory chain complex, with significant downregulation of NDUFS1, NDUFS2, and MT-ND4, proteins essential for energy production. In U373 cells, the fluid shear stress and atherosclerosis pathways were activated, with SQSTM1/p62 significantly upregulated. Notably, SQSTM1 was upregulated in both cell lines (4.7-fold in U87 and 2.9-fold in U373), suggesting a potential link between calcium influx inhibition and GBM stress response mechanisms. Conclusion: This study provides a comprehensive molecular map of amlodipine-induced proteomic alterations in GBM, highlighting its potential as a repurposed therapeutic agent. The distinct pathway alterations observed between U87 and U373 cell lines underscore the complexity of GBM biology and suggest that calcium channel blockers may exert cell-line-specific effects.

Chemotherapy remains central to breast cancer treatment, particularly for aggressive subtypes like triple-negative breast cancer. Despite its widespread use, the toxicity of chemotherapeutic agents and frequent resistance limit clinical success. Epigenetic therapy offers a promising translational approach due to its reversible modulation of gene expression via histone and non-histone modifications that regulate key signaling pathways, including those involved in DNA repair. CREB-binding protein (CBP), a key histone acetyltransferase, is involved in ATM activation, a central component of the DNA damage response. The loss of CBP was found to sensitize breast cancer cells to chemo- and radiotherapy, thereby identifying CBP as a potential therapeutic vulnerability. In the present study, we investigated the proteomic consequences of pharmacological inhibition of CBP in breast cancer cells using two domain-specific inhibitors, C646 (HAT domain) and inobrodib (bromodomain), and assessed their translational potential in combination with doxorubicin. Using in vitro and in vivo breast cancer models, we showed that CBP inhibition disrupts DNA repair and cell-cycle regulatory pathways, thereby enhancing doxorubicin-induced cytotoxicity and apoptosis. Interestingly, the combination groups displayed the most pronounced effects on tumor growth and showed elevated levels of cleaved caspase-3, while suppression of ki67 expression and H3K27 acetylation. Additionally, the combination of CBP inhibitors with doxorubicin did not affect the body weight or the organ indices. These findings support a rational epigenetic-chemotherapy combination approach and provide preliminary preclinical evidence for further investigation of CBP-targeted strategies to improve chemotherapy efficacy while mitigating toxicity.