Tissue Concentrations Research Articles

Jianpi-Huatan-Huoxue-Anshen formula ameliorates gastrointestinal inflammation and microecological imbalance in chemotherapy-treated mice transplanted with H22 hepatocellular carcinoma

BACKGROUND Jianpi-Huatan-Huoxue-Anshen formula [Tzu-Chi cancer-antagonizing & life-protecting II decoction (TCCL)] is a Chinese medical formula that has been clinically shown to reduce the gastrointestinal side effects of chemotherapy in cancer patients and improve their quality of life. However, its effect and mechanism on the intestinal microecology after chemotherapy are not yet clear. AIM To discover the potential mechanisms of TCCL on gastrointestinal inflammation and microecological imbalance in chemotherapy-treated mice transplanted with hepatocellular carcinoma (HCC). METHODS Ninety-six mice were inoculated subcutaneously with HCC cells. One week later, the mice received a large dose of 5-fluorouracil by intraperitoneal injection to establish a HCC chemotherapy model. Thirty-six mice were randomly selected before administration, and feces, ileal tissue, and ileal contents were collected from each mouse. The remaining mice were randomized into normal saline, continuous chemotherapy, Yangzheng Xiaoji capsules-treated, and three TCCL-treated groups. After treatment, feces, tumors, liver, spleen, thymus, stomach, jejunum, ileum, and colon tissues, and ileal contents were collected. Morphological changes, serum levels of IL-1β, IL-6, IL-8, IL-10, IL-22, TNF-α, and TGF-β, intestinal SIgA, and protein and mRNA expression of ZO-1, NF-κB, Occludin, MUC-2, Claudin-1, and IκB-α in colon tissues were documented. The effect of TCCL on the abundance and diversity of intestinal flora was analyzed using 16S rDNA sequencing. RESULTS TCCL treatment improved thymus and spleen weight, thymus and spleen indexes, and body weight, decreased tumor volumes and tumor tissue cell density, and alleviated injury to gastric, ileal, and colonic mucosal tissues. Among proteins and genes associated with inflammation, IL-10, TGF-β, SIgA, ZO-1, MUC-2, and Occludin were upregulated, whereas NF-κB, IL-1β, IL-6, TNF-α, IL-22, IL-8, and IκB-α were downregulated. Additionally, TCCL increased the proportions of fecal Actinobacteria , AF12 , Adlercreutzia , Clostridium , Coriobacteriaceae , and Paraprevotella in the intermediate stage of treatment, decreased the proportions of Mucipirillum , Odoribacter , RF32 , YS2 , and Rikenellaceae but increased the proportions of p_Deferribacteres and Lactobacillus at the end of treatment. Studies on ileal mucosal microbiota showed similar findings. Moreover, TCCL improved community richness, evenness, and the diversity of fecal and ileal mucosal flora. CONCLUSION TCCL relieves pathological changes in tumor tissue and chemotherapy-induced gastrointestinal injury, potentially by reducing the release of pro-inflammatory factors to repair the gastrointestinal mucosa, enhancing intestinal barrier function, and maintaining gastrointestinal microecological balance. Hence, TCCL is a very effective adjuvant to chemotherapy.

The Assessment of Anthropometric Measures and Changes in Selected Biochemical Parameters in Obese Children in Relation to Blood Lead Level

Background: Our paper draws attention to the impact of lead (Pb) on the specificity of obesity development in children exposed to environmental pollution. An advantage of this paper is the homogeneous study group comprising children of identical age from a single geographic region. Moreover, while the influence of environmental toxins on adults has been extensively explored, this study delves into pediatric populations, which have yet to receive comprehensive scrutiny within the scientific literature. Methods: Initially, a group of 136 obese children (the research program lasted three consecutive years: 2016, 2017, and 2018) living in the north-western region of Poland, from whom biochemical tests and auxological data were obtained, were enrolled for analysis. Blood lead levels (BLLs) were determined in 115 children. The age of the children ranged from 7.1 to 10.4 years. The body mass index (BMI) of children averaged 21.5 ± 2.2. Results: The results showed that a large proportion of the participants had BLLs above the threshold for Pb. BLLs ≤ 5 µg/dL (considered safe for children and pregnant women) were found in over 70% of the participants, with BLLs in the range of 5.01–10.00 µg/dL in over 26% of the children, and concentrations > 10 µg/dL (considered toxic threshold for adults) in nearly 2% of the children. The results of our research revealed a positive association between BLLs and average systolic and diastolic blood pressure in the studied children. Moreover, we found a negative correlation between BLLs and absolute fat tissue content and triglyceride concentration. Among the included biochemical factors, only insulin demonstrated a statistically significant relationship with fat mass. This result suggests that early carbohydrate metabolism disorders in overweight children involve decreased peripheral tissue insulin sensitivity. Conclusions: Lead exposure may significantly contribute to the development of hypertension, insulin resistance, and glucose metabolism disorders in overweight and obese children. It is essential to implement multidirectional actions to increase awareness of the harmful effects of xenobiotic exposure, including lead, in order to prevent early-life exposure.

Pharmacokinetics of intramuscular L-carvone in sheep.

To measure and model concentrations of the analgesic L-carvone, a natural component of spearmint, over time when administered IM to sheep and to characterize L-carvone's effects on CBCs and clinical biochemistry panels. L-carvone formulated as a 50% solution (v/v) in ethanol and propylene glycol was administered at 71.6 mg/kg IM, split between each semitendinosus muscle in 6 sheep. Venous blood was sampled over 24 hours, and plasma was separated by centrifugation. Additional blood was collected for CBC and serum biochemical analysis, and tissues were sampled after euthanasia. L-carvone concentrations in plasma and tissue homogenates were measured using HPLC-MS-MS. Plasma pharmacokinetic data were described using a nonlinear mixed effects model. Complete blood count and biochemistry data were compared to baseline values using repeated-measures ANOVA and Holm-Šidák tests (P < .05). Maximum plasma concentrations ranged from 0.28 to 1.93 µg/mL and occurred within 9 to 15 minutes after injection. Pharmacokinetics were best described using 2 compartments. Elimination half-life was 33.7 minutes and 390.2 minutes in the central and peripheral compartments, respectively. Mild increases in neutrophil count and significant increases in creatinine kinase and aspartate aminotransferase were associated with injection site myonecrosis. No physical examination, behavioral, or other clinically significant laboratory changes were noted. Intramuscular L-carvone exhibits rapid time to peak concentration, relatively slow plasma elimination, and low tissue concentrations after 24 hours. L-carvone exhibits a favorable pharmacokinetic profile for an analgesic drug. A new L-carvone formulation or administration route is needed to reduce inflammation and necrosis at the injection site.

Target-site cefiderocol pharmacokinetics in soft tissues of healthy volunteers.

Cefiderocol may potentially be used to treat skin and soft tissue infections (SSTIs). However, the pharmacokinetics of cefiderocol in human soft tissues have not yet been determined. The objective of the present PK study was to investigate whether target-site concentrations of cefiderocol are sufficiently high for the treatment of SSTIs. In this pharmacokinetic study, a single intravenous dose of 2 g cefiderocol was administered to eight healthy male volunteers. Drug concentrations were determined in plasma, muscle and subcutis over 8 h. Free plasma concentrations were calculated using the plasma protein binding determined with ultrafiltration. Free tissue concentrations were obtained using microdialysis. Penetration ratios were calculated as AUC0-8h_free_tissue/AUC0-8h_free_plasma. A population pharmacokinetic model was developed, and the probability of target attainment (PTA) was determined using Monte Carlo simulations. Cefiderocol showed good tissue penetration, with mean penetration ratios ± standard deviation of 0.99 ± 0.33 and 0.92 ± 0.30 for subcutis and muscle, respectively. Cefiderocol pharmacokinetics in plasma were best described with a two-compartment model, and tissue concentrations were described by scaling the tissue concentrations to concentrations in the peripheral compartment of the plasma model. For a thrice-daily regimen with 2 g doses intravenously infused over 3 h, PTA was ≥90% for MIC values up to 4 mg/L, both based on free plasma and soft tissue pharmacokinetics. This study indicates that a dose of 2 g cefiderocol achieves concentrations in plasma considered sufficient for treating relevant bacterial species. Assuming a comparable PK/PD target for soft tissues, sufficiently high concentrations would also be achieved in soft tissues.

Comparative Evaluation of Aminoguanidine, Semicarbazide and Thiosemicarbazide Treatment for Methylglyoxal-Induced Neurological Toxicity in Experimental Models

Background: Advanced glycation end products (AGEs) are complex compounds that play a critical role in neurological disorders, including the pathogenesis of Alzheimer's disease. Methylglyoxal (MG) is recognized as the primary precursor of AGEs. Methylglyoxal is produced endogenously and also introduced through dietary exposures. Objectives: This study aimed to investigate and compare the effects of aminoguanidine (AG), semicarbazide (SC), and thiosemicarbazide (TSC) on MG-induced neurological toxicity in rats. Methods: Male Wistar rats were exposed orally to MG, MG + AG, MG + SC, and MG + TSC for 70 days. Neurobehavioral, biochemical, and histopathological changes were evaluated. Results: The findings indicated that oral administration of MG for 70 days resulted in memory impairment and increased anxiety in neurobehavioral tests. Additionally, MG elevated protein carbonylation in brain tissues. Semicarbazide was found to prevent MG-induced memory problems, while both SC and AG reduced carbonyl content in brain tissues. Advanced glycation and TSC were effective in alleviating anxiety induced by MG exposure. Histopathological analysis revealed that MG caused cell damage and neuronal necrosis in the hippocampus, particularly in the cornu ammonis 1 (CA1) and dentate gyrus (DG) regions. However, AG, SC, and TSC improved neuronal survival in these areas. Conclusions: The data suggest that SC, AG, and TSC may offer neuroprotective effects against MG-induced neurobehavioral toxicity. Further studies are required to explore the mechanisms of action of these compounds.

A rare occurrence of Vancomycin-induced gastrointestinal hemorrhage without thrombocytopenia: a case report and literature review

BackgroundVancomycin-induced bleeding has been reported, attributed to the mechanism of immune thrombocytopenia. A rare case of vancomycin-induced gastrointestinal hemorrhage in a young patient with no underlying disease, receiving intravenous vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) infection, is presented. This occurrence occurred without thrombocytopenia. Relevant cases reported in the literature were also reviewed.Case presentationA 34-year-old male patient presented with maxillofacial multiple spaces infection accompanying left temporal abscess, bilateral lung abscesses. Culture results from both blood and secretion indicated that the infection was caused by MRSA. The patient received standard-dose vancomycin (1 g q12h intravenously guttae) for treatment. On the 5th day of therapy, he presented with bright red blood in his stool; however, vancomycin treatment was continued. By the 9th day, a decrease in hemoglobin level to 76 g/L and a platelet (PLT) count of 424 × 109/L raised concerns about gastrointestinal hemorrhage. The hemoglobin level decreased to 62 g/L on day 12. Due to the high tissue concentration of linezolid, administration of linezolid at a dose of 600 mg q12h intravenously guttae commenced on the 13th day as an alternative to vancomycin(D13-D17). Subsequently, on the 17th day, there was an improvement in hemoglobin level to 78 g/L. However, despite treatment with linezolid, the patient’s fever showed no significant improvement, prompting a switch back to vancomycin at a dosage of 1 g q12h intravenously guttae(D18-D22). On the 21st day, there was a recurrence of gastrointestinal hemorrhage, accompanied by a hemoglobin level of 42 g/L and a PLT count of 224 × 109/L. Gastroscopy revealed the presence of a gastroduodenal ulcer. The patient had no prior history of hemorrhoids, gastrointestinal ulcers, liver cirrhosis, or purpura. Prior to admission, he had not been administered non-steroidal anti-inflammatory drugs (NSAIDs) or steroids. During hospitalization, the only medications given were vancomycin, ambroxol and lidocaine. Additional tests ruled out immunological disorders as the cause of gastrointestinal ulcers, and a positive vancomycin rechallenge test indicated an association between vancomycin and bleeding. After discontinuation of vancomycin, no further bleeding occurred. This case highlights a rare occurrence of vancomycin-induced bleeding without thrombocytopenia, classified as “Certain” according to the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) scale for standardized case causality assessment.ConclusionThis case represents the first documented instance of vancomycin-induced bleeding without thrombocytopenia, as confirmed by a positive rechallenge test. This discovery will aid in the early detection of this rare adverse reaction in future cases.

Heavy metal accumulation and interaction dynamics in Brachidontes pharaonis: a bioindicator study in the Red Sea.

This work evaluates utilizing the native mussel Brachidontes pharaonis as a bioindicator and sentinel organism for monitoring heavy metals Cu, Zn, and Cd along the Red Sea coast of Egypt. Samples were collected from four coastal locations, and the concentrations of heavy metals in the mussels' tissues, shells, seawater, and sediments were analyzed. Subsequently, bioassay experiments were conducted by exposing the organisms to single, binary, and tertiary metal mixtures, and the accumulation of heavy metals was determined to elucidate the dynamics of metal-metal interactions. Field samples revealed significant variations in heavy metal concentrations in the mussels' soft tissues across different locations, with Zn ranging from 58.1 to 121.0µg/g dw (dry weight), Cu ranging between 18.3 and 36.7µg/g dw, and Cd ranging from 0.3 to 1.04µg/g dw. Conversely, the shells exhibited minimal spatial variations, with much lower contents of Cu (ranging from 1.9 to 2.8µg/g dw) and Zn (ranging from 1.8 to 1.9µg/g dw). However, the shells accumulated Cd at higher levels (ranging from 1.4 to 2.1µg/g dw) compared to the soft tissues. Following a 96-h bioassay experiment, the soft tissues displayed a linear accumulation of metals with increasing exposure dose, with Cd showing the highest accumulation rate (approximately threefold) followed by Zn (twofold) and Cu (1.7-fold). In binary and tertiary exposures, the metals exhibited a general antagonistic interaction, affecting each other's accumulation. On the other hand, the accumulation of heavy metals in the shells after the 96-h bioassay exposure did not follow a consistent linear pattern, suggesting that accumulation during this short experimental period occurs primarily through adsorption rather than the biological pathway.

Изменение состава пектиновых веществ при замораживании и хранении растительной продукции

To keep up with the growing demand, producers of frozen plant products have to develop new freezing technologies that would preserve the sensory and biological properties of fruits and vegetables. Pectins are important structural and moisturebinding components of plant cells that improve their stability at high and low temperatures. The research objective was to study the effect of blanching and various freezing methods on the composition of pectin substances during long-term storage of fruits and vegetables. The research featured scorzonera, salsify, kohlrabi, apples, and plums. The freezing modes included two temperature modes (–24 and –35°C) and three freezing methods, i.e., blanching, air-freezing represented by natural air-freezing, artificial convection, and fluidization, and immersion in a mix of water, ethyl alcohol, sucrose, and sodium chloride. The frozen samples were stored in sealed bags at –18°C for 7–12 months. The water-soluble pectin, intermediate fraction, and protopectin obtained by extraction were determined using the colorimetric carbazole method. The qu alitative analysis relied on infrared spectroscopy. Blanching reduced the pectin content by 2–10% in vegetables and by 18–21% in apples. Fluidization and immersion freezing had the least damaging effect on pectins. Air-freezing with natural convection caused the greatest damage to protopectin. During storage, the maximal loss of pectins (66%) occurred in the salsify sample subjected to natural air convection at –24°C. The least damage (9%) was detected in the kohlrabi sample frozen at –24°C in ice environment. A higher moisture content in the native state correlated with minimal losses of pectins by the end of refrigerated storage. The research also included identification of absorption bands for pectic substances in fro zen scorzonera and salsify. In this study, pectin content depended on moisture content in tissues, blanching process, and freezing method. All frozen samples demonstrated losses of protopectin and an increase in the intermediate fraction. An intense freezing process had a positive effect on the pectin content during long-term storage. However, after six months of storage, the samples demonstrated significant fractional changes and pectin losses.

TRLR-02 TARGETING GLIOBLASTOMA MICROENVIRONMENT TO UNLEASH IMMUNE FORCES

Abstract Brain cancer has persistently eluded therapeutic advances over the past three decades. Here, we aim to raise awareness of the potential differences between the cancer microenvironment within the brain vs. peripheral organ cancers, which may contribute to the therapeutic setbacks observed in brain cancer treatment. While the blood-brain barrier has long been implicated in drug impermeability, its impact on brain cancer may extend far beyond mere drug exclusion. Studies have shown that soluble factors such as VEGF are more concentrated in brain cancer than in any other malignancies. Moreover, recent studies revealed that VEGF, TWEAK, and others can also press on the immune brakes. Therefore, we hypothesize that normalizing the tumor microenvironment could pave the way for effective therapeutic interventions, especially immunotherapy. Our in vitro studies confirmed abundant production of VEGF by glioblastoma 1 (GBM1) cell line, which is exceptionally well scavenged by the anti-VEGF antibody – bevacizumab. Moreover, in vitro, co-culture of T cells and GBM1 cell line without vascular component demonstrated no therapeutic activity of bevacizumab or typical immunotherapeutic drug – anti-PD1 checkpoint inhibitor – nivolumab given in monotherapies. However, a combination of both antibodies revealed therapeutic efficacy in a dose-dependent manner in our experimental system. Currently, intravenous delivery of bevacizumab is the standard of care in patients with glioblastoma recurrence, but its effectiveness has not been proven in this group of patients. Intravenous nivolumab failed in clinical trials. Based on our observations and the negligible penetration of antibodies to the brain, we hypothesize that transiently opening the blood-brain barrier may be necessary to enhance antibody delivery to the tumor microenvironment, alleviate immune suppression, and unlock immune cell activity. Therefore, achieving high antibody concentrations in brain cancer tissue, coupled with a combination of classic checkpoint inhibitors with scavengers of soluble immunosuppressive molecules, could herald a new era of brain cancer therapy.

Changes of collagen content in lung tissues of plateau yak and its mechanism of adaptation to hypoxia.

Collagen is crucial for tissue structure, functional maintenance, and cellular processes such as proliferation and differentiation. However, the specific changes in collagen expression and its associated genes in the lung tissues of yaks at high altitudes and their relationship with environmental adaptation remain poorly understood. Studying differences in the content of collagen fibers and gene expression between yaks at high (4,500 m) and low (2,600 m) altitudes, as well as between cattle at low altitudes (2,600 m). Using Masson staining, we found that the collagen fiber content in the lung tissues of yaks at low altitude was significantly higher compared to yaks at high altitude and cattle at the same altitude (P < 0.05). It was revealed through transcriptomic analyses that genes differentially expressed between high and low altitude yaks, as well as between low altitude yaks and cattle, were notably enriched in pathways related to cell adhesion, collagen synthesis, focal adhesion, and ECM-receptor interactions. Specifically, genes involved in mesenchymal collagen synthesis (e.g., COL1A1, COL1A2, COL3A1), basement membrane collagen synthesis (e.g., COL4A1, COL4A2, COL4A4, COL4A6), and peripheral collagen synthesis (e.g., COL5A1, COL6A1, COL6A2, COL6A3) were significantly upregulated in the lung tissues of yaks at low altitude compared to their high altitude counterparts and cattle (P < 0.05). In conclusion, yaks at lower altitudes exhibit increased collagen synthesis by upregulating collagen gene expression, which contributes to maintaining alveolar stability and septal flexibility. Conversely, the expression of collagen genes in yak lung tissues was down-regulated with the increase in altitude, and it was speculated that the decrease in collagen may be used to constrain the function of elastic fibers that are more abundant at high altitude, so as to enable them to adapt to the harsh environment with hypoxia and high altitude. This adaptation mechanism highlights the role of collagen in environmental acclimatization and contributes to our understanding of how altitude and species influence collagen-related physiological processes in yaks.

Bladder cancer associated with elevated heavy metals: Investigation of probable carcinogenic pathways through mitochondrial dysfunction, oxidative stress and mitogen-activated protein kinase

ObjectiveCarcinogenic mechanisms of heavy metals/ trace elements (HMTE) in bladder cancer (BC) are exactly unknown. Mitochondrial dysfunction (MD), oxidative stress (OS), and mitogen-activated protein kinases (MAPK) are probable carcinogenic mechanisms. The purpose is to investigate probable carcinogenic pathways of HMTE in BC using six MD genes, seven OS markers, and p38-MAPK. MethodsStudy included 125 BC/radical cystectomy (RC) patients between October 2020 and October 2022, and 72 controls. Exclusion criteria included previous neoplasm, chemo- or radiotherapy. Two samples (cancer/noncancer) were taken from RC specimens. Tissues/plasma/urine cadmium (Cd), lead (Pb), cobalt (Co), nickel (Ni), strontium (Sr), aluminium (Al), zinc (Zn), boron (B) were measured by ICP-OES. Tissue MD genes (mt-CO3, mt-CYB, mt-ATP 6, mt-ATP8, mt-CO1, mt-ND1), and serum OS markers (8-OHdG, MDA, 3-NT, AGEs, AOPP, ROS, SOD2), p38-MAPK were assessed by RT-PCR, and ELISA, respectively. ResultsBC and adjacent tissue showed higher (Al, Co, Pb, Ni, Zn, Cd,Sr), lower B concentrations, compared to controls. High tissue concentrations (Cd, Co, Pb, Ni, Sr) were associated with higher MD genes, OS, MAPK and lower SOD2 levels. The same differences were greater in 41 patients with concomitant elevation of two or more HMTE. Noninclusion of BC-related oncogenes (e.g. RAS) is a limitation. ConclusionsEvidence suggests that high BC tissue (Cd, Co, Pb, Ni, Si) concentrations are associated with over-expressed MD genes, OS, p38-MAPK and low SOD2. These findings provide important understanding keys of probable carcinogenic pathways in BC associated with HMTE. So, efforts should be performed to minimize and counteract exposure to toxic HMTE.

Ultrashort Oncologic Whole-Body [18F]FDG Patlak Imaging Using LAFOV PET.

Methods to shorten [18F]FDG Patlak PET imaging procedures ranging from 65-90 to 20-30 min after injection, using a population-averaged input function (PIF) scaled to patient-specific image-derived input function (IDIF) values, were recently evaluated. The aim of the present study was to explore the feasibility of ultrashort 10-min [18F]FDG Patlak imaging at 55-65 min after injection using a PIF combined with direct Patlak reconstructions to provide reliable quantitative accuracy of lung tumor uptake, compared with a full-duration 65-min acquisition using an IDIF. Methods: Patients underwent a 65-min dynamic PET acquisition on a long-axial-field-of-view (LAFOV) Biograph Vision Quadra PET/CT scanner. Subsequently, direct Patlak reconstructions and image-based (with reconstructed dynamic images) Patlak analyses were performed using both the IDIF (time to relative kinetic equilibrium between blood and tissue concentration (t*) = 30 min) and a scaled PIF at 30-60 min after injection. Next, direct Patlak reconstructions were performed on the system console using only the last 10 min of the acquisition, that is, from 55 to 65 min after injection, and a scaled PIF using maximum crystal ring difference settings of both 85 and 322. Tumor lesion and healthy-tissue uptake was quantified and compared between the differently obtained parametric images to assess quantitative accuracy. Results: Good agreement was obtained between direct- and image-based Patlak analyses using the IDIF (t* = 30 min) and scaled PIF at 30-60 min after injection, performed using the different approaches, with no more than 8.8% deviation in tumor influx rate value (Ki ) (mean difference ranging from -0.0022 to 0.0018 mL/[min × g]). When direct Patlak reconstruction was performed on the system console, excellent agreement was found between the use of a scaled PIF at 30-60 min after injection versus 55-65 min after injection, with 2.4% deviation in tumor Ki (median difference, -0.0018 mL/[min × g]; range, -0.0047 to 0.0036 mL/[min × g]). For different maximum crystal ring difference settings using the scan time interval of 55-65 min after injection, only a 0.5% difference (median difference, 0.0000 mL/[min × g]; range, -0.0004 to 0.0013 mL/[min × g]) in tumor Ki was found. Conclusion: Ultrashort whole-body [18F]FDG Patlak imaging is feasible on an LAFOV Biograph Vision Quadra PET/CT system without loss of quantitative accuracy to assess lung tumor uptake compared with a full-duration 65-min acquisition. The ultrashort 10-min direct Patlak reconstruction with PIF allows for its implementation in clinical practice.

Nicorandil antiallodynic activity in a model of neuropathic pain is associated with the activation of ATP-dependent potassium channels and opioidergic pathways, and reduced production of cytokines and neutrophils recruitment in paw, sciatic nerve, and dorsal root ganglia.

Recently, we demonstrated that nicorandil inhibits mechanical allodynia induced by paclitaxel. In the present study, we evaluated the effect induced by nicorandil in a model of neuropathic pain induced by chronic constriction injury (CCI) in mice. We also investigated putative mechanisms underlying such an effect. CCI was induced by three ligatures of the left sciatic nerve. Mechanical allodynia was evaluated by measuring the paw withdrawal threshold with an electronic von Frey apparatus. Concentrations of cytokines and myeloperoxidase activity were determined in the paw tissue, sciatic nerve, and dorsal root ganglia (DRG). Oral administration of two doses of nicorandil (150mg/kg po), but not equimolar doses of nicotinamide or nicotinic acid, attenuated mechanical allodynia induced by CCI. Nicorandil activity was reduced by previous administration of glibenclamide (40mg/kg) or naltrexone (5mg/kg or 10mg/kg). Two doses of nicorandil (150mg/kg, po) reduced tumor necrosis factor-α, interleukin-1β and interleukin-6, but not CXCL-1, concentrations in the paw tissue of CCI mice. Two doses of nicorandil (150mg/kg, po) reduced concentrations of all these mediators in the sciatic nerve and DRG. Two doses of nicorandil (150mg/kg, po) also reduced the myeloperoxidase activity in the paw tissue, sciatic nerve, and DRG. Nicorandil exhibits antiallodynic activity in a model of neuropathic pain induced by CCI. Inhibition of cytokines production and reduction of neutrophils recruitment in paw tissue, sciatic nerve, and DRG as well as activation of ATP-dependent potassium channels and opioidergic pathways, underlie nicorandil antiallodynic activity.

Placenta may exert fetal protection against maternal high salt diet intake via renin-angiotensin-aldosterone system

ObjectiveThis study investigated the effects of high compared to normal dietary salt intake on fetoplacental vascular function, activity of renin-angiotensin-aldosterone system (RAAS), placental pro- and anti-angiogenic factors and biomarkers of placental remodeling and oxidative stress during healthy uncomplicated pregnancy. Materials and MethodsBased on their 24-hour sodium excretion pregnant women (37–40 weeks’ gestation) were categorized into three groups: normal salt (NS, <5.75 g/day, N=12), high salt (HS, 5.75–10.25 g/day, N=36), and very high salt (VHS, >10.25 g/day, N=17). Pulsatility (PI) and resistive index of middle cerebral artery (MCA) and umbilical artery, plasma renin activity (PRA), serum aldosterone, soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) concentrations, as well as placental vascular endothelial growth factor C (VEGF-C), oxidative/antioxidative stress markers (TBARS/FRAP) and matrix metalloproteinase 9 (MMP-9) concentration were measured. ResultsPI MCA was significantly decreased in HS/VHS groups compared to NS group. HS/VHS intake did not suppress PRA and aldosterone concentration. Serum PlGF concentration was significantly increased while sFlt-1 concentration and sFlt-1/PlGF ratio were significantly decreased in VHS group compared to NS group. MMP-9, VEGF-C concentration, TBARS and FRAP in placental tissue were similar between study groups. ConclusionsHS/VHS diet does not suppress RAAS during pregnancy; however, it is associated with decreased PI MCA, a significantly decreased sFlt-1/PlGF ratio and unchanged biomarkers of placental remodeling or oxidative stress in healthy pregnant women, suggesting the presence of a possible protective or compensatory mechanism aimed at preserving placental function and pregnancy outcome itself in terms of maternal HS intake.

Characterization and functional analysis of novel α-bisabolol synthase (MrBAS) promoter from Matricaria recutita

Matricaria recutita is widely used in industry and as a medicinal plant because it contains α-bisabolol. Alpha-bisabolol has broad application prospects due to its healthy function and medical value. The activity of the α-bisabolol synthase (MrBAS) promoter determines the expression of the MrBAS gene, which in turn influences the synthesis and accumulation of α-bisabolol. However, the activity and tissue specificity of the MrBAS promoter have not yet been characterized. In this study, a 1327-base pair (bp) region upstream of the MrBAS of the translation start site was cloned from the genome of M. recutita. MrBAS promoter sequence analysis revealed multiple light-responsive elements, and further dark treatment reduced α-bisabolol content in flowers. The α-bisabolol content and MrBAS expression levels in various flower tissues showed a strong correlation. The 5′ deletion analysis revealed that the MrBAS promoter sequence could drive β-glucuronidase (GUS) gene expression in Nicotiana benthamiana leaves, with activity decreasing as the fragment shortened. Transgenic experiments demonstrated that the MrBAS promoter could specifically drive GUS gene expression in Arabidopsis anthers, pollen tubes, and petals. Thus, the MrBAS promoter has the potential to be a tool for directing transgene expression specifically in flower organs, offering new research avenues for cultivar development.

Effect of a multidisciplinary lifestyle intervention on body composition in people with osteoarthritis: Secondary analysis of the “Plants for Joints” randomized controlled trial

ObjectiveThe Plants for Joints (PFJ) intervention significantly improved pain, stiffness, and physical function, and metabolic outcomes, in people with metabolic syndrome-associated osteoarthritis (MSOA). This secondary analysis investigated its effects on body composition. MethodIn the randomized PFJ study, people with MSOA followed a 16-week intervention based on a whole-food plant-based diet, physical activity, and stress management, or usual care. For this secondary analysis, fat mass, muscle mass, and bone mineral density were measured using dual-energy X-ray absorptiometry (DEXA) for all participants. Additionally, in a subgroup (n ​= ​32), hepatocellular lipid (HCL) content and composition of visceral adipose tissue (VAT) were measured using magnetic resonance spectroscopy (MRS). An intention-to-treat analysis with a linear-mixed model adjusted for baseline values was used to analyse between-group differences. ResultsOf 66 people randomized, 64 (97%) completed the study. The PFJ group experienced significant weight loss (−5.2 ​kg; 95% CI –6.9, −3.6) compared to controls, primarily from fat mass reduction (−3.9 ​kg; 95% CI –5.3 to −2.5). No significant differences were found in lean mass, muscle strength, or bone mineral density between groups. In the subgroup who underwent MRI scans, the PFJ group had a greater reduction in HCL (−6.5%; 95% CI –9.9, 3.0) compared to controls, with no observed differences in VAT composition. ConclusionThe PFJ multidisciplinary intervention positively impacted clinical and metabolic outcomes, and appears to significantly reduce body fat, including liver fat, while preserving muscle mass and strength.

Neoastilbin ameliorates sepsis-induced liver and kidney injury by blocking the TLR4/NF-κB pathway.

Sepsis frequently causes systemic inflammatory response syndrome and multiple organ failure in patients. Neoastilbin (NAS) is a flavonoid that plays vital functions in inflammation. This work aims to investigate the protective effects of NAS against sepsis-induced liver and kidney injury and elucidate its underlying mechanisms. The mouse model was established using cecal ligation puncture (CLP) induction. NAS was given to mice by gavage for 7 consecutive days before surgery. Liver and kidney function, oxidative stress, and inflammatory factors in serum or tissues were examined by ELISA or related kits. The expression of relevant proteins was assessed by Western blot. Hematoxylin and eosin and/or periodic acid-Schiff staining revealed that NAS ameliorated the pathological damage in liver and kidney tissues of CLP-induced mice. NAS improved liver and kidney functions, as evidenced by elevated levels of blood urea nitrogen, Creatinine, ALT, and AST in the serum of septic mice. TUNEL assay and the expression of Bcl-2 and Bax showed that NAS dramatically reduced apoptosis in liver and renal tissues. NAS treatment lowered the levels of myeloperoxidase and malondialdehyde, while elevated the superoxide dismutase content in liver and kidney tissues of CLP-induced mice. The levels of inflammatory cytokines (IL-6, TNF-α, and IL-1β) in the serum and both tissues of CLP-injured mice were markedly decreased by NAS. Mechanically, NAS downregulated TLR4 expression and inhibited NF-κB activation, and overexpression of TLR4 reversed the protective effects of NAS against liver and kidney injury. Collectively, NAS attenuated CLP-induced apoptosis, oxidative stress, inflammation, and dysfunction in the liver and kidney by restraining the TLR4/NF-κB pathway.

The Marine-Origin Exopolysaccharide-Producing Bacteria Micrococcus Antarcticus HZ Inhibits Pb Uptake in Pakchoi (Brassica chinensis L.) and Affects Rhizosphere Microbial Communities

Exopolysaccharides (EPSs) produced by microorganisms play an important role in biotolerance and reducing heavy metal (HM) contamination by limiting the migration of HMs into plants. However, research on the application of EPS-producing marine bacteria for soil heavy metal remediation remains limited, particularly regarding their mechanisms of HM immobilization in soil and impact on plant growth. In this study, the EPS-producing marine bacterium Micrococcus antarcticus HZ was investigated for its ability to immobilize Pb and produce EPSs in soil filtrate. The effects on the growth quality and biomass of pakchoi (Brassica chinensis L.), as well as bacterial communities in inter-root soil contaminated with Pb, were also investigated. The results indicated that HZ could reduce the Pb concentration in the soil filtrate, achieving a removal rate of 43.25–63.5%. The EPS content and pH levels increased in the presence of Pb. Pot experiments showed that adding HZ significantly increased the biomass of pakchoi (9.45–14.69%), vitamin C (Vc) (9.69–12.92%), and soluble protein content (22.58–49.7%). HZ reduced the Pb content in the roots (17.52–47.48%) and leaves (edible tissues) (43.82–52.83%) of pakchoi. HZ increased soil enzyme activities (alkaline phosphatase, dehydrogenase, and urease), and the contents of ammonium nitrogen and nitrate nitrogen. Additionally, HZ also increased the relative abundance of beneficial bacteria (e.g., Proteobacteria, Cyanobacteria, and Chlorobacteria) in the inter-root soil, which have prophylactic and heavy-metal fixation functions. In summary, HZ reduces effective Pb content in edible tissues, roots, and inter-root soil by regulating inter-root soil microbial community structure, increasing soil pH, nitrogen content, and soil enzyme activity, and altering dominant phylum abundance.

High-affinity potassium transporter TaHAK1 implicates in cesium tolerance and phytoremediation

Cesium (Cs) is a toxic alkaline metal affecting human health. Plant high-affinity K transporters (HAKs) involved in Cs uptake and transport have been identified in several plants. However, the molecular regulatory mechanisms of Cs uptake and transport, and homeostasis between Cs and K by HAKs remain unknown. In this study, TaHAK1 was overexpressed in rice (TaHAK1-OEs) to evaluate Cs absorption capacity and the Cs and K homeostasis mechanisms. Results showed that TaHAK1 promoted seedling growth by fixing Cs in the root cell wall and modifying Cs distribution. Transcriptome and bioinformatics analyses revealed that 37,828 differentially expressed genes (DEGs) were significantly induced in TaHAK1-OEs, of which the pathways involved in cell wall biosynthesis and ion absorption transport were notably affected including genes, XTHs, CSLEs, HAKs, and ABCs. Moreover, under Cs-contaminated soil, TaHAK1-OEs exhibited improved Cs tolerance by decreasing Cs accumulation and increasing K content in different tissues, particularly in the grains, indicating that TaHAK1 acts as a candidate gene for screening genetic modification of Cs phytoremediation and developing low-Cs-accumulation rice varieties. This study provides new insights into the uptake and translocation of Cs and the homeostasis of Cs and K in plants, and also supplies new strategy to improve phytoremediation efficiency.

A Bis-Boron Amino Acid for Positron Emission Tomography and Boron Neutron Capture Therapy.

Trifluoroborate boronophenylalanine (BBPA) is a boron amino acid analog of 4‑boronophenylalanine (BPA) but with a trifluoroborate group (-BF3-) instead of a carboxyl group (-COOH). Clinical studies have shown that 18F-labeled BBPA ([18F]BBPA) can produce high-contrast tumor images in positron emission tomography (PET). Beyond PET imaging, BBPA is a theranostic agent for boron neutron capture therapy (BNCT). Because BBPA possesses an identical chemical structure to BNCT and PET, it can potentially predict the boron concentration for BNCT using [18F]BBPA-PET. The synthesis of BBPA was achieved by selectively fluorinating the α-aminoborate compound, taking advantage of the varying rates of solvolysis of the B-F bond. The study showcased the high-contrast [18F]BBPA-PET imaging in various tumor models, highlighting its broad applicability for both [18F]BBPA-PET and BBPA-BNCT. [18F]BBPA-PET tumor uptake remains consistent across various doses, including those used in BNCT. This enables accurate estimation of the boron concentration in tumors using [18F]BBPA-PET. With its dual boron structure, BBPA increases boron concentration in tumor cells and tumor tissues compared to BPA. Thus, less boron carrier is needed. This study introduces a new theranostic boron carrier that enhances boron accumulation in tumors, predicts boron concentration, and enhances the accuracy and effectiveness of BNCT.