Search Results (52)

Background: Shentong Zhuyu Decoction (STZYD) is a traditional Chinese medicine formula that has shown promise in alleviating neuropathic pain (NPP), yet its central mechanisms remain unclear. Methods: We investigated the STZYD effects on NPP using network pharmacology, in vivo assays, and analytical chemistry, focusing on molecular pathways and GABAergic neuronal modulation. Results: Network pharmacology revealed 254 potential STZYD targets enriched in calcium signaling and GABAergic synapse pathways, especially the NMDAR-2B/CaMKII/CREB axis. High-dose STZYD (1.25 g·mL⁻¹) and ifenprodil (6 mg·kg⁻¹) reversed hyperalgesia and anxiety-like behaviors in spared nerve injury (SNI) mice, and microdialysis showed that STZYD and ifenprodil reduced the glutamate, D-serine, aspartate, glycine, and gamma-aminobutyric acid levels in the interpeduncular nucleus (IPN). Immunofluorescence and fiber photometry showed reduced c-Fos expression and suppressed GCaMP signals in IPN GABAergic neurons, with chemogenetic experiments confirming their role in pain modulation. Multimodal molecular biology experiments demonstrated that STZYD and ifenprodil significantly downregulated the GluN2B, p-CaMKII, and p-CREB expressions within the IPN. We identified 145 constituents in STZYD through high-resolution mass spectrometry analysis, among which 40 were absorbed into plasma and 7 were able to cross the blood–brain barrier and accumulate in the IPN. Molecular docking revealed the strong binding of licoricesaponin K2 and senkyunolide F to NMDAR-2B. Conclusions: STZYD exerts dose-dependent antinociceptive effects by modulating IPN GABAergic neuronal activity through the inhibition of the NMDAR-2B-mediated CaMKII/CREB pathway. Full article

Malnutrition afflicts millions of the world’s children and predisposes to death from diarrhea and infectious diseases. Children with severe acute malnutrition (SAM) are at highest risk. Our review of the endocrinology and metabolomics of SAM implicates critical roles for white adipose tissue and its regulatory hormones and growth factors in the adaptation to nutritional deprivation and the restoration of metabolic homeostasis: white adipose provides substrates and energy for hepatic glucose production and cardiopulmonary and central nervous system function, and products of fat metabolism inhibit muscle glucose uptake and utilization and spare muscle protein. Collectively, these effects maintain glucose availability for the brain, red blood cells, and renal medulla and conserve muscle mass. White adipose tissue also secretes leptin, which facilitates the immune response and may protect against mortality from infection. Euglycemia and survival in SAM are thereby prioritized over linear growth, which is suppressed owing to inhibition of insulin-like growth factor 1 production and action. Diversion of energy from growth serves to maintain essential bodily functions in critically ill malnourished children, who have limited energy reserves. Thus, short-term reductions in growth rate have adaptive benefits in SAM. Under favorable conditions, clinical and metabolic recovery are accompanied by catch-up growth, which can mitigate, and in many cases reverse, the stunting of growth in childhood. Nevertheless, clinical recovery can be complicated by preferential accrual of central fat and a relative deficiency of lean/skeletal mass, with potential long-term complications including insulin resistance, glucose intolerance, and metabolic syndrome. Full article

This review synthesizes preclinical evidence on the behavioral and neurobiological effects of cannabis exposure during prenatal and adolescent developmental periods, with a focus on anxiety, social behavior, learning and memory, and associated brain changes. Understanding the differential impact of cannabis exposure across these windows is critical, given the increasing prevalence of cannabis use and the rising potency of its primary psychoactive component, delta-9-tetrahydrocannabinol (THC). Both prenatal and adolescent periods represent vulnerable windows for disruption of the endocannabinoid system, which plays a central role in typical neurodevelopment. Exogenous activation of this system via THC can lead to atypical brain maturation and subsequent behavioral impairments. These impairments are associated with region-specific alterations in cortical and subcortical structures and are highly dependent on the timing of exposure. For instance, prenatal exposure may disrupt medial prefrontal cortex development, leading to long-term social deficits while sparing memory function. In contrast, adolescent exposure tends to impair hippocampal function, resulting in learning and memory deficits. The manuscript is organized developmentally, beginning with the effects of prenatal exposure and then discussing consequences of adolescent exposure. By delineating the distinct behavioral and neurobiological outcomes associated with the timing of cannabis exposure, this review highlights the importance of developmental stage in assessing the risks of exogenous cannabinoid use and identifies critical periods for targeted research and intervention. Full article

Background/objectives: Brain cancer remains difficult to treat, with survival statistics stagnant for decades. The resistance of glioblastoma brain tumours can greatly challenge the effectiveness of conventional cancer radiotherapy. However, high dose rate radiotherapy has unique effects that allow for normal tissue sparing whilst maintaining tumour control. The addition of targeted radiosensitisers, such as the chemotherapeutic drug methotrexate (MTX) or the high-Z halogenated pyrimidine drug iododeoxyuridine (IUdR), can improve radiotherapy outcomes. Combining these radiosensitiser agents with ultra-high dose rate (UHDR) synchrotron X-rays can bear synergistic effects to enhance the efficacy of these multi-modal UHDR therapies, providing a means to overcome the radioresistance of brain cancer. Methods: Here, we use controlled in vitro assays following treatment, including a clonogenic assay to determine long-term cell survival and γH2AX immunofluorescent confocal microscopy to quantify double-strand DNA breaks (DSBs). Results: We find significant enhancement for highly synergistic combinations of IUdR+MTX with synchrotron X-rays. Cell survival results demonstrate 5.4 times increased 9L gliosarcoma cell killing when these agents are combined with UHDR synchrotron X-rays compared with conventional X-rays alone at the same 5 Gy dose. The underlying mechanisms are unveiled using γH2AX imaging and reveal significant increases in DSBs and dying cells following exposure to UHDR radiation. Conclusions: Our results demonstrate that highly synergistic combination treatments using UHDR synchrotron radiation can yield significantly improved brain cancer killing compared with conventional radiotherapy. We anticipate that these additive, multi-modal combination therapies will provide options for more targeted and effective use of radiotherapies for the future treatment of brain cancer. Full article

Background: Failure to accurately estimate gestational age remains an important dilemma for optimal evidence-based antenatal care. Currently, when the last menstrual period (LMP) is unknown, ultrasonography measurement is the best method for estimating gestational age (GA). This study aims to assess the feasibility and accuracy of ultrasonography measurement of the transverse cerebellar diameter (TCD) to deduce fetal GA after 13 weeks of gestation. Methods: A prospective study was conducted on 384 normal singleton pregnancies. Demographic information and biometric measurements, including TCD, were collected using a data sheet. The data were then analyzed using SPSS version 27, DATAtab, and the R program. Results: The study found a strong significant association between GA based on TCD and the LMP, GA based on femur length (FL), GA based on biparietal diameter (BPD), GA based on abdominal circumference (AC), and GA based on the average gestational age (AVG) (r = 0.976, 0.970, 0.966, 0.968, and 0.984, respectively, p < 0.001). Furthermore, there was perfect agreement between GA estimated using TCD and GA based on LMP, with a mean difference of 0.41 weeks and upper and lower limits of agreement of −1.43 to 2.26 weeks. Conclusions: Ultrasonography measurements of the TCD accurately predict gestational age with excellent concordance with GA based on the LMP, FL, AC, and BPD. TCD can be used as a reliable estimator of GA in the second and third trimesters of pregnancy with the benefit of its brain-sparing effect in fetuses of fetal intrauterine growth restriction pregnancies. Combining TCD with FL, BPD, and AC provides the most accurate method of GA prediction. Full article

Glioblastoma (GBM) is a highly malignant brain tumor with extensive cellular heterogeneity and plasticity. Bone morphogenetic protein 4 (BMP4) has shown potential as a therapeutic agent by promoting differentiation, but its effects are complex and context dependent. While BMP4’s role in differentiation is well established, its impact on senescence remains unclear. This study investigates BMP4’s ability to induce senescence in GBM cells. Primary GBM cultures were treated with BMP4 and analyzed for senescence markers, including cell enlargement, p21 expression, senescence-related gene enrichment, and senescence-associated-β-galactosidase activity. A p21 knockout model was used to determine its role in BMP4-induced senescence, and sensitivity to the senolytic agent navitoclax was evaluated. BMP4 induced senescence in the GBM cultures, particularly in mesenchymal (MES)-like GBM cells with high baseline p21 levels. The knockout of p21 nearly abolished BMP4-induced senescence, maintaining cell size and proliferation. Furthermore, navitoclax effectively eliminated BMP4-induced senescent cells through apoptosis, while sparing cells with normal p21 expression. Our findings highlight BMP4 as an inducer of p21-dependent senescence in GBM, particularly in MES-like cells. This study clarifies BMP4’s dual roles in differentiation and senescence, emphasizing their context dependence. Given the strong link between MES-like cells and therapy resistance, their heightened susceptibility to senescence may aid in developing targeted therapies for GBM and potentially other cancers with similar cellular dynamics. Full article

Radiation therapy (RT) is a cornerstone in the management of pediatric central nervous system (CNS) tumors. Recent advancements in RT delivery and techniques aim to enhance therapeutic effectiveness while minimizing both acute and long-term complications associated with pediatric brain RT. This paper highlights innovative developments in the field, including the clinical indications, benefits, and challenges of proton therapy and stereotactic radiotherapy. The ongoing refinement of risk-adapted RT volumes is highlighted, with examples of newly proposed germinoma RT volumes and hippocampal-sparing RT. Additionally, emerging experimental approaches, including FLASH therapy and theranostics, are also discussed as promising future directions. Further prospective, multi-institutional collaborative studies are essential to validate and expand upon the benefits outlined in this review. Full article

Background/Objectives: Brain cancer is notoriously resistant to traditional treatments, including radiotherapy. Microbeam radiation therapy (MRT), arrays of ultra-fast synchrotron X-ray beams tens of micrometres wide (called peaks) and spaced hundreds of micrometres apart (valleys), is an effective alternative to conventional treatments. MRT’s advantage is that normal tissues can be spared from harm whilst maintaining tumour control. Combining MRT with targeted radiosensitisers, such as nanoparticles, chemotherapeutic drugs, and halogenated pyrimidine drugs, can further improve radiotherapy by enhancing radiation damage. However, the underlying mechanisms of MRT are still being understood, which is essential to ensuring the reliable and successful use of MRT. Methods: An in vitro study was performed using γH2AX imaging, and quantification was performed via confocal microscopy and a clonogenic cell survival assay. Results: We show that methotrexate chemotherapeutics and iododeoxyuridine enhance MRT cell-killing and thulium oxide nanoparticles (TmNPs) broaden MRT peaks, and using γH2AX immunofluorescent confocal microscopy to quantify DNA damage, we further our knowledge of MRT mechanisms. γH2AX images verify the biological responses of cells aligning with the physical collimation of MRT, and we can accurately measure MRT microbeam characteristics bio-dosimetrically. The peak-to-valley dose ratio (PVDR), the ratio of the peak dose to the valley dose that characterises an MRT field, was accurately measured biologically using γH2AX imaging, despite studies previously finding this challenging. Conclusions: The measurement of biological PVDR has been performed for the first time with high-Z radiosensitisers, including nanoparticles, and several novel radiosensitiser-enhanced MRT mechanisms were discovered. Our results deepen our understanding of MRT with radiosensitisers, and can contribute to its accurate and future successful use in treating cancer. Full article

Background: Proton beam radiation therapy (PBRT) is an advanced cancer treatment modality that utilizes the distinctive physical properties of protons to precisely deliver radiation to tumor targets while sparing healthy tissue. This cannot be obtained with photon radiation. In this systematic review and meta-analysis, we aimed to comprehensively assess the risk of brainstem toxicity in pediatric brain tumor patients undergoing PBRT. Methods: With adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a predetermined search strategy was used to identify eligible articles from PubMed, Web of Science, Scopus, and Cochrane Library through July 2024. Results: The current study included a total of 11 eligible articles. The pooled prevalence of patients who suffered from brainstem toxicity was 1.8% (95% CI: 1%, 2.6%). The pooled prevalences of patients with Grade 1 to Grade 5 brainstem toxicity were found to be 10.6% (95% CI: 8.8%, 30%), 1.5% (95% CI: 0.6%, 2.5%), 0.7% (95% CI: 0.3%, 1.1%), 0.4% (95% CI: 0.1%, 0.7%), and 0.4% (95% CI: 0.1%, 0.8%), respectively, with an overall pooled prevalence of 0.7% (95% CI: 0.4%, 1%). Conclusions: This study revealed a relatively low incidence of symptomatic brainstem toxicity and its related mortality in the pediatric population undergoing PBRT. However, further research is encouraged to study the broader effects of PBRT and to explore various factors that may influence the risk of brainstem toxicity in patients treated with PBRT. Full article

Cancer is the second leading cause of death worldwide. Around half of all cancer patients undergo some type of radiation therapy throughout the course of their treatment. Photon radiation remains (RT) the most widely utilized modality of radiotherapy despite recent advancements in proton radiation therapy (PBT). PBT makes use of the particle’s biological property known as the Bragg peak to better spare healthy tissue from radiation damage, with data to support that this treatment modality is less toxic than photon RT. Hence, proton radiation dosimetry looks better compared to photon dosimetry; however, due to proton-specific uncertainties, unexpected acute, subacute, and long-term toxicities can be encountered. Reported neurotoxicity resulting from proton radiation treatments include radiation necrosis, moyamoya syndrome, neurosensory toxicities, brain edema, neuromuscular toxicities, and neurocognitive toxicities. Pulmonary toxicities include pneumonitis and fibrosis, pleural effusions, and bronchial toxicities. Pericarditis, pericardial effusions, and atrial fibrillations are among the cardiac toxicities related to proton therapy. Gastrointestinal and hematological toxicities are also found in the literature. Genitourinary toxicities include urinary and reproductive-related toxicities. Osteological, oral, endocrine, and skin toxicities have also been reported. The side effects will be comparable to the ones following photon RT, nonetheless at an expected lower incidence. The toxicities collected mainly from case reports and clinical trials are described based on the organs affected and functions altered. Full article

Introduction: The main goal of radiotherapy (RT) is to deliver a precise dose to the target while sparing the surrounding normal tissue and minimizing side effects. Appropriate patient immobilization is crucial, especially for head and neck cancer (HNC) and Brain Cancer (BC). Conventional closed-face masks (CFMs), while effective in minimizing head motion, can cause significant discomfort, anxiety, and claustrophobia. Open-face masks (OFMs) have been developed to increase patient comfort while providing precise immobilization. Methods: Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) extension for scoping reviews and the Arskey and O’Malley framework, an electronic search of EMBASE, PubMed, SCOPUS, and Web of Science was conducted to identify original studies reporting the use and description of OFMs in clinical practice up to April 2024. The inclusion criteria were English-language articles focusing on OFMs for HNC and BC patients undergoing RT. Results: Of 618 titles, 19 articles fulfilled the selection criteria. Most studies were comparative (n = 13) or observational (n = 6). The articles were categorized by treatment site, resulting in three groups: BC (n = 14, 68.4%), HNC (n = 4, 21.4%), and mixed (n = 2, 10.5%), which includes both BC and HNC. Of note, 82.4% (n = 16) of the included studies were published from 2020 onwards, emphasizing the recent adoption of OFM in clinical practice. Conclusions: The reviewed studies show that OFMs, in combination with SGRT, offer significant advantages in terms of patient comfort and positioning accuracy in HNC and BC treatments. Reproducibility in the sub-millimeter and sub-degree range can be achieved, which supports the use of OFMs in clinical practice. Future research should explore innovative combinations of immobilization and monitoring to further improve RT outcomes and ensure precise treatment while increasing patient comfort. Full article

Low birth weight (BW) calves exhibit higher mortality rates, reduced body weights at parturition, lower first-lactation milk yields, and longer parturition to first insemination intervals. In human medicine, small for gestational age (SGA) births are associated with increased perinatal morbidity and long-term metabolic risks. This study aimed to define SGA in Holstein Friesian (HF) calves, evaluate their body measurements and proportions, and identify its prenatal risk factors. Four linear regression models were built with weight as a function for gestation length for bull and heifer calves born from nulli- or multiparous dams. Calves with a BW below the 10th percentile were classified as SGA. Differences in body measurements were analyzed using ANOVA, and logistic regression models identified prenatal risk factors to be born SGA. Gestation length, calf sex, and dam parity were crucial variables in defining SGA. SGA calves had significantly smaller body measurements (p < 0.001) and larger body proportions (p < 0.001) compared to average and large calves. For nulliparous dams, a higher 2nd trimester temperature–humidity index (p = 0.032) and older age at parturition (>26 months, p = 0.026) significantly increased the birth of SGA calves. For multiparous dams, both low (<5800 kg, p = 0.049) and high (6700–8600 kg, p = 0.027) milk yields during gestation lead to more SGA births, although very high-yielding dams (>8600 kg) did not birth more SGA calves. This study establishes SGA in HF calves, suggests SGA calves are asymmetrical with evidence of “brain sparing”, and highlights the impact of prenatal factors on calf size at birth. Further research is needed to determine the long-term effects of being born SGA on growth, reproductive performance, and productivity. Full article

Helium ion therapy (HRT) is a promising modality for the treatment of pediatric tumors and those located close to critical structures due to the favorable biophysical properties of helium ions. This in silico study aimed to explore the potential benefits of HRT in advanced juvenile nasopharyngeal angiofibroma (JNA) compared to proton therapy (PRT). We assessed 11 consecutive patients previously treated with PRT for JNA in a definitive or postoperative setting with a relative biological effectiveness (RBE) weighted dose of 45 Gy (RBE) in 25 fractions at the Heidelberg Ion-Beam Therapy Center. HRT plans were designed retrospectively for dosimetric comparisons and risk assessments of radiation-induced complications. HRT led to enhanced target coverage in all patients, along with sparing of critical organs at risk, including a reduction in the brain integral dose by approximately 27%. In terms of estimated risks of radiation-induced complications, HRT led to a reduction in ocular toxicity, cataract development, xerostomia, tinnitus, alopecia and delayed recall. Similarly, HRT led to reduced estimated risks of radiation-induced secondary neoplasms, with a mean excess absolute risk reduction of approximately 30% for secondary CNS malignancies. HRT is a promising modality for advanced JNA, with the potential for enhanced sparing of healthy tissue and thus reduced radiation-induced acute and long-term complications. Full article

The advent of FLASH radiotherapy (FLASH-RT) has brought forth a paradigm shift in cancer treatment, showcasing remarkable normal cell sparing effects with ultra-high dose rates (>40 Gy/s). This review delves into the multifaceted mechanisms underpinning the efficacy of FLASH effect, examining both physicochemical and biological hypotheses in cell biophysics. The physicochemical process encompasses oxygen depletion, reactive oxygen species, and free radical recombination. In parallel, the biological process explores the FLASH effect on the immune system and on blood vessels in treatment sites such as the brain, lung, gastrointestinal tract, skin, and subcutaneous tissue. This review investigated the selective targeting of cancer cells and the modulation of the tumor microenvironment through FLASH-RT. Examining these mechanisms, we explore the implications and challenges of integrating FLASH-RT into cancer treatment. The potential to spare normal cells, boost the immune response, and modify the tumor vasculature offers new therapeutic strategies. Despite progress in understanding FLASH-RT, this review highlights knowledge gaps, emphasizing the need for further research to optimize its clinical applications. The synthesis of physicochemical and biological insights serves as a comprehensive resource for cell biology, molecular biology, and biophysics researchers and clinicians navigating the evolution of FLASH-RT in cancer therapy. Full article

Cardiac arrest survivors suffer the repercussions of anoxic brain injury, a critical factor influencing long-term prognosis. This injury is characterised by profound and enduring metabolic impairment. Ketone bodies, an alternative energetic resource in physiological states such as exercise, fasting, and extended starvation, are avidly taken up and used by the brain. Both the ketogenic diet and exogenous ketone supplementation have been associated with neuroprotective effects across a spectrum of conditions. These include refractory epilepsy, neurodegenerative disorders, cognitive impairment, focal cerebral ischemia, and traumatic brain injuries. Beyond this, ketone bodies possess a plethora of attributes that appear to be particularly favourable after cardiac arrest. These encompass anti-inflammatory effects, the attenuation of oxidative stress, the improvement of mitochondrial function, a glucose-sparing effect, and the enhancement of cardiac function. The aim of this manuscript is to appraise pertinent scientific literature on the topic through a narrative review. We aim to encapsulate the existing evidence and underscore the potential therapeutic value of ketone bodies in the context of cardiac arrest to provide a rationale for their use in forthcoming translational research efforts. Full article