Search Results (137)

Breast cancer screening, while vital for reducing mortality, faces significant limitations in sensitivity and specificity, particularly in dense breasts. Current modalities primarily detect anatomical changes, often missing biologically aggressive tumors at their earliest stages. The altered metabolism of cancer cells establishes a characteristic inverted pH gradient that drives tumor invasion, metastasis, and treatment resistance. This makes tumor acidity a compelling, functional biomarker for early detection. This review synthesizes the emerging role of pH as a diagnostic biomarker and provides a critical evaluation of advanced imaging techniques for its non-invasive or minimal measurement. We detail the biological underpinnings of tumor acidosis, emphasizing its regulation through glycolytic reprogramming and dysregulated proton transport. Our analysis encompasses a broad spectrum of pH-sensitive imaging modalities, including magnetic resonance methods such as Chemical Exchange Saturation Transfer (CEST) MRI for extracellular pH mapping and multi-nuclear Magnetic Resonance Spectroscopy (MRS) using ¹H, ³¹P, and ¹⁹F nuclei to probe various cellular compartments. Furthermore, we examine hyperpolarized ¹³C MRI for real-time metabolic flux imaging, where metrics such as the lactate-to-pyruvate ratio demonstrate significant predictive value for treatment response. The review also assesses optical and photoacoustic imaging techniques, which offer high sensitivity but are often constrained to superficial tumors. Imaging tumor pH provides a powerful functional window into the earliest metabolic shifts in breast cancer, far preceding macroscopic anatomical changes. The ongoing development and evidence support the role of the pH-sensitive imaging techniques in diagnosis, lesion characterization, and therapy. Additionally, it holds promise for supplementing breast cancer screening by enabling earlier, more specific detection and personalized risk stratification, ultimately aiming to improve patient outcomes. Full article

Background: Diabetes mellitus is a multifactorial disease characterized by complex metabolic dysfunctions and chronic complications induced by hyperglycaemia. The design of multitarget ligands, capable of simultaneously controlling different pathogenic processes, was proposed as a promising approach to identify novel antidiabetic drugs endowed with improved efficacy. Methods: (5-Arylidene-4-oxothiazolidin-3-yl)alkanoic acid derivatives 1a–g and 2a–g were synthesized as potential multitarget antidiabetic agents. They were tested in vitro as inhibitors of both human recombinant AKR1B1 and PTP1B, and kinetic studies and molecular docking simulations for both enzymes were performed. Their effects on cellular glucose uptake, insulin signalling, and mitochondrial potential were assayed in cultures of murine C2C12 myocytes. A lipid accumulation assay was performed in HepG2 liver cells. The effects on high glucose-induced sorbitol accumulation were evaluated in lens HLE and retinal MIO-M1 cells. Results: All compounds displayed excellent AKR1B1 inhibitory activity (IC₅₀ 0.03–0.46 μM 1a–g; IC₅₀ 0.48–6.30 μM 2a–g); 1g and 2e–g also appreciably inhibited PTP1B at micromolar concentrations. Propanoic derivatives 2e–g significantly stimulated glucose uptake in C2C12 myocytes, in an insulin-independent way, reduced lipid accumulation in HepG2 liver cells, and caused hyperpolarization of C2C12 mitochondria at 10 μM concentration. Derivative 2e significantly reduced sorbitol accumulation in both HLE and MIO-M1 cells at a 5 μM concentration. Conclusions: The results reported here provided new insights into the mechanisms of action and structure/activity relationships of 4-thiazolidinone derivatives, underscoring the capability of compounds 2e–g of eliciting insulin-mimetic effects independent of hormone signalling. Among them, compound 2e also proved to inhibit AKR1B1-dependent sorbitol accumulation and, thus, emerged as a promising multitarget agent that can be considered for further investigations. Full article

Parahydrogen-induced hyperpolarization (PHIP), introduced nearly four decades ago, provides an elegant solution to one of the fundamental limitations of nuclear magnetic resonance (NMR)—its notoriously low sensitivity. By converting the spin order of parahydrogen into nuclear spin polarization, NMR signals can be boosted by several orders of magnitude. Here we present a portable, compact, and cost-effective setup that brings PHIP and Signal Amplification by Reversible Exchange (SABRE) experiments within easy reach, operating seamlessly across ultra-low-field (0–10 μT) and high-field (>1 T) conditions at 50% parahydrogen enrichment. The system provides precise control over bubbling pressure, temperature, and gas flow, enabling systematic studies of how these parameters shape hyperpolarization performance. Using the benchmark Chloro(1,5-cyclooctadiene)[1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene]iridium(I) (Ir–IMes) catalyst, we explore the catalyst activation time and response to parahydrogen flow and pressure. Polarization transfer experiments from hydrides to [1-¹³C]pyruvate leading to the estimation of heteronuclear J-couplings are also presented. We further demonstrate the use of Chloro(1,5-cyclooctadiene)[1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene]iridium(I) (Ir–SIPr), a recently introduced catalyst that can also be used for pyruvate hyperpolarization. The proposed design is robust, reproducible, and easy to implement in any laboratory, widening the route to explore and expand the capabilities of parahydrogen-based hyperpolarization. Full article

Blarina paralytic peptides (BPPs), neurotoxins from shrew saliva that paralyze mealworms, share high sequence similarity with human synenkephalin [1–53] (hSYN), a peptide released from proenkephalin together with opioid peptides that mediate analgesic and antidepressant effects in the brain. Both synthetic BPP2 and hSYN induce a hyperpolarizing shift in the human T-type voltage-gated calcium channel (hCa_v3.2) at sub-micromolar concentrations, although only BPP2 causes paralysis in insects. To gain insight into the functions of these insectivorous animal-specific neurotoxins and the largely uncharacterized brain peptides, we investigated the structure prediction of BPPs and SYNs and their interactions with hCa_v3.2. AlphaFold 3 modeling complemented available cryo-EM data and accurately reproduced the overall channel architecture; however, this inactivated-state model proved unsuitable for predicting agonistic binding of BPPs and SYNs. In contrast, docking simulations using an activated-state hCa_v3.2 homology model revealed distinct ligand-dependent differences in binding energies, affinity, and conformational flexibility. Notably, the C-terminal tail of BPPs—particularly its variable length and flexibility—was identified as a key determinant for the interactions with the S4 voltage-sensing domain of the channel. These findings provide new insights into the evolutionary adaptation of venom peptides in mammals and into potential therapeutic strategies targeting neurological disorders. Full article

Background: Standard imaging in neurosurgery often fails to visualize infiltrative tumor regions that extend beyond contrast enhancement. Metabolic imaging using hyperpolarized 13C-MRI may offer new intraoperative insights into tumor biology. Objective: To systematically assess the clinical and technical evidence on hyperpolarized MRI for metabolic tumour characterization in patients with malignant brain tumors. Eligibility criteria: We included original human studies reporting on hyperpolarized 13C-MRI for perioperative and diagnostic use in brain tumor patients. Reviews, animal studies, and technical-only reports were excluded. Information sources: Searches were conducted in PubMed, Embase, and Web of Science on 26 December 2024. Risk of bias: Methodological quality was assessed using the QUADAS-2 tool. Synthesis of results: A qualitative synthesis was performed, and where feasible, random-effects meta-analysis was used to calculate standardized mean differences (SMDs) and heterogeneity statistics. Results: Three studies (n = 15 patients) met inclusion criteria. The bicarbonate-to-pyruvate ratio showed a significant difference between tumor and non-tumour brain (SMD = 1.34, p = 0.002), whereas pyruvate-to-lactate ratio (kPL) values showed minimal difference (SMD = 0.06, p = 0.730). Asmall effect was observed for kPL between tumor and normal-appearing white matter (SMD = –0.33). One study provided qualitative data only. Overall heterogeneity was high (I² = 69.4%). Limitations: Limitations include small sample sizes, heterogeneous methodologies, and limited availability of patient-level data. Interpretation: Hyperpolarized 13C-MRI shows metabolic differentiation between tumor and healthy tissue in certain parameters, especially bicarbonate metabolism. While promising, the technology requires further clinical validation before routine intraoperative application. Full article

Despite a specific histone mutation defining the unique genetic makeup, diffuse midline gliomas are heterogeneous tumors with a wide range of morphologic and molecular spectrum. We investigated the feasibility of using hyperpolarized carbon-13(¹³C) MR metabolic imaging to differentiate distinctive molecular features from two H3K27M-mutant, biopsy-originated diffuse midline glioma xenografts. ¹³C MR metabolic imaging data were acquired on a 3T scanner from 12 rats that had been implanted with SF8628 or SF7761 diffuse midline glioma cells in brainstem, following injection of hyperpolarized [1-¹³C]pyruvate. Despite the two tumors’ similar appearance of T₂-hyperintensity throughout the cerebellum and pons without contrast enhancement, ¹³C metabolic imaging data revealed that SF8627 had significantly higher ratios of lactate to pyruvate, lactate to total carbon, and normalized lactate than SF7761. Elevated lactate levels in SF8628 were associated with large amounts of lactate dehydrogenase (LDH)-A and carbonic anhydrase-IX staining in SF8628 compared to SF7761, which implied that the highly hypoxic condition in SF8628 appeared to contribute to the high level of LDH-A enzyme activity, which, in turn, induced the large conversion from hyperpolarized pyruvate to lactate. Our findings suggest that this advanced metabolic imaging technique may be used for the noninvasive characterization of molecular hypoxia and lactate dehydrogenase-A activity in these pediatric brainstem gliomas. Full article

Dietary polyphenols are recognized as crucial modulators of gastrointestinal motility, holding therapeutic promise for conditions like irritable bowel syndrome, postoperative ileus, and functional dyspepsia. However, their reported effects are heterogeneous, ranging from spasmolytic to prokinetic. This review aims to clarify these inconsistencies by synthesizing experimental evidence on structure–activity relationships and underlying mechanisms. Relevant publications were identified in PubMed and Google Scholar using terms related to polyphenols and gastrointestinal motility. References were selected for relevance, and the narrative review integrates findings from in vitro, ex vivo, in vivo, and clinical studies. Across various experimental models, polyphenols function as multi-target modulators of gastrointestinal smooth muscle. The primary mechanisms identified involve the blockade of voltage-dependent L-type Ca²⁺ channels, activation of K⁺ channels (BK, K_ATP), and modulation of the NO/cGMP and cAMP/PKA pathways. Flavones and multiple flavonols consistently demonstrate spasmolytic activity via Ca²⁺ channel antagonism. In contrast, flavanones engage BK and K_ATP channels to induce membrane hyperpolarization. Complex extracts from plants like ginger and turmeric exhibit mixed pro- or antimotility effects, reflecting the diverse profiles of their constituent compounds. While robust ex vivo pharmacology and some in vivo and human data exist, a high degree of dataset heterogeneity and inconsistent reporting impedes direct translational efforts. Polyphenols are promising multi-mechanistic modulators of gastrointestinal motility with clear structure–activity patterns. To advance their clinical application, future research must focus on establishing standardized in vivo pharmacokinetics, conducting targeted structure–activity studies, employing bioassay-guided fractionation, and designing rigorous clinical trials. Full article

Ischemia/reperfusion (I/R) injury following stroke results in increased neuronal cell death due to mitochondrial hyperactivity. Ischemia results in loss of regulatory phosphorylations on cytochrome c oxidase (COX) and cytochrome c of the electron transport chain (ETC), priming COX for hyperactivity. During reperfusion, the ETC operates at maximal speed, resulting in hyperpolarization of the mitochondrial membrane potential (ΔΨ_m) and reactive oxygen species (ROS) production. We have shown that COX-inhibitory near-infrared light (IRL) provides neuroprotection in small and large animal models of brain I/R injury. IRL therapy is non-invasive and non-pharmacological and does not rely on blood flow. We identified specific wavelengths of IRL, 750 and 950 nm, that inhibit COX activity. To model the mitochondrial effects following neuronal I/R, SH-SY5Y cells underwent oxygen–glucose deprivation/reoxygenation (OGD/R) ± IRL applied at the time of reoxygenation. Untreated cells exhibited ΔΨ_m hyperpolarization, whereas IRL treated cells showed no significant difference compared to control. IRL treatment suppressed ROS production, decreased the level of cell death, and reduced the time to normalize mitochondrial activity to baseline levels from 4–5 to 2.5 h of reperfusion time. We show that IRL treatment is protective by limiting ΔΨ_m hyperpolarization and ROS production, and by speeding up cellular recovery. Full article

Background: Potent androgen receptor pathway inhibitors induce small cell neuroendocrine prostate cancer (SCNC), a highly aggressive subtype of metastatic androgen deprivation-resistant prostate cancer (ARPC) with limited treatment options and poor survival rates. Patients with metastases in the liver have a poor prognosis relative to those with bone metastases alone. The mechanisms that underlie the different behavior of ARPC in bone vs. liver may involve factors intrinsic to the tumor cell, tumor microenvironment, and/or systemic factors, and identifying these factors is critical to improved diagnosis and treatment of SCNC. Metabolic reprogramming is a fundamental strategy of tumor cells to colonize and proliferate in microenvironments distinct from the primary site. Understanding the metabolic plasticity of cancer cells may reveal novel approaches to imaging and treating metastases more effectively. Methods: Using magnetic resonance (MR) imaging and spectroscopy, we interrogated the physiological and metabolic characteristics of SCNC patient-derived xenografts (PDXs) propagated in the bone and liver, and used correlative biochemical, immunohistochemical, and transcriptomic measures to understand the biological underpinnings of the observed imaging metrics. Results: We found that the influence of the microenvironment on physiologic measures using MRI was variable among PDXs. However, the MR measure of glycolytic capacity in the liver using hyperpolarized ¹³C pyruvic acid recapitulated the enzyme activity (lactate dehydrogenase), cofactor (nicotinamide adenine dinucleotide), and stable isotope measures of fractional enrichment of lactate. While in the bone, the congruence of the glycolytic components was lost and potentially weighted by the interaction of cancer cells with osteoclasts/osteoblasts. Conclusion: While there was little impact of microenvironmental factors on metabolism, the physiological measures (cellularity and perfusion) are highly variable and necessitate the use of combined hyperpolarized ¹³C MRI and multiparametric (anatomic, diffusion-, and perfusion- weighted) ¹H MRI to better characterize pre-treatment tumor characteristics, which will be crucial to evaluate treatment response. Full article

Background: Most of the existing hyperpolarized (HP) ¹³C MRI analyses use univariate rate maps of pyruvate-to-lactate conversion (k_PL), and radiomic-style multiparametric models extracting complex, higher-order features remain unexplored. Purpose: To establish a multivariate framework based on whole abdomen/pelvis HP ¹³C-pyruvate MRI and evaluate the association between multiparametric features of metabolism (MFM) and clinical outcome measures in advanced and metastatic prostate cancer. Methods: Retrospective statistical analysis was performed on 16 participants with metastatic or local-regionally advanced prostate cancer prospectively enrolled in a tertiary center who underwent HP-pyruvate MRI of abdomen or pelvis between November 2020 and May 2023. Five patients were hormone-sensitive and eleven were castration-resistant. GMP-grade [1-¹³C]pyruvate was polarized using a 5T clinical-research DNP polarizer, and HP MRI used a set of flexible vest-transmit, array-receive coils, and echo-planar imaging sequences. Three basic metabolic maps (k_PL, pyruvate summed-over-time, and mean pyruvate time) were created by semi-automatic segmentation, from which 316 MFMs were extracted using an open-source, radiomic-compliant software package. Univariate risk classifier was constructed using a biologically meaningful feature (k_PL,median), and the multivariate classifier used a two-step feature selection process (ranking and clustering). Both were correlated with progression-free survival (PFS) and overall survival (OS) (median follow-up = 22.0 months) using Cox proportional hazards model. Results: In the univariate analysis, patients harboring tumors with lower-k_PL,median had longer PFS (11.2 vs. 0.5 months, p < 0.01) and OS (NR vs. 18.4 months, p < 0.05) than their higher-k_PL,median counterparts. Using a hypothesis-generating, age-adjusted multivariate risk classifier, the lower-risk subgroup also had longer PFS (NR vs. 2.4 months, p < 0.002) and OS (NR vs. 18.4 months, p < 0.05). By contrast, established laboratory markers, including PSA, lactate dehydrogenase, and alkaline phosphatase, were not significantly associated with PFS or OS (p > 0.05). Key limitations of this study include small sample size, retrospective study design, and referral bias. Conclusions: Risk classifiers derived from select multiparametric HP features were significantly associated with clinically meaningful outcome measures in this small, heterogeneous patient cohort, strongly supporting further investigation into their prognostic values. Full article

Cardioprotection against ischemia is achieved using openers of mitochondrial ATP-sensitive K⁺ (mitoKATP) channels such as diazoxide (DZX), leading to pharmacological preconditioning (PPC). We previously reported that PPC decreases the abundance of ventricular Cav1.2 channels, but PPC’s effects on other channels remain largely unexplored. In this study, we hypothesized that DZX regulates the expression of hyperpolarization-activated cyclic nucleotide potassium channel 4 (HCN4) channels in sinoatrial node cells (SANCs), the specialized cardiomyocytes that generate the heartbeat. DZX increased the heart rate in intact adult rats. Patch-clamp experiments revealed an increase in the magnitude of ionic currents through HCN4 channels, which was abolished by the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) and the selective mitoKATP channel inhibitor 5-hydroxydecanoate (5-HD). Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot assays showed that DZX increased HCN4 channel expression at the mRNA and protein levels. Immunofluorescence analyses revealed that PPC increased HCN4 fluorescence, which was abolished by NAC. DZX increased nuclear translocation of c-Fos and decreased protein abundance of RE1 silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF), suggesting the involvement of these factors. Our results suggest that PPC increases the heart rate by upregulating HCN4 channel expression through a mechanism involving c-Fos, REST, and ROS. Full article

It is increasingly recognized that early perturbation of energy metabolism might have important implications in management and ultimately the neurological outcome in patients with traumatic brain injury (TBI). At the same time, treatments and screening tools successfully developed in preclinical TBI models have failed to translate to the clinic. As ferrets possess primate-like gyrencephalic brains that may better replicate the human response to neurologic injury, the goal of this study was to noninvasively measure brain energy metabolism after injury in a ferret model of TBI. To this end, metabolic imaging of hyperpolarized (HP) [1-¹³C]pyruvate (Pyr) and its conversion to lactate (Lac) and bicarbonate (Bic) was performed in ferrets before and after combined under-vehicle blast and controlled cortical impact injury. Reduced Bic/Pyr, reflecting reduced pyruvate dehydrogenase activity, was detected 8–10 days post-injury whereas no difference in Lac/Pyr was observed. These results demonstrate the feasibility of using metabolic imaging of HP [1-¹³C]Pyr to measure perturbations in brain energy metabolism in a novel highly translatable animal model of TBI. The method may contribute to both improved understanding of injury mechanisms and more effective drug development. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of approximately 13% for advanced stages. While the majority of PDAC cases are sporadic, a significant subset is attributable to hereditary and familial predispositions, accounting for approximately 25% of cases. This article synthesizes recent advancements in the understanding, detection, and management of hereditary pancreatic cancer (PC). Results: Our review highlights the critical role of genetic testing (GT) in identifying high-risk individuals (HRIs), with germline pathogenic variants (PVs) found in up to 20% of hereditary PDAC cases. Since the implementation of next-generation sequencing (NGS) panels in 2014, detection capabilities have been significantly enhanced. HRIs can be included in screening programs that facilitate the early detection of PDAC. Early detection strategies, including the use of microribonucleic acid (miRNAs) signatures and novel imaging techniques like hyperpolarized 13C-magnetic resonance spectroscopy (MRS) have shown promising results. The identification of germline pathogenic variants (PVs) or mutations in homologous recombination (HR) genes plays a predictive role in the response to various treatments, prolonging patient survival. Discussion: Universal germline testing for PDAC, as recommended by the National Comprehensive Cancer Network (NCCN), is now a standard practice, facilitating the identification of at-risk individuals and enabling targeted surveillance and intervention. Multidisciplinary management, integrating genetic counseling, imaging, and gastrointestinal services, is essential for optimizing outcomes. Conclusions: Advances in genetic testing and biomarker research are transforming the landscape of hereditary PC management. Early detection and personalized treatment strategies are pivotal in improving survival rates. Ongoing multi-institutional research efforts are crucial for validating biomarkers and developing preventive measures, ultimately aiming to reduce the burden of this aggressive cancer. Full article

Multi-drug therapies are common in cardiovascular disease intervention; however, io channel/pump coordination has not been tested electrophysiologically. Apparently, inward currents were not elicited by Yoda1/10 nM or Dobutamine/100 nM alone in Ah-type baroreceptor neurons, but were by their combination. To verify this, electroneurography and the whole-cell patch-clamp technique were performed. The results showed that Ah- and C-volley were dramatically increased by the combination at 0.5 V and 5 V, in contrast to A-volley, as consistent with repetitive discharge elicited by step and ramp with markedly reduced current injection/stimulus intensity. Notably, a frequency-dependent action potential (AP) duration was increased with Iberiotoxin-sensitive K⁺ component. Furthermore, an increased peak in AP measured in phase plots suggested enhanced Na⁺ influx, cytoplasmic Ca²⁺ accumulation through reverse mode of Na⁺/Ca²⁺ exchanger, and, consequently, functional KCa1.1 up-regulation. Strikingly, the Yoda1- or Dbtm-mediated small/transient Na⁺/K⁺-pump currents were robustly increased by their combination, implying a quick ion equilibration that may also be synchronized by hyperpolarization-induced voltage-sag, enabling faster repetitive firing. These novel findings demonstrate multi-channel/pump collaboration together to integrate neurotransmission at the cellular level for baroreflex, providing an afferent explanation in sexual dimorphic blood pressure regulation, and raising the caution regarding the individual drug concentration in multi-drug therapies to optimize efficacy and minimize toxicity. Full article