Biological Effects Research Articles

Miniaturized microdosimeters for hadron therapy

Microdosimetry measures the stochastic fluctuations of energy imparted by radiation at the micrometer level and can provide measurable quantities linked to biological effectiveness. Reference instruments are Tissue-Equivalent Proportional Counters, gas-filled detectors operated in single-event proportional mode with a chemical composition similar to biological materials. The Legnaro National Laboratories of INFN have extensive experience in the design and construction of miniaturized microdosimetric gas counters able to sustain the high fluence rates of hadron therapy beams without significant pile-up effects. This work discusses the current state-of-the-art detection technologies in microdosimetry for hadron therapy, with a focus on miniaturized gas counters. It describes in particular the development of engineered compact detectors optimized for use in clinics, featuring enhanced stability and reproducibility of response, carried out within INFN projects.

Leucine-rich repeat-containing protein 19 suppresses colorectal cancer by targeting cyclin-dependent kinase 6/E2F1 and remodeling the immune microenvironment

BACKGROUNDColorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, primarily due to tumor heterogeneity and treatment resistance. The leucine-rich repeat-containing protein 19 (LRRC19) has been linked to immune regulation and tumor suppression, yet its specific role in CRC remains poorly understood.AIMTo investigate the tumor-suppressive role of LRRC19 in CRC, focusing on cell cycle, immune microenvironment, and chemotherapy response.METHODSBioinformatics analyses of Gene Expression Omnibus and The Cancer Genome Atlas databases identified differentially expressed genes in CRC. LRRC19 expression was validated in CRC tissues and cell lines by quantitative PCR, immunohistochemistry, and Western blotting. Functional assays, including proliferation, soft agar colony formation, flow cytometry, and xenograft models, assessed biological effects. Mechanistic studies with dual-luciferase reporter assays, molecular docking, and drug sensitivity testing explored LRRC19’s interaction with the cyclin-dependent kinase 6 (CDK6)/E2F1 axis and oxaliplatin (OXA) response. Single-cell sequencing and immune infiltration analyses assessed its impact on the immune microenvironment.RESULTSLRRC19 expression was significantly downregulated in CRC and associated with poor prognosis. Overexpression of LRRC19 inhibited CRC cell proliferation, induced G0/G1 phase arrest, and suppressed tumor growth in vivo. Mechanistically, LRRC19 suppressed CDK6 transcription by downregulating E2F1, leading to cell cycle arrest. Additionally, LRRC19 promoted immune cell infiltration, particularly B cells and CD4+ T cells, while decreasing immunosuppressive cells. LRRC19 also sensitized CRC cells to OXA, enhancing chemotherapy efficacy.CONCLUSIONLRRC19 suppresses CRC by targeting the CDK6/E2F1 axis, modulating the immune microenvironment, and enhancing chemotherapy sensitivity, making it a promising therapeutic target for precision medicine in CRC.

Cardiovascular Aging and Exercise: Implications for Heart Failure Prevention and Management.

A demographic shift toward an aging population is occurring worldwide. Commensurate with this trend, age-related diseases are also rising. Although aging is an immutable part of life, biological aging is a highly heterogeneous process influenced by health-related behaviors, genetics, and the environment. The biological effects of aging are evident across all organ systems. Some individuals demonstrate an accelerated aging phenotype, which is associated with substantial morbidity and mortality. Moreover, common cardiovascular conditions, such as heart failure with preserved ejection fraction, can be conceptualized as a consequence of accelerated aging. Physical activity and exercise training modify the biological effects of accelerated aging considerably. They are associated with various salutary benefits and have emerged as potent therapeutics in disease states characterized by the accelerated aging phenotype. In this state-of-the-art review, we discuss the age-related changes observed in cardiovascular and peripheral tissues, the implications of age acceleration, and the effectiveness and mechanisms of physical activity and exercise training to curb the deleterious effects of aging and improve outcomes.

Assessment of Growth and Physiological Responses of Lemna minor Exposed to 4-Aminodiphenylamine, a Tire Wear Compound

4-Aminodiphenylamine (4-ADPA) is a common additive in rubber tires, known for its antioxidant properties. It plays a crucial role in enhancing tire durability by preventing issues such as drying, cracking, and degradation from prolonged exposure to environmental factors like heat, oxygen, and ozone. However, despite its advantages in extending tire lifespan, the use of 4-ADPA raises significant environmental concerns. As tires wear down, microscopic tire wear particles (TWPs) containing 4-ADPA are released into the environment with substantial leaching, contaminating the waterways. The 4-ADPA leachates pollute and pose a threat to aquatic ecosystems, affecting various forms of marine life. The current study investigates the ecotoxicological effects of 4-ADPA on the aquatic plant Lemna minor (L. minor), focusing on its impact on relative growth and physiological biomarkers. Several parameters were assessed to evaluate ecotoxicity, including frond morphology, fresh biomass, total frond number, chlorophyll content, and starch accumulation. L. minor was grown for 7 and 14 days under controlled laboratory conditions using Hoagland media with varying concentrations of 4-ADPA (10–100 μg/L), while a control group was maintained in media without 4-ADPA. The results indicate that exposure to 4-ADPA led to a dose-dependent reduction in fresh biomass, total frond number, and chlorophyll levels. Lugol’s staining revealed increased starch accumulation in the fronds after exposure to 4-ADPA. The biological effects observed in L. minor following exposure to 4-ADPA, even at environmentally relevant concentrations, demonstrate a significant ecotoxicological impact on aquatic ecosystems. Further research involving additional species and investigating the mechanisms behind 4-ADPA toxicity is recommended to better understand its long-term consequences.

Single-pulse Gy-scale irradiation of biological cells at 1013Gy/s average dose-rates from a laser-wakefield accelerator.

We report on the first experimental characterization of a laser-wakefield accelerator able to deliver, in a single pulse, doses in excess of 1Gy on timescales of the order of a hundred femtoseconds, reaching unprecedented average dose-rates of up to 1013Gy/s. The irradiator is demonstrated to deliver doses tuneable up to 2.2Gy in a cm2area and with a high degree of longitudinal and transverse uniformity in a single irradiation. Proof-of-principle irradiation of patient-derived glioblastoma stem-like cells and human skin fibroblast cells show indications of a differential cellular response, when compared to reference irradiations at conventional dose-rates. These include a statistically significant increase in relative biological effectiveness (1.40±0.08 at 50% survival for both cell lines) and a significant reduction of the relative radioresistance of tumour cells. Data analysis provides preliminary indications that these effects might not be fully explained by induced oxygen depletion in the cells but may be instead linked to a higher complexity of the damages triggered by the ultra-high density of ionising tracks of femtosecond-scale radiation pulses. These results demonstrate an integrated platform for systematic radiobiological studies at unprecedented beam durations and dose-rates, a unique infrastructure for translational research in radiobiology at the femtosecond scale.

Synthesis and Antiviral Activity of Nanowire Polymers Activated with Ag, Zn, and Cu Nanoclusters

Background/Objectives: Airborne viral diseases pose a health risk, due to which there is a growing interest in developing filter materials capable of capturing fine particles containing virions from the air and that also have a virucidal effect. Nanofiber membranes made of poly(vinylidene fluoride) dissolved in N,N-dimethylacetamide and functionalized with copper, silver, and zinc nanoclusters were fabricated via electrospinning. This study aims to evaluate and compare the virucidal effects of nanofibers functionalized with metal nanoclusters against the human influenza A virus A/WSN/1933 (H1N1) and SARS-CoV-2. Methods: A comprehensive characterization of materials, including X-ray diffraction, scanning electron microscopy, microwave plasma atomic emission spectroscopy, thermogravimetric analysis, contact angle measurements, nitrogen sorption analysis, mercury intrusion porosimetry, filtration efficiency, and virucidal tests, was used to understand the interdependence of the materials’ physical characteristics and biological effects, as well as to determine their suitability for application as antiviral materials in air filtration systems. Results: All the filter materials tested demonstrated very high particle filtration efficiency (≥98.0%). The material embedded with copper nanoclusters showed strong virucidal efficacy against the SARS-CoV-2 alpha variant, achieving an approximately 1000-fold reduction in infectious virions within 12 h. The fibrous nanowire polymer functionalized with zinc nanoclusters was the most effective material against the human influenza A virus strain A/WSN/1933 (H1N1). Conclusions: The materials with Cu nanoclusters can be used with high efficiency to passivate and kill the SARS-CoV-2 alpha variant virions, and Zn nanoclusters modified activated porous membranes for killing human influenza A virus A7WSN/1933 (H1N1) virions.

Analysis of Heavy Metal Pollution Characteristics and Biological Effects in Lake Sediments: Implications for Health Risk Assessment

Heavy metals have long been a significant and challenging topic in the research and treatment of lake water environments due to their non-degradability and ease of bioaccumulation. With the advancement of industries such as manufacturing, agriculture, and heavy industry, coupled with the increasing demand for heavy metals, the levels of heavy metals entering the environment have been rising annually. This trend necessitates more refined control measures for heavy metals in the environment. Currently, research on heavy metals in lake sediments in China mainly focuses on spatial distribution, morphological analysis, and ecological risk assessment. However, the characteristics of heavy metal migration, transformation, and biological effects are still largely unquantifiable. This article analyzes soil pollution cases in multiple regions of China and summarizes the nine main sources of heavy metals in the environment. It discusses the characteristics and biological effects of heavy metal migration and transformation. Finally, from the perspective of human health risk assessment, it explores the future development direction of heavy metal research.

Artemisia absinthium L. Extract Targeting the JAK2/STAT3 Pathway to Ameliorate Atherosclerosis.

Artemisia absinthium L. contributes to ecological stabilization in arid regions through its deep root system for sand fixation and soil microenvironment modulation, thereby effectively mitigating desertification. Total terpenoids have been extracted from A. absinthium (AATP) and found to have antioxidant and anti-inflammatory activities. Terpenoids are a class of natural products derived from methyl hydroxypropanoic acid, for which their structural units consist of multiple isoprene (C5) units. They are one of the largest and most structurally diverse classes of natural compounds. However, there are still large gaps in knowledge regarding their exact biological activities and effects. Atherosclerosis (AS) is a prevalent cardiovascular disease marked by the chronic inflammation of the vascular system, and lipid metabolism plays a key role in its pathogenesis. This study determined the extraction and purification processes of AATP through single-factor experiments and response surface optimization methods. The purity of AATP was increased from 20.85% ± 0.94 before purification to 52.21% ± 0.75, which is 2.5 times higher than before purification. Studies have shown that the total terpenoids of A. absinthium significantly reduced four indices of serum lipids in atherosclerosis (AS) rats, thereby promoting lipid metabolism, inhibiting inflammatory processes, and hindering aortic wall thickening and hepatic fat accumulation. It is known from network pharmacology studies that AATP regulates the Janus kinase/signal transducer (JAK/STAT) signaling axis. Molecular docking studies have indicated that the active component of AATP effectively binds to Janus kinase (JAK2) and signal transducer (STAT3) target proteins. The results indicate that AATP can inhibit the release of pro-inflammatory mediators (such as reactive oxygen species (ROS)) in LPS-induced RAW264.7 macrophages. It also inhibits the M1 polarization of RAW264.7 macrophages. Protein immunoblotting analysis revealed that it significantly reduces the phosphorylation levels of Janus kinase (JAK2) and the signal transducer and activator of transcription 3 (STAT3). Research indicates that the active components in A. absinthium may exert anti-atherosclerotic effects by regulating lipid metabolism and inhibiting inflammatory responses. It holds potential value for development as a functional food or drug for the prevention and treatment of atherosclerosis.

Integrative Modeling of Urinary Metabolomics and Metal Exposure Reveals Systemic Impacts of Electronic Waste in Exposed Populations

Background: Informal electronic waste (e-waste) recycling practices release a complex mixture of pollutants, particularly heavy metals, into the environment. Chronic exposure to these contaminants has been linked to a range of health risks, but the molecular underpinnings remain poorly understood. In this study, we investigated the alterations in metabolic profiles due to e-waste exposure and linked these metabolites to systemic biological effects. Methods: We applied untargeted high-resolution metabolomics using dual-column LC-MS/MS and a multi-step analysis workflow combining MS1 feature detection, MS2 annotation, and chemical ontology classification, to characterize urinary metabolic alterations in 91 e-waste workers and 51 community controls associated with the Agbogbloshie site (Accra, Ghana). The impacts of heavy metal exposure in e-waste workers were assessed by establishing linear regression and four-parameter logistic (4PL) models between heavy metal levels and metabolite concentrations. Results: Significant metal-associated metabolomic changes were identified. Both linear and nonlinear models revealed distinct sets of exposure-responsive compounds, highlighting diverse biological responses. Ontology-informed annotation revealed systemic effects on lipid metabolism, oxidative stress pathways, and xenobiotic biotransformation. This study demonstrates how integrating chemical ontology and nonlinear modeling facilitates exposome interpretation in complex environments and provides a scalable template for environmental biomarker discovery. Conclusions: Integrating dose–response modeling and chemical ontology analysis enables robust interpretation of exposomics datasets when direct compound identification is limited. Our findings indicate that e-waste exposure induces systemic metabolic alterations that can underlie health risks and diseases.

A new developed nano-curcumin containing dental hemostatic material; in vitro and the clinical assessments

Curcumin has antioxidant, anti-inflammatory, and cardiovascular protective effects. This study aimed to develop and evaluate an innovative biodegradable hemostatic gelatinous sponge containing curcumin nanoparticles for use in dentistry. This research investigated the efficacy and safety of this material in both in vitro tests and some clinical settings. The novel sponge was prepared via the freeze-drying method. It was characterized by common approaches. The biocompatibility and biological effects of the new sponge were evaluated in vitro. In the next step, thirty-eight patients who needed dental extraction on two teeth were selected for clinical assessment. The prepared sponge was placed inside the cavity of the experimental group. On the control side, the teeth were extracted normally. All patients were studied for pain, swelling, repair of the extracted site, clot quantity, and the occurrence of dry sockets. Results revealed a porous structure with micro- and nanosized pores and a 12-day degradation period. The produced sponge could absorb blood 38 times its weight. It showed no toxic effect. In the clinical study, pain reduction was larger in the experimental group compared to the control group. The extracted site was normal in terms of repair and clot formation. Finally, there was no dry socket in any of the experimental and control groups. The abovementioned advantages may make the new sponge more effective in tooth extraction and other surgical applications in dentistry.

Unlocking the Power of Capsaicin: A Comprehensive Review of Its Mechanisms and Applications

Capsaicin is the main bioactive compound in chili peppers (Capsicum sp.) that has attracted widespread attention in pharmacology and health. This substance functions by stimulating the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor, which is involved in the sense of pain, the control of body temperature, and inflammatory reactions. This study reviews the mechanism of action of capsaicin and its applications in various fields of health and clinical therapy. Capsaicin has diverse pharmacological effects, including as an analgesic, antioxidant, cardioprotective, anti-cancer, and metabolic regulator agent in the management of obesity. In addition, this compound shows potential in neurodegenerative therapy, such as Alzheimer’s and Parkinson’s diseases, by reducing oxidative stress and neuroinflammation. Capsaicin also has gastroprotective, dermatoprotective, antimicrobial, and anti-inflammatory effects, making it a potential ingredient in various medical applications. However, side effects such as gastrointestinal irritation, burning sensation, and possible long-term toxicity need to be considered in its use. Therefore, further research is needed to develop safer and more effective formulations. In addition to its medical applications, capsaicin is also used in the food and biotechnology industries. With a deeper understanding of its mechanisms of action such as affecting the nervous system, body fat profiles, and controlling hunger and other mechanisms described in this paper, capsaicin has the potential to be an important component in the development of molecular-based therapies. Further studies are needed to optimize its therapeutic benefits and explore its safety in broader clinical applications. HIGHLIGHTS Capsaicin exerts its biological effects primarily through activation of the TRPV1 receptor, inducing calcium influx and neuropeptide release that mediate pain perception, thermoregulation, and inflammatory responses. Capsaicin demonstrates a broad spectrum of pharmacological properties, including antioxidant, anti-obesity, cardioprotective, anticancer, and antimicrobial activities via multiple cellular pathways. Capsaicin shows therapeutic potential in the management of neurodegenerative and metabolic disorders such as Alzheimer’s disease, Parkinson’s disease, and obesity by modulating oxidative stress and metabolic signaling mechanisms. Capsaicin’s clinical applications are limited by adverse effects, such as local irritation and gastrointestinal discomfort, thereby necessitating the development of safer and better-tolerated analogs. The discovery of endogenous and synthetic TRPV1 ligands reinforces capsaicin’s therapeutic relevance beyond nociception, extending to cardiovascular, dermatological, and gastrointestinal health. GRAPHICAL ABSTRACT

Nghiên cứu đánh giá hoạt tính của viên sủi ngâm thảo dược xuất phát từ bài thuốc tắm lá của dân tộc Dao xã Ba Vì, Hà Nội

After more than 15 years of implementing Directive No. 24-CT/TW, the awareness and responsibility of Party committees, government authorities, and the public regarding the role and position of traditional Vietnamese medicine and the Vietnam Oriental Medicine Association have significantly improved. This shift has contributed to the advancement of diagnostic and therapeutic techniques in traditional medicine towards greater specialization and uniqueness, gradually affirming the effectiveness of non-pharmaceutical diagnostic and treatment methods, as well as the practical value of traditional remedies and medicinal herbs. In this context, the folk remedies of the Dao ethnic community continue to play an important role in public healthcare. The Dao people's experience in using medicinal herbs shows potential applications in supporting the treatment of various internal diseases (such as kidney stones, cardiovascular conditions, respiratory issues, joint pain, hepatitis, etc.) through decoctions or by incorporating herbal ingredients into daily diets. Similarly, skin conditions (such as itching, ulcers, boils, etc.) are often treated using decoctions for washing, bathing, or localized soaking. However, a notable issue is that most of the medicinal plants used by the Dao people have not been fully scientifically identified or systematically evaluated for their pharmacological effects. Therefore, this study was conducted to determine the scientific identities of several herbal species and to evaluate the biological effects of the Dao’ Relaxing Trieu Loc effervescent herbal soaking tablet. Preliminary results identified 4 out of the 9 herbal species used in the tablet formulation. Notably, the product exhibited nitric oxide (NO) inhibitory activity with an IC₅₀ value of 0.084 mg/mL, showed no cytotoxicity on RAW 264.7 macrophage cells at concentrations below 1 mg/mL, and did not cause skin allergic reactions in initial testing. Keywords: Herbal Effervescent Soak, Dao Ethnic Group, Dao’ Relaxing Trieu Loc, Anti-inflammatory

PEMFs Restore Mitochondrial and CREB/BDNF Signaling in Oxidatively Stressed PC12 Cells Targeting Neurodegeneration.

Alzheimer's disease (AD), the most prevalent form of neurodegenerative dementia, is characterized by progressive cognitive decline and neuronal loss. Despite advances in pharmacological treatments, current therapies remain limited in efficacy and often induce adverse effects. Increasing evidence highlights oxidative stress, mitochondrial dysfunction, and disrupted neurotrophic signaling as key contributors to AD pathogenesis. Pulsed electromagnetic fields (PEMFs) are emerging as a non-invasive, multifactorial approach with promising biological effects. In this study, we investigated the neuroprotective potential of PEMFs in NGF-differentiated PC12 cells exposed to hydrogen peroxide (H2O2) or amyloid-β peptide (Aβ), both of which model pathological features of AD. PEMF treatment significantly counteracted H2O2- and Aβ-induced cytotoxicity by restoring cell viability, reducing reactive oxygen species production, and improving catalase activity. Furthermore, PEMFs preserved the mitochondrial membrane potential and decreased caspase-3 activation and chromatin condensation. Mechanistically, PEMFs inhibited ERK phosphorylation and enhanced cAMP levels, CREB phosphorylation, and BDNF expression, pathways known to support neuronal survival and plasticity. In conclusion, these findings suggest that PEMFs modulate multiple stress response systems, promoting neuroprotection under oxidative and amyloidogenic conditions.

Nicotine from a Different Angle: Biological Effects from a Psychoneuroimmunological Perspective.

Statistical data demonstrate a concurrent rise in smoking prevalence and mental disorders, such as depression and anxiety, which may be attributed to contemporary lifestyle factors, including social media and recent global events. This indicates a potential correlation between these trends, as individuals with mental disorders may engage in smoking as a form of self-medication to alleviate anxiety. However, smoking is harmful and increases the risk of many diseases. Therefore, smoking cessation strategies are increasingly being considered. Nicotine is a naturally produced alkaloid in plants that makes smoking so addictive. Unfortunately, the public's lack of understanding of the effects of nicotine leads to misleading claims in the public and media about its biological effects. Thus, current narrative literature review is focused on the examination of the biological effects of organic nicotine from various angles, considering the psychological aspects of addiction and the immune system. Analysis of recent data showed that nicotine not only causes addiction but also has therapeutic benefits in certain diseases (depression, anxiety, schizophrenia) and has anti-inflammatory properties (autoimmunity, neurodegenerative diseases), and a deeper understanding and a broader approach to its effects is needed.

Endogenous Ribonucleases: Therapeutic Targeting of the Transcriptome Through Oligonucleotide-Triggered RNA Inactivation

The selective regulation of gene expression at the RNA level represents a rapidly evolving field offering substantial clinical potential. This review examines the molecular mechanisms of intracellular enzymatic systems that utilize single-stranded nucleic acids to downregulate specific RNA targets. The analysis encompasses antisense oligonucleotides and synthetic mimics of small interfering RNA (siRNA), microRNA (miRNA), transfer RNA-derived small RNA (tsRNA), and PIWI-interacting RNA (piRNA), elucidating their intricate interactions with crucial cellular machinery, specifically RNase H1, RNase P, AGO, and PIWI proteins, mediating their biological effects. The functional and structural characteristics of these endonucleases are examined in relation to their mechanisms of action and resultant therapeutic outcomes. This comprehensive analysis illuminates the interactions between single-stranded nucleic acids and their endonuclease partners, covering antisense inhibition pathways as well as RNA interference processes. This field of research has important implications for advancing targeted RNA modulation strategies across various disease contexts.

Pinus-derived membrane vesicles disrupt pathogenic metabolism in fungi.

Much of what we know about the biological impacts of vesicles (MVs) is derived from Arabidopsis thaliana. Our study focused on vesicles from species in the non-model plant group, Pinus (pine) (P. elliottii, P. radiata, and P. patula × Pinus tec (hybrid)). These plants have tougher tissues and strong, acicular-shaped leaves (needles). Herein, we first developed a protocol to guide effective collection of juice fluid from needles and roots in a clean and efficient manner. The effects of these vesicles were characterized in terms of the global nutrient profile of the pine pitch canker fungus, Fusarium circinatum, generated from growing fungal spores on ~400 substrates embedded across BioLog phenotypic microarray (PM) plates (PM1, PM2A: carbon sources; PM3B: nitrogen sources; PM9: osmolytes/pH; PM24C: chemicals). Our findings revealed that MVs, specifically needle-derived MVs (ndMVs) from P. elliottii, disrupt metabolite assimilation in several important pathways, including carbon and nitrogen metabolism. The PM data were also strongly correlated with observed phenotypic effects, including reduced viability and germination of spores in liquid media, as well as impaired filamentous growth on solid media. Importantly, these MV-induced phenotypic effects were reproducible in other filamentous pathogens (e.g., Botrytis cinerea, Chrysoporthe cubensis and F. graminearum) and during a glasshouse trial conducted with F. circinatum-infected P. elliottii seedlings, demonstrating the stable biological effects of ndMVs. Cumulatively, our results suggest that plant-derived vesicles can disrupt metabolism in pathogenic fungi and, therefore, serve as a cost-effective and sustainable source of novel plant protection molecules.

An example of drug repurposing: ebastine in combination with docetaxel as a treatment for metastatic castration-resistant prostate cancer–the EXUROC prostate study, a clinical trial protocol

BackgroundThis clinical trial investigates the addition of a repurposed drug, the cationic amphiphilic drug (CAD) ebastine, to docetaxel in metastatic castration resistant prostate cancer (mCRPC). Preclinical data have shown that chemotherapy-resistant prostate cancer cells can be re-sensitized and that combining CAD with docetaxel significantly inhibits tumor growth in xenograft mouse models of docetaxel-resistant mCRPC. The primary objective of this study is to evaluate the impact of ebastine plus docetaxel versus docetaxel alone for mCRPC, measured as Bis(monoacylglycero)phosphate (BMP) and lysophospholipids in urine and blood. Secondary endpoints are prostate-specific antigen (PSA) and radiologic progression-free survival.MethodsThis randomized, open-label, phase ll trial will include 30 patients with disease progression after prior therapy for mCRPC, in a 2:1 ratio favoring the intervention arm. Inclusion criteria are metastatic adenocarcinoma/poorly differentiated carcinoma of the prostate, serum testosterone levels ≤ 50 ng/dL., and that patients are planned for docetaxel treatment.DiscussionThe trial was initiated on 1 June 2024 and is currently recruiting participants. Results are expected to be available by Q4 2027. This phase II study aims to evaluate the clinical effectiveness of CADs, with a specific focus on biomarkers such as BMP and lysophospholipids. This biomarker-driven approach offers a unique opportunity to gain insight into the biological effects of the combination treatment, particularly its impact on lysosomal lipid metabolism. If the biological rationale is confirmed, the study will proceed to a phase II/III large-scale randomized trial.Trial registrationThe trial is registered on ClinicalTrials.gov as NCT06480110.

Sustained acoustic medicine increases local circulation with a diclofenac delivery patch: a randomized placebo controlled study

BackgroundSustained Acoustic Medicine (SAM) is a non-invasive long-term wearable device that delivers localized long duration high-frequency continuous ultrasound. SAM's biomechanical and diathermic stimuli enhance local circulation and oxygenation, accelerate tissue healing, and alleviate pain. The sonophoresis effects of SAM further improve transdermal drug delivery. Diclofenac is a topical Nonsteroidal anti-inflammatory drug for treating localized musculoskeletal (MSK) pain. Its efficacy is significantly dependent on skin porosity. This study aims to determine the diathermic effects of SAM and diclofenac on localized blood circulation.MethodsSixty-four healthy participants were randomly assigned to four groups (Active SAM group: n = 32, Placebo SAM group: n = 32): (A) Coupling gel + placebo SAM), (B) Coupling gel + active SAM, (C) 2.5% Diclofenac gel + placebo SAM, and (D) 2.5% Diclofenac gel + active SAM. Both forearms were treated with a placebo and active SAM devices for 1 h. The blood flux (perfusion units, PU) and temperature (degrees centigrade) change were recorded at 10 min intervals for 60 min using high-laser-power Doppler flowmetry. Blood circulation and temperature were recorded and reported (Clinical trial Identifier: NCT06510062).ResultsSAM increased blood flow significantly over 60 min by 19.2 PU (p < 0.0001) with coupling patch and 18.6 PU with 2.5% diclofenac patch (p < 0.0001) vs. placebo. Surface level tissue temperature increased by Δ2.4°C (p < 0.0001) with gel coupling patch and Δ2.2°C (p < 0.0001) with 2.5% diclofenac patch vs. placebo ultrasound treatment (p < 0.0001). There was no significant difference between standard coupling ultrasound gel and 2.5% diclofenac gel in blood flow and temperature. SAM provided a significant temperature increase at 20 min and a circulation increase at 10 min, which remained for the duration of the 60 min. All participants completed the study with no adverse events.ConclusionSAM treatment significantly increases local blood circulation after 10 min, increases temperature after 20 min, and sustains the effects of SAM's stimulation. The 2.5% diclofenac gel does not affect SAM's biological effects to increase local circulation. The study concludes that the application of diclofenac does not affect the diathermic properties of SAM exposure while enhancing the efficacy of diclofenac delivery through sonophoresis.Clinical Trial Registrationidentifier NCT06510062.

Advances on resource, biosynthesis pathway, bioavailability, and bioactivity of dihydrodaidzein

Abstract Compared with metabolic precursor daidzein, dihydrodaidzein exhibits higher activity and broader biological effects, and have gradually attracted the attention in recent years. This review provides a systematic overview of resources, physicochemical properties, in vivo metabolism and microbial transformation, bioavailability and bioactivity of dihydrodaidzein. Dihydrodaidzein is mainly derived from biosynthesis, and it can also be produced by chemical synthesis and enzyme catalyzation. Gut microorganisms play a key role in the in vivo metabolism of dihydrodaidzein, in which it can be generated from daidzein and further converted into the more active equol. There are several high productive strains of dihydrodaidzein identified, including Aeroto-Niu-O16, TM-40, Lactobacillus acidipiscis HAU-FR7 and Slackia isoflavoniconvertens DSM22006. Among others, these strains contain genes involved in isoflavone conversion, including the daidzein, dihydrodaidzein and tetrahydrodaidzein reductase (dzr, ddr, tdr) and dihydrodaidzein racemase (ifcA). Although dihydrodaidzein (0.14 g/L) exhibited better water solubility than of daidzein (0.085) and better absorbed, it also suffers low oral bioavailability. Therefore, emerging nanocarrier technologies can be explored to encapsulate dihydrodaidzein to enhance its cellular uptake, targeted delivery and functional efficacy. It has been found to have superior pharmacological activities in antioxidant, cardiovascular disease, prevention of osteoporosis and estrogen-like activity. A comprehensive summary of dihydrodaidzein will allow more researchers to target their research, thus promoting its use in food and nutraceuticals. Graphical abstract

A Novel Treatment Strategy for Unresectable Locally Recurrent Rectal Cancer-Upfront Carbon-Ion Radiotherapy Followed by Surgical Resection of the Irradiated Intestines.

Background/Objectives: Carbon-ion radiotherapy (CIRT) is a promising treatment option for unresectable locally recurrent rectal cancer (LRRC). However, CIRT is contraindicated in cases where recurrent tumors are attached to the intestine. To address this limitation, we developed a novel treatment strategy involving curative-dose CIRT to recurrent tumors, including the adjacent intestine, without dose constraints, followed by surgical resection of the irradiated intestine. This study aimed to assess the feasibility of this approach. Methods: Patients were eligible for this study if the distance between the unresectable recurrent tumor and the adjacent intestines was less than 3 mm. Between 2019 and 2023, twelve patients were enrolled. CIRT was administered at curative doses of 70.4 or 73.6 Gy (relative biologic effectiveness (RBE)), including the adjacent intestines, without dose constraints. Surgical resection was not intended to excise the tumor itself, but was performed solely to remove the irradiated intestines. Irradiated intestine resection was planned within eight weeks after the completion of CIRT. Results: All patients completed the scheduled treatment course. The median interval between completing CIRT and surgery was 4 (3-8) weeks. No patients experienced acute AEs related to CIRT. Regarding late AEs, two patients developed Grade I sciatic neuralgia, and one patient developed Grade III neuralgia. We considered this symptom, which later resulted in a limp in his left leg, acceptable because this patient could ambulate with assistance. Clavien-Dindo Grade III postoperative complications occurred in one patient. The median follow-up duration was 40 (20-60) months. One patient was diagnosed with in-field recurrence, and three patients were diagnosed with out-of-field recurrence. These patients received reirradiation with CIRT. Four patients experienced lung recurrence, and one patient died from rectal-cancer-specific causes. Conclusions: This novel treatment strategy may provide favorable outcomes for patients with unresectable LRRC. This approach can be applied to the currently accepted indications for CIRT, and we believe that CIRT is a feasible treatment option for future patients.