Tissue Protection Research Articles

Assessing the Protective Effects of Benoxacor, Fenclorim, Melatonin, and 2,4,6-Trichlorophenoxyacetic Acid Against Herbicide Injury in Tomato

Safeners protect crops by enhancing their ability to metabolize various compounds, including herbicides. They increase a crop’s tolerance to herbicide damage, activating herbicide-metabolizing proteins, and aiding in their detoxification. This study aimed to investigate the chemical effects of safeners in tomato cultivation and focus on injury reduction and tissue protection. The experiment followed a randomized factorial design (5 × 4) with four replications repeated twice. We evaluated the effects of herbicides dicamba, 2,4-D, metribuzin, and sulfentrazone (diluted to 1% of the recommended field rate) and safeners benoxacor, fenclorim, melatonin, 2,4,6-T, and an untreated control. Safeners were applied to the seeds before sowing, and herbicides were applied as a foliar spray 25 days after sowing. Visual injury was evaluated 7, 14, and 21 days after application (DAA). Biomass measurements were taken 21 DAA. Results showed that preconditioning tomato seeds with 2,4,6-T, melatonin, and fenclorim 7 DAA significantly decreased injury by 25, 25, and 23%, respectively. Moreover, applying melatonin, benoxacor, and 2,4,6-T 21 DAA led to significantly greater dry biomass, which increased by 1.5, 1.42, and 1.44 times, respectively, compared with the control. This research provides valuable insights into the chemical effects of benoxacor, fenclorim, 2,4,6-T, and melatonin safeners in tomato cultivation. The findings demonstrate the potential for preconditioning tomato plants with 2,4,6-T, melatonin, and fenclorim to reduce herbicide injury. Additionally, melatonin, benoxacor, and 2,4,6-T stimulated growth, increasing tomato dry biomass. Understanding plant defense mechanisms and the protective effects of safeners against herbicide damage contributes to developing effective weed management strategies.

Modern radiotherapy for breast cancer: Update and new developments

AbstractThe delivery of radiotherapy for breast cancer has evolved significantly over the years. The aim of this review is to highlight important developments and current concepts. Postoperative hypofractionated three-dimensional conformal or intensity-modulated photon radiotherapy continues to be the standard application after breast-conserving surgery to improve local control. New therapy techniques in deep inspiration breath hold or physical-biological advantages of proton beam therapy offer innovative therapy methods with regard to the protection of normal tissue and reduced cardiotoxicity. Ultra-hypofractionated therapy concepts and the integration of a simultaneous integrated boost in hypofractionated therapy concepts also enable the duration of treatment to be reduced to a few days or weeks. In low-risk constellations, the radiation volume may also be de-escalated to partial breast irradiation, and if life expectancy is severely restricted at the same time, the omission of postoperative radiotherapy might be critically discussed. The oncological benefit of an irradiation of the regional lymph node regions continues to be confirmed in locally advanced, node-positive carcinomas and further enables the omission of surgical axillary lymph node dissection with low morbidity in individualized therapy approaches.

Treatment of diametaphyseal forearm fractures in children and adolescents : Antegrade intramedullary nail osteosynthesis and its alternatives

Osteosynthesis in dislocated diametaphyseal forearm fractures is intended to restore anatomy and function. Antegrade intramedullary nailing in the radius is used to restore length, rotation, and axis within the age-specific correction limits. Sufficient stability ensures early functional postoperative treatment without load. Dislocated diametaphyseal forearm or radius fractures that cannot be closed, stably reduced, or remain outside the age-specific correction limits. Radius or forearm fractures located distal or proximal to the defined area. Soft tissue defects, contamination or infections located in the access path. In the course of the Thompson approach, the soft spot between the extensor digitorum and extensor carpi radialis brevis muscles is located and an approx. 3-4 cm skin incision is made. Then blunt preparation down to the bone, sparing the profundus and superficial radial nerve. Retraction of the musculature with two Langenbeck hooks. Opening of the cortex with an awl. If necessary, a2.5 mm drill with tissue protection can be used beforehand if the cortex is very hard. Atitanium elastic nail (TEN) diameter is selected so that it fills approximately 2/3 of the medullary canal. It is recommended to flatten the TEN runner with parallel flattening forceps. After closed reduction, the TEN is then brought up in front of the growth plate with slightly rotating movements. The TEN is bent over at the proximal end and pinched off above the muscle bellies. Alternative procedures include Kirschner wire osteosynthesis or retrograde TEN from radial or dorsal, with or without bending. The aim of osteosynthesis is early functional follow-up without load. Sports abstinence is recommended for 8weeks. Metal removal can be performed after consolidation between 3and 6months. Clearly dislocated or outside the correction limits infantile radius and forearm fractures show very good treatment results with alow risk profile after the described osteosynthesis technique. Pseudarthrosis and nerve damage were not observed. Secondary dislocation has not occurred.

Abstract 4137854: Effect of Sacubitril/valsartan on Left Ventricular Tissue Characterization in Heart Failure with Left Ventricular Ejection Fraction Below 50%

Background: The effects of sacubitril/valsartan (ARNI) on myocardial tissue characterization in heart failure (HF) with left ventricular ejection fraction (LVEF) <50% are still unclear. Objective: The present study investigated the effects of 9 months of ARNI treatment on LV structure and myocardial tissue characteristics in HF with LVEF <50% using cardiac magnetic resonance (CMR). Methods: This study was a prospective, 2-arm, randomized, open-label clinical trial (SAVE-HF). Sixty-four HF outpatients with LVEF<50% were randomized 1:1 from ACE inhibitor/ARB to ARNI (ARNI group) or control group (continued ACE inhibitor/ARB). CMR was performed to evaluate LV structure and tissue characteristics, including changes in LV extracellular volume fraction (delta ECV) before and after the 9-month period. The primary endpoint was difference in ECV between the two groups. Secondary endpoints included changes in LV volumes and mass, LVEF, extracellular mass (ECM) calculated as LV mass times ECV/100, and intracellular mass (ICM) calculated as LV mass minus ECM. Results: A total of 59 of 64 stable patients (68±12 years; 52 men) completed the 9-month intervention followed by repeated CMR. ARNI decreased systolic BP levels from the first month by approximately 10 mmHg. ARNI group exhibited significant reductions in LV end-diastolic and end-systolic volumes and LV mass. While LVEF and ECV remained unchanged (31.6±5.0 vs. 31.9±5.0%, p=0.26), both ECM and ICM significantly decreased after ARNI. In the control group, systolic BP, LV volumes and LV mass, ECV, ECM and ICM were unchanged. Comparing the two groups, while delta ECV was not significantly different, delta ECM was greater in ARNI group than control group (-3.6±7.3 vs. 0.2±5.3 g, p=0.025), indicating improved LV tissue characteristics. Conclusions: ARNI reduced LV volume and LV mass, accompanied with reduction of both ECM and ICM, and consequently unchanged ECV. These findings may suggest that ARNI may improve LV tissue characteristics and protect from LV remodeling in HF patients with their LVEF<50%.

Interleukin-22 inhibits right ventricular remodelling by a unique mechanism in a pulmonary artery constriction model

Abstract Background Fibrosis and remodeling of right ventricle (RV) are associated with prognosis in patients with RV failure. Interleukin-22 (IL-22) is a member of the IL-10 cytokine family, play roles in tissue protection and wound repair. We have previously shown that IL-22 plays an important role in cardiac remodeling after acute myocardial infarction; however, the role of IL-22 in RV fibrosis and remodeling remains elusive. Purpose We investigated the role of IL-22 in the pathogenesis of RV remodeling during pressure overload. Methods Pulmonary artery banding (PAB) is performed by placing a 6-0 suture around the pulmonary artery over a 24 G needle in wild type mice (C57BL/6J) and IL-22 knockout mice (IL-22 KO). Only mice with moderate pulmonary artery stenosis (peak pressure gradient across the pulmonary band: 25–40 mmHg at 1 week after surgery by echo Doppler) were included in the study protocol. Four weeks after PAB, RV function was measured by echocardiography and real-time PCR analysis was performed to measure Col1a1, Col3a1, BNP, and transcriptome analysis was performed. Survival confirmation of mice with moderate pulmonary artery stenosis was also performed up to 56 days. Results IL-22 KO mice had significantly higher 56-day mortality rate compared with WT mice after PAC (p<0.01). Four weeks after PAB, IL-22 KO mice showed markedly increased RV weight (IL-22 KO mice vs. wild-type mice; RV/LV+IVS: 0.48±0.05 vs 0.40±0.02, P=0.002). IL-22 KO mice exhibited significant RV enlargement and RV dysfunction 4 weeks after PAB. (IL-22 KO mice vs wild type mice; RVEDV: 10±2.3mm2 vs 12.9±3.1mm2, P=0.005, TAPSE: 10.8±1.8mm vs 9.5±1.7mm, P=0.04, FAC: 35.2±7.8% vs 23±6.0%, P<0.001). The expressions of Col1a1 and Col3a1 were no difference between in IL22-KO mice and Wild mice. However, BNP, a cardioprotective marker, tended to be lower in IL-22KO mice. The transcriptome analysis also showed that the group of fibrosis-related genes that are elevated in PAC in WT mice were less elevated in IL-22 KO mice. Conclusion These results suggest that IL-22 is involved in RV remodelling during RV pressure loading without a general mechanism.

Therapeutic potential of EVs loaded with CB2 receptor agonist in spinal cord injury via the Nrf2/HO-1 pathway

ABSTRACT Background Spinal cord injury (SCI) poses a challenge due to limited treatment options. Recently, the effect and mechanism of Exo-loaded cannabinoid receptor type 2 (CB2) agonist AM1241(Exo + AM1241) have been applied in other inflammatory diseases but not in SCI. Methods The SCI model was set up using C57BL/6 mice, followed by the treatment of Exo, AM1241, and Exo + AM1241. We assessed the effects of the following treatments on motor function recovery using BMS, and evaluated histological changes, apoptosis activity, inflammation, and oxidative stress in the SCI mice model. Additionally, the effect of following treatments on spinal cord neural stem cells (NSCs) was evaluated under lipopolysaccharides (LPS) induced inflammatory and oxidative models and, glutamate (Gluts) induced cell apoptosis models. Result Our results demonstrated that Exo + AM1241 treatment significantly improved motor function recovery, after SCI by decreasing proinflammatory cytokines, and suppressing astrocyte/microglia (GFAP/Iba1) activation in the injury zone. Additionally, this treatment reduces pro-apoptotic proteins (Bax and caspase 3), increases the levels of the anti-apoptotic protein Bcl-2, enhances antioxidant defenses by boosting SOD and GSH, and lowers oxidative stress markers such as MDA. It also activates the Nuclear factor erythroid-2 (Nrf2) related factor 2 signaling pathway, thereby enhancing tissue protection against damage and cell death.

Impact of Neuron-Derived HGF on c-Met and KAI-1 in CNS Glial Cells: Implications for Multiple Sclerosis Pathology.

Demyelination and axonal degeneration are fundamental pathological characteristics of multiple sclerosis (MS), an inflammatory disease of the central nervous system (CNS). Although the molecular mechanisms driving these processes are not fully understood, hepatocyte growth factor (HGF) has emerged as a potential regulator of neuroinflammation and tissue protection in MS. Elevated HGF levels have been reported in MS patients receiving immunomodulatory therapy, indicating its relevance in disease modulation. This study investigated HGF's neuroprotective effects using transgenic mice that overexpressed HGF. The experimental autoimmune encephalomyelitis (EAE) model, which mimics MS pathology, was employed to assess demyelination and axonal damage in the CNS. HGF transgenic mice showed delayed EAE progression, with reduced CNS inflammation, decreased demyelination, and limited axonal degeneration. Scanning electron microscopy confirmed the preservation of myelin and axonal integrity in these mice. In addition, we explored HGF's effects using a cuprizone-induced demyelination model, which operates independently of the immune system. HGF transgenic mice exhibited significant protection against demyelination in this model as well. We also investigated the expression of key HGF receptors, particularly c-Met and KAI-1. While c-Met, which is associated with increased inflammation, was upregulated in EAE, its expression was significantly reduced in HGF transgenic mice, correlating with decreased neuroinflammation. Conversely, KAI-1, which has been linked to axonal protection and stability, showed enhanced expression in HGF transgenic mice, suggesting a protective mechanism against axonal degeneration. These findings underscore HGF's potential in preserving CNS structure and function, suggesting it may be a promising therapeutic target for MS, offering new hope for mitigating disease progression and enhancing neuroprotection.

Anti irradiation nanoparticles shelter immune organ from radio-damage via preventing the IKK/IκB/NF-κB activation

BackgroundNormal tissue and immune organ protection are critical parts of the tumor radiation therapy process. Radiation-induced immune organ damage (RIOD) causes several side reactions by increasing oxidative stress and inflammatory responses, resulting in unsatisfactory curability in tumor radiation therapy. The aim of this study was to develop a novel and efficient anti irradiation nanoparticle and explore its mechanism of protecting splenic tissue from radiation in mice.MethodsNanoparticles of triphenylphosphine cation NIT radicals (NPs-TPP-NIT) were prepared and used to protect the spleens of mice irradiated with X-rays. Splenic tissue histopathology and hematological parameters were investigated to evaluate the protective effect of NPs-TPP-NIT against X-ray radiation. Proteomics was used to identify differentially expressed proteins related to inflammatory factor regulation. In addition, in vitro and in vivo experiments were performed to assess the impact of NPs-TPP-NIT on radiation therapy.ResultsNPs-TPP-NIT increased superoxide dismutase, catalase, and glutathione peroxidase activity and decreased malondialdehyde levels and reactive oxygen species generation in the spleens of mice after exposure to 6.0 Gy X-ray radiation. Moreover, NPs-TPP-NIT inhibited cell apoptosis, blocked the activation of cleaved cysteine aspartic acid–specific protease/proteinase, upregulated the expression of Bcl-2, and downregulated that of Bax. We confirmed that NPs-TPP-NIT prevented the IKK/IκB/NF-κB activation induced by ionizing radiation, thereby alleviating radiation-induced splenic inflammatory damage. In addition, when used during radiotherapy for tumors in mice, NPs-TPP-NIT exhibited no significant toxicity and conferred no significant tumor protective effects.ConclusionsNPs-TPP-NIT prevented activation of IKK/IκB/NF-κB signaling, reduced secretion of pro-inflammatory factors, and promoted production of anti-inflammatory factors in the spleen, which exhibited radiation-induced damage repair capability without diminishing the therapeutic effect of radiation therapy. It suggests that NPs-TPP-NIT serve as a potential radioprotective drug to shelter immune organs from radiation-induced damage.

Perda precoce dos elementos 11 e 12 por trauma dental, com intervenção ortodôntica preventiva na odontopediatria: relato de caso

Dental trauma is one that affects the hard tissues embraced, supporting structures or soft tissues in the oral cavity. It is observed more frequently in male children of school age (07 to 12 years old). The most affected teeth in the trauma taken are central and lateral incisors. With regard to tooth avulsions, the protection of children's bone tissue favors a higher frequency in this population than in the adult population. Dental avulsion occurs after displacement of the element out of its alveolus. There is a break in the blood supply to the pulp of the tooth and when this happens the chance of replantation achieved is totally impossible. Thus bringing several harms to the patient such as difficulty in speech, poor aesthetics, or even mesialize or distalize some other acquired element. Space maintainers are used as removable or fixed appliances to treat malocclusion or esthetic defects. They are braces made of acrylics with two extended teeth. Choosing a removable appliance comes with benefits such as better hygiene, satisfactory aesthetics, low cost, and maintenance of the cervico-occlusal space, in addition to the mesio-distal space. The objective of this study was to report a clinical case of avulsion of element 11 and 12 caused by trauma in childhood with the use of a space maintainer. We conclude that it is possible to treat a patient with dentoalveolar trauma with intervention using a space maintainer, since in the present case success was obtained in the selection of therapy, restoring aesthetics and function to the patient. Thus reducing possible orthodontic problems of the child, with follow-up until his/her old age.

Proton beam therapy in a patient with secondary glioblastoma (32 years after postoperative irradiation of medulloblastoma): case report and literature review

ObjectiveThis report details the experience of a patient who developed a second primary glioblastoma (GB), offering insights into the treatment process and reviewing relevant literature.Case presentationA male patient, who was diagnosed with medulloblastoma at age 9, received treatment with cobalt-60 craniospinal irradiation (CSI) (36 Gy/20 fractions) and a tumor bed boost (total of 56 Gy). After 32 years, at age 41, an MRI revealed a space-occupying mass in the left cerebellar hemisphere. Surgical resection was performed, and postoperative pathology confirmed a diagnosis of radiation-induced glioblastoma (RIGB). Given the history of irradiation and the current tolerability of brainstem doses, proton beam therapy (PBT) combined with Temozolomide (75 mg/m2) was chosen. The treatment plan included 60 Gy on the gross tumor bed and 54 Gy on the clinical target volume, delivered in 30 fractions. The patient underwent regular follow-up and achieved a complete response.Clinical discussionFor childhood cancer survivors, the development of a second primary tumor significantly impacts prognosis. RIGB is a rare form of secondary tumor with distinct molecular characteristics compared to primary GB and recurrent secondary GB. Molecular markers such as IDH and MGMT status can help differentiate between primary GB, recurrent secondary GB, and radiation-induced secondary GB in patients with a history of prior radiation therapy. Surgical resection remains a primary treatment option, while PBT is preferred for postoperative treatment due to its superior protection of normal tissues and the ability to deliver high-dose irradiation.ConclusionRIGB is a rare second primary tumor that requires strategic molecular profiling and individualized management. Proton beam therapy provides effective high-dose irradiation in the postoperative phase and is the preferred treatment option for such cases.

Distribution of Immunomodulation, Protection and Regeneration Factors in Cleft-Affected Bone and Cartilage.

Craniofacial clefts can form a significant defect within bone and cartilage, which can negatively affect tissue homeostasis and the remodeling process. Multiple proteins can affect supportive tissue growth, while also regulating local immune response and tissue protection. Some of these factors, like galectin-10 (Gal-10), nuclear factor kappa-light-chain-enhancer of activated B cells protein 65 (NF-κB p65), heat shock protein 60 (HSP60) and 70 (HSP70) and cathelicidin (LL-37), have not been well studied in cleft-affected supportive tissue, while more known tissue regeneration regulators like type I collagen (Col-I) and bone morphogenetic proteins 2 and 4 (BMP-2/4) have not been assessed jointly with immunomodulation and protective proteins. Information about the presence and interaction of these proteins in cleft-affected supportive tissue could be helpful in developing biomaterials and improving cleft treatment. Two control groups and two cleft patient groups for bone tissue and cartilage, respectively, were organized with five patients in each group. Immunohistochemistry with the semiquantitative counting method was implemented to determine Gal-10-, NF-κB p65-, HSP60-, HSP70-, LL-37-, Col-I- and BMP-2/4-positive cells within the tissue. Factor-positive cells were identified in each study group. Multiple statistically significant correlations were identified. A significant increase in HSP70-positive chondrocytes in cleft patients could indicate that HSP70 might be reacting to stressors caused by the local tissue defect. A significant increase in Col-I-positive osteocytes in cleft patients might indicate increased bone remodeling and osteocyte activity due to the presence of a cleft. Correlations between factors indicate notable differences in molecular interactions within each group.

PROTECTIVE EFFECTS OF ANTIOXIDANTS AGAINST BURN-RELATED INJURIES

Thermal burn injuries are still a serious public health concern. Severe burns cause both local skin and distant-organ injuries. Many pathological mechanisms are involved in burn-induced injuries. Overproduction of reactive oxygen species (ROS) and oxidative stress play key roles in the pathogenesis of the systemic response and serious complications after burns. Antioxidants are intensively studied, and their beneficial effects are documented. Regardless of that, they still attract the researchers' interest in uncovering new evidence about their favorable impact on burn injuries. This review aims to describe recent evidence related to the mechanisms of tissue protection after administering some antioxidants with biogenic origins in burns.

The Metformin Immunoregulatory Actions in Tumor Suppression and Normal Tissues Protection.

The immune system is the key player in a wide range of responses in normal tissues and tumors to anticancer therapy. Inflammatory and fibrotic responses in normal tissues are the main limitations of chemotherapy, radiotherapy, and also some newer anticancer drugs such as immune checkpoint inhibitors (ICIs). Immune system responses within solid tumors including anti-tumor and tumor-promoting responses can suppress or help tumor growth. Thus, modulation of immune cells and their secretions such as cytokines, growth factors and epigenetic modulators, pro-apoptosis molecules, and some other molecules can be suggested to alleviate side effects in normal tissues and drug-resistance mechanisms in the tumor. Metformin as an anti-diabetes drug has shown intriguing properties such as anti-inflammation, anti-fibrosis, and anticancer effects. Some investigations have uncovered that metformin can ameliorate radiation/chemotherapy toxicity in normal cells and tissues through the modulation of several targets in cells and tissues. These effects of metformin may ameliorate severe inflammatory responses and fibrosis after exposure to ionizing radiation or following treatment with highly toxic chemotherapy drugs. Metformin can suppress the activity of immunosuppressive cells in the tumor through the phosphorylation of AMP-activated protein kinase (AMPK). In addition, metformin may stimulate antigen presentation and maturation of anticancer immune cells, which lead to the induction of anticancer immunity in the tumor. This review aims to explain the detailed mechanisms of normal tissue sparing and tumor suppression during cancer therapy using adjuvant metformin with an emphasis on immune system responses.

Characterization of a Novel Macrocyclic Molecular Glue That Selectively Inhibits the Nucleoside Transporter ENT1 and Demonstrates Tissue Protection in Ischemic-Reperfusion AKI In Vivo

Characterization of a Novel Macrocyclic Molecular Glue That Selectively Inhibits the Nucleoside Transporter ENT1 and Demonstrates Tissue Protection in Ischemic-Reperfusion AKI In Vivo

The Potential and Challenges of Proton FLASH in Head and Neck Cancer Reirradiation.

Ultrahigh-dose-rate therapy, also known as FLASH radiotherapy (RT), is an emerging technique that is garnering significant interest in cancer treatment due to its potential to revolutionize therapy. This method can achieve comparable tumor control to conventional-dose-rate RT while offering the enhanced protection of normal tissue through the FLASH-sparing effect. This innovative technique has demonstrated promising results in preclinical studies involving animals and cell lines. Particularly noteworthy is its potential application in treating head and neck (HN) cancers, especially in patients with challenging recurrent tumors and reirradiation cases, where the toxicity rates with conventional radiotherapy are high. Such applications aim to enhance tumor control while minimizing side effects and preserving patients' quality of life. In comparison to electron or photon FLASH modalities, proton therapy has demonstrated superior dosimetric and delivery characteristics and is a safe and effective FLASH treatment for human malignancies. Compared to the transmission proton FLASH, single-energy Bragg peak FLASH is a novel delivery method that allows highly conformal doses to targets and minimal radiation doses to crucial OARs. Proton Bragg peak FLASH for HN cancer has still not been well studied. This review highlights the significance of proton FLASH in enhancing cancer therapy by examining the advantages and challenges of using it for HN cancer reirradiation.

A microscopic oxygen transport model for ultra-high dose rate radiotherapy in vivo: The impact of physiological conditions on FLASH effect.

Ultra-high dose rate irradiation (≥40Gy/s, FLASH) has been shown to reduce normal tissue toxicity, while maintaining tumor control compared to conventional dose-rate radiotherapy. The radiolytic oxygen (O2) depletion (ROD) resulting from FLASH has been proposed to explain the normal tissue protection effect; however, in vivo experiments have not confirmed that FLASH induced global tissue hypoxia. Nonetheless, the experiments reported are based on volume-averaged measurement, which have inherent limitations in detecting microscopic phenomena, including the potential preservation of stem cells niches due to local FLASH-induced O2 depletion. Computational modeling offers a complementary approach to understand the ROD caused by FLASH at the microscopic level. We developed a comprehensive model to describe the spatial and temporal dynamics of O2 consumption and transport in response to irradiation in vivo. The change of oxygen enhancement ratio (OER) was used to quantify and investigate the FLASH effect as a function of physiological and radiation parameters at microscopic scale. We considered time-dependent O2 supply and consumption in a 3D cylindrical geometry, incorporating blood flow linking the O2 concentration ([O2]) in the capillary to that within the tissue through the Hill equation, radial and axial diffusion of O2, metabolic and zero-order radiolytic O2 consumption, and a pulsed radiation structure. Time-evolved distributions of [O2] were obtained by numerically solving perfusion-diffusion equations. The model enables the computation of dynamic O2 distribution and the relative change of OER (δROD) under various physiological and radiation conditions in vivo. Initial [O2] level and the subsequent changes during irradiation determined δROD distribution, which strongly depends on physiological parameters, i.e., intercapillary spacing, ultimately determining the tissue area with enhanced radioresistance. We observed that the δROD/FLASH effect is affected by and sensitive to the interplay effect among physiological and radiation parameters. It renders that the FLASH effect can be tissue environment dependent. The saturation of FLASH normal tissue protection upon dose and dose rate was shown. Beyond ∼60Gy/s, no significant decrease in radiosensitivity within tissue region was observed. In turn, for a given dose rate, the change of radiosensitivity became saturated after a certain dose level. Pulse structures with the same dose and instantaneous dose rate but with different delivery times were shown to have distinguishable δROD thus tissue sparing, suggesting the average dose rate could be a metric assessing the FLASH effect and demonstrating the capability of our model to support experimental findings. On a macroscopic scale, the modeling results align with the experimental findings in terms of dose and dose rate thresholds, and it also indicates that pulse structure can vary the FLASH effect. At the microscopic level, this model enables us to examine the spatially resolved FLASH effect based on physiological and irradiation parameters. Our model thus provides a complementary approach to experimental methods for understanding the underlying mechanism of FLASH radiotherapy. Our results show that physiological conditions can potentially determine the FLASH efficacy in tissue protection. The FLASH effect may be observed under optimal combination of physiological parameters, not limited to radiation conditions alone.

The alternative polyadenylation regulator CFIm25 promotes macrophage differentiation and activates the NF-κβ pathway.

Macrophages are required for our body's development and tissue repair and protect against microbial attacks. We previously reported a crucial role for regulation of mRNA 3'-end cleavage and polyadenylation (C/P) in monocyte to macrophage differentiation. The CFIm25 subunit of the C/P complex showed a striking increase upon differentiation of monocytes with Phorbol Myristate Acetate, suggesting that it promotes this process. To test this hypothesis, CFIm25 was overexpressed in two different monocytic cell lines, followed by differentiation. Both cell lines showed a significant increase in macrophage characteristics and an earlier slowing of the cell cycle. In contrast, depletion of CFIm25 hindered differentiation. Cell cycle slowing upon CFIm25 overexpression was consistent with a greater decrease in the proliferation markers PCNA and cyclin D1, coupled with increased 3'UTR lengthening of cyclin D1 mRNA. Since choice of other poly(A) sites could be affected by manipulating CFIm25, we identified additional genes with altered use of poly(A) sites during differentiation and examined how this changed upon CFIm25 overexpression. The mRNAs of positive regulators of NF-κB signaling, TAB2 and TBL1XR1, and NFKB1, which encodes the NF-κB p50 precursor, underwent 3'UTR shortening that was associated with increased protein expression compared to the control. Cells overexpressing CFIm25 also showed elevated levels of phosphorylated NF-κB-p65 and the NF-κB targets p21, Bcl-XL, ICAM1 and TNF-α at an earlier time and greater resistance to NF-κB chemical inhibition. In conclusion, our study supports a model in which CFIm25 accelerates the monocyte to macrophage transition by promoting alternative polyadenylation events which lead to activation of the NF-κB pathway.

Does the Maximum Initial Beam Energy for Proton Therapy Have to Be 230 MeV?

Proton therapy is increasingly widespread and requires an accelerator to provide the high energy protons. Most often, the accelerators used for proton therapy are cyclotrons and the maximum initial beam energy (MIBE) is about 230 MeV or more to be able to achieve a range of approximately 30 cm in water. We ask whether such a high energy is necessary for adequate dosimetry for pathologies to be treated with proton beams. Eight patients of different clinical sites (brain, prostate, and head and neck cancers) were selected to conduct this study. We analyzed the tumor dose coverage and homogeneity, as well as healthy tissue protection for MIBE values of 120, 160, 180, 200 and 230 MeV. For each patient, a proton plan was developed using the particular MIBE and then using multifield optimization (MFO). In this way, 34 plans in total were generated to fulfill the unique clinical goals. This study found that MIBE of 120 MeV for brain tumors; 160 MeV for head and neck cancer; and remarkably, for prostate cancer, only 160 MeV for one patient case and 180 MeV for the remainder satisfied the clinical goals (words: 187 < approx. 200 words or less)

The role of gut microbiota metabolites in the regeneration and protection of nervous tissue: a narrative review

The gut microbiota modulates various physiological functions in the human body, including digestion, immune regulation, gut barrier maintenance, and even nervous system activity. The bidirectional communication between gut microbes and the brain, known as the microbiota–gut–brain axis, is crucial for balanced metabolism. Recent studies have indicated that gut microbiota metabolites, such as short-chain fatty acids, indole derivatives, neurotransmitters, and other bioactive compounds, can positively impact neurogenesis, myelination, and axonal regeneration, suggesting their potential in therapeutic strategies for neuroprotection and neuroregeneration. Despite the growing number of studies on gut microbiota metabolites, understanding their role in neuroprotective mechanisms remains limited. This article reviews the classification, production, functions and therapeutic potential of the most well-known gut microbiota metabolites, as well as their impact on neurogenesis, synaptogenesis, energy metabolism, immune modulation, and blood–brain barrier integrity, which will provide a foundation for the study of gut microbiota metabolites in the field of biomedical engineering.

Effect of Vernonia Cinerea Water Extract on the Protection of Liver Tissue in Chronic Nicotine-Treated Rats

Nicotine, a highly toxic alkaloid found in tobacco, is known for its addictive properties and systemic side effects, including carcinogenic potential and multi-organ damage. Recent evidence indicates that nicotine can significantly impair liver function and regeneration by promoting fibrogenesis and oxidative stress. This study aimed to investigate the protective effects of Vernonia cinerea (VC) against nicotine-induced liver damage in Wistar rats, focusing on inflammation and pro-fibrosis markers. Thirty male Wistar rats were divided into three groups: a control group, a nicotine group (1 mg/kg/day), and a nicotine plus VC group (1 mg/kg/day nicotine and 100 mg/kg/day VC). Liver tissues were examined using Hematoxylin and Eosin staining, and Masson's trichrome staining to evaluate histological changes. Kupffer cell counts were determined using a Panoramic digital slide scanner. Statistical analyses were conducted to compare the groups. Nicotine exposure led to significant liver damage, characterized by increased inflammation, collagen deposition, and disruption of liver architecture. VC supplementation ameliorated these effects, reducing inflammation and fibrosis markers. Kupffer cell counts were lower in the nicotine plus VC group compared to the nicotine group alone. Conclusion: VC demonstrates a protective role in mitigating nicotine-induced liver damage, highlighting its potential as a therapeutic agent for preventing liver fibrosis and maintaining liver health in nicotine-exposed individuals.