Native T1-mapping as a predictor of progressive renal function decline in chronic kidney disease patients.

BACKGROUND: To investigate the potential of Native T1-mapping in predicting the prognosis of patients with chronic kidney disease (CKD). METHODS: We enrolled 119 CKD patients as the study subjects and included 20 healthy volunteers as the control group, with follow-up extending until October 2022. Out of these patients, 63 underwent kidney biopsy measurements, and these patients were categorized into high (25-50%), low (< 25%), and no renal interstitial fibrosis (IF) (0%) groups. The study's endpoint event was the initiation of renal replacement therapy, kidney transplantation, or an increase of over 30% in serum creatinine levels. Cox regression analysis determined factors influencing unfavorable kidney outcomes. We employed Kaplan-Meier analysis to contrast kidney survival rates between the high and low T1 groups. Additionally, receiver-operating characteristic (ROC) curve analysis assessed the predictive accuracy of Native T1-mapping for kidney endpoint events. RESULTS: T1 values across varying fibrosis degree groups showed statistical significance (F = 4.772, P < 0.05). Multivariate Cox regression pinpointed 24-h urine protein, cystatin C(CysC), hemoglobin(Hb), and T1 as factors tied to the emergence of kidney endpoint events. Kaplan-Meier survival analysis revealed a markedly higher likelihood of kidney endpoint events in the high T1 group compared to the low T1 value group (P < 0.001). The ROC curves for variables (CysC, T1, Hb) tied to kidney endpoint events demonstrated area under the curves(AUCs) of 0.83 (95%CI: 0.75-0.91) for CysC, 0.77 (95%CI: 0.68-0.86) for T1, and 0.73 (95%CI: 0.63-0.83) for Hb. Combining these variables elevated the AUC to 0.88 (95%CI: 0.81-0.94). CONCLUSION: Native T1-mapping holds promise in facilitating more precise and earlier detection of CKD patients most at risk for end-stage renal disease.

Cycloartane-type triterpenoids and steroids from Trichilia connaroides and their multidrug resistance reversal activities.

Four undescribed cycloartane-type triterpenoids (1-4) and seven undescribed steroids (6-12), along with five known analogues (5 and 13-16), were isolated from the leaves of Trichilia connaroides. Their structures were identified based on the NMR data and HRESIMS, and the absolute configurations were determined through single-crystal X-ray diffraction analysis, Mosher's method, and ECD calculations. The multidrug resistance (MDR) reversal activities of all the isolates were assessed, and compounds 10 and 11 showed significant activities to reverse the MDR of MCF-7/DOX cells with IC50 values of 2.90 and 3.76 µM, respectively. These bioactive compounds may bring fresh insights into the research and development of MDR reversal agents.

Native T1 Mapping in Assessing Kidney Fibrosis for Patients With Chronic Glomerulonephritis.

Purpose: To assess the utility of non-contrast enhanced native T1 mapping of the renal cortex in assessing renal fibrosis for patients with chronic glomerulonephritis (CGN). Methods: A total of 119 patients with CGN and 19 healthy volunteers (HVs) were recruited for this study. Among these patients, 43 had undergone kidney biopsy measurements. Clinical information and biopsy pathological scores were collected. According to the results of the renal biopsy, the patients were classified into the high (25-50%), low (<25%) and no renal interstitial fibrosis (IF) (0%) groups. The correlations between the T1 value in the renal cortex and each of the clinical parameters were separately analyzed. The relationships between each fibrosis group and the T1 value were also evaluated and compared between groups. Binary logistic regression analysis was further used to determine the relationship between the T1 value and renal fibrosis. Receiver operating characteristic (ROC) curves were plotted to analyze the diagnostic value of the T1 value for renal fibrosis. Results: Compared with those of the HVs, the T1 values were significantly higher in patients at all stages of chronic kidney disease (CKD) (all p < 0.05). Significant T1 differences were also revealed between patients with different stages of CKD (p < 0.05). Additionally, the T1 value correlated well with CKD stage (p < 0.05), except between CKD 2 and 3. In addition, the T1 value was positively correlated with cystatin C, neutrophil gelatinase-associated lipocalin, and serum creatinine and negatively correlated with hemoglobin, kidney length, estimated glomerular filtration rate and hematocrit (all p < 0.05). Compared with those of the no IF group, the T1 values were increased in the low- and high-IF groups (both p < 0.05). Logistic regression analysis showed that an elevated T1 value was an independent risk factor for renal fibrosis. ROC analysis suggested that the optimal critical value of T1 for predicting renal fibrosis was 1,695 ms, with a specificity of 0.778 and a sensitivity of 0.625. Conclusion: Native T1 mapping demonstrated good diagnostic performance in evaluating renal function and was an effective noninvasive method for detecting renal fibrosis in CGN patients.

Structural elucidation and immunomodulatory evaluation of a polysaccharide from Stevia rebaudiana leaves.

Stevia rebaudiana, a sweetener with medicinal functions, has attracted extensive attention due to its application in food and pharmaceutical fields. However, a few studies were performed to explore polysaccharides in this plant. Herein, SRP70-1 was derived from S. rebaudiana. Structural analysis (monosaccharide composition analysis, high-performance liquid chromatography-multi-angle light scattering detection, gas chromatography-mass spectrometry, and nuclear magnetic resonance spectroscopy) revealed that SRP70-1 was composed of mannose, glucose, galactose, and arabinose at the molar ratio of 1.35:1.00:3.23:3.47, with an absolute molecular weight of 7698 Da. SRP70-1 was found to contain â†’ 5)-α-l-Araf-(1→, →2,3,5)-α-l-Araf-(1→, →4)-ß-l-Arap-(1→, →4)-ß-d-Galp-(1→, →6)-ß-d-Galp-(1→, →4)-ß-d-Manp-(1→, →6)-ß-d-Manp-(1→, and terminal α-l-Araf, ß-d-Galp, and ß-d-Glcp residues. Cell experiments showed that SRP70-1 could significantly promote phagocytosis and increase the release of nitric oxide and cytokines including IL-1ß, IL-6, and TNF-α. Further zebrafish experiments confirmed the immunological enhancement effects of SRP70-1. This study revealed that SRP70-1 may be useful for the development of functional foods.

A heteropolysaccharide purified from leaves of Ilex latifolia displaying immunomodulatory activity in vitro and in vivo.

A novel polysaccharide (ILP50-2) was extracted, isolated and purified from the leaves of Ilex latifolia Thunb. Its structure was characterized as a repeating unit consisting of α-L-Araf-(1→, →3)-α-L-Araf-(1→, →5)-α-L-Araf-(1→, →3,5)-α-L-Araf-(1→, →2)-α-L-Rhap-(1→, →2,4)-α-L-Rhap-(1→, ß-D-Galp-(1→, →4)-ß-D-Galp-(1→, →4)-ß-D-Glcp-(1→, →6)-α-D-Manp-(1→, and →3,6)-α-D-Galp-(1→. The absolute molecular weight of ILP50-2 was 1.49 × 105 g/mol, which adapted a compact coil conformation in 0.1 M NaCl solution with Rz of 25.4 nm. Furthermore, ILP50-2 exhibited immunoregulatory activity, mainly through enhancing the phagocytosis ability of macrophages and prompting the release of nitric oxide (NO) and cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß). Simultaneously, ILP50-2 was found to significantly increase the release of ROS and NO in zebrafish embryos, showing immunoregulatory effects in vivo.

Nitric oxide inhibitory iridoids as potential anti-inflammatory agents from Valeriana jatamansi.

Five new iridoids, jatadomins A-E (1-5), together with six known analogues (6-11) and one known sesquiterpenoid (12), were isolated from the roots of Valeriana jatamansi Jones. Their structures were determined by analysis of their NMR, HRESIMS, and electronic circular dichroism calculations (ECD) data. The biological evaluation revealed that compounds 1-6 had anti-inflammatory activities by inhibiting nitric oxide (NO) release in LPS-induced murine microglial BV-2 cells, with IC50 values of 24.4, 9.2, 21.2, 25.9, 30.6, and 0.4 µM, respectively. Further molecular docking studies revealed a potential mechanism for NO inhibition by the bioactive compounds.

Exosomal microRNAs-mediated intercellular communication and exosome-based cancer treatment.

Exosomes are extracellular vesicles with a diameter of about 30 to 100 nm, which play a crucial role in intercellular communication. Compared with normal cells, the release rate of tumor-derived exosomes (TDEs) significantly increased, and exosomal contents, especially microRNAs (miRNAs), greatly changed. TDEs contribute to the proliferation, metastasis and resistance of tumor cells, regulate immune response and tumor autophagy, and mediate tumor-stroma communication. In addition, exosomes may be involved in tumor complications. In view of the role of exosomes in intercellular communication, exosomes have been developed as tumor biomarkers, therapeutic targets, and drug delivery systems for tumor diagnosis, prognosis and treatment. Despite the many advantages of exosomes, there are many challenges in exosomal development and application, such as incomprehensive understanding of biological functions, safety and specificity for therapeutic use. This article reviews the biogenesis of TDEs and focuses on the role of exosomal miRNAs in intercellular communication and exosome-based treatment for cancer.

New insights into molecular chaperone TRAP1 as a feasible target for future cancer treatments.

Tumor necrosis factor receptor-associated protein 1 (TRAP1), a molecular chaperone, is a major member of the mitochondrial heat shock protein 90 (Hsp90) family. Studies have shown that TRAP1 can prevent hypoxia-induced damage to cardiomyocytes, maintain cardiomyocytes viability and mitochondrial membrane potential, and protect cardiomyocytes. In addition, it can also protect astrocytes from ischemic damage in vitro. In recent years, there have been many new discoveries in tumors. The abnormal expression of TRAP1 is closely related to the occurrence and development of various tumors. TRAP1 protein seems to be a central regulatory protein, involved in the activation of various oncogenic proteins and signaling pathways, and has a balanced function at tumor transformation and the intersection of different metabolic processes. Targeting its chaperone activity and molecular interactions can destroy the metabolism and survival adaptability of tumor cells, paving the way for the development of highly selective mitochondrial anti-tumor drugs. Moreover, the combination of TRAP1 inhibition and current traditional cancer therapies has shown promising applications. These findings have important implications for the diagnosis and treatment of tumors. Therefore, we reviewed the recently identified functions of the molecular chaperone TRAP1 in cancer development and progression, as well as the discovery and recent advances in selective TRAP1 inhibitors as anticancer drug therapies, opening up new attractive prospects for exploring strategies for targeting TRAP1 as a tumor cell target.

A single injection of bleomycin reduces glycosaminoglycan sulfation up to 30 days in the C57BL/6 mouse model of lung fibrosis.

Bleomycin is a clinically used anticancer drug, but it induces lung fibrosis in certain cancer patients with unknown mechanism. Glycosaminoglycans (GAGs) are required for lung morphogenesis during animal development. In current study, GAG disaccharides including heparan sulfate (HS) and chondroitin sulfate (CS) from bleomycin-induced and control lung tissues in lung fibrosis mouse model were tagged with 1-phenyl-3-methyl-5-pyrazolone (PMP) and deuterated PMP, respectively. The differentially isotope-tagged disaccharides were quantitatively compared by LC-MS. At day 10, the amount of CS disaccharides (U0a0, U0a6, and U0a4) and non-sulfated HS disaccharide (U0A0) were increased by 1.3-, 1.6-, 11.7-, and 2.2-fold, respectively, whereas the amount of CS disaccharide (U0a2), hyaluranan disaccharide (UßA0), and six HS disaccharides (U0A6, U2A0, U0H6, U0S0, U2S0, and U2S6) were decreased from1.1- to 14.3-fold compared to that of the controls. At day 15, under-sulfation of both HS and CS disaccharides was persisted. At day 30, the CS disaccharide compositions were recovered to that of the control levels whereas the HS were still remarkably under-sulfated. In conclusion, GAGs, especially HS, from fibrotic lungs induced by a single injection of bleomycin were significantly under-sulfated up to 30 days, suggesting GAGs might be another class of defective signaling molecules involved in bleomycin-induced lung fibrosis.

Clerodane Diterpenoids Isolated from the Leaves of Casearia graveolens.

A phytochemical survey aiming to acquire pharmacologically active substances has resulted in the isolation of nine new clerodane diterpenoids, named graveospenes A-I (1-9), from the leaves of Casearia graveolens. Spectroscopic methods were employed to establish the structures with their absolute configurations being confirmed by ECD data analysis. A biological evaluation was performed, and compound 1 was found to be cytotoxic to both human lung cancer cells (A549) and human hepatocellular carcinoma cells (HepG2). A mechanism-of-action study on 1 revealed this compound to induce apoptosis of A549 cells and impede them at the G0/G1 stage.

Roles of galectin-3 in metabolic disorders and tumor cell metabolism.

The galactoside-binding protein galectin-3 is commonly overexpressed by cancer cells and promotes cancer progression and metastasis. Over the past few years, evidence has emerged that galectin-3 is also overexpressed in several metabolic malfunction conditions such as diabetes, obesity and atherosclerosis and is involved in the regulation of the occurrence and development of these diseases. Recently, Galectin-3 expression is shown also to be associated with glycolysis and mitochondrial metabolism in tumors, and promotes tumor metabolic reprogramming for their adaption to the microenvironment stress imposed by oxygen and nutrients deprivation. This brief review summarizes the current understanding of the roles and actions of galectin-3 in these metabolic diseases and in tumor metabolism.

Pantoprazole pretreatment elevates sensitivity to vincristine in drug-resistant oral epidermoid carcinoma in vitro and in vivo.

Resistance to chemotherapeutic agents is a major cause of treatment failure in patients with oral cancer. Proton pump inhibitors (PPIs), essentially H+-K+-ATPase inhibitors which are currently used in the treatment of acid related diseases, have demonstrated promising antitumor and chemo-sensitizing efficacy. The main purpose of the present study was to investigate whether pantoprazole (PPZ, one of PPIs) could increase the sensitivity of chemoresistant oral epidermoid carcinoma cells (KB/V) to vincristine (VCR) and elucidate the underlying action mechanism. Results showed that combination treatment of PPZ and VCR synergistically inhibited the proliferation of KB/V cells in vitro and in vivo. Furthermore, administration of PPZ and VCR not only induce apoptosis and G2/M phase arrest in KB/V cells but also suppress the migration and invasion of KB/V cells. The mechanism underlying synergistic anti-tumor effect of PPZ and VCR was related to the inhibition of the function and expression of P-glycoprotein (P-gp) and the down-regulation of EGFR/MAPK and PI3K/Akt/mTOR signaling pathways in KB/V cells. Additionally, we observed that PPZ treatment induced an increase in lysosomal pH and inhibited the activity of lysosomal enzyme acid phosphatase in KB/V cells, which could functionally reduce the sequestration of VCR in lysosomes and sensitized KB/V cells to VCR. In conclusion, our study demonstrated that PPZ could be included in new combined therapy of human oral cancer (especially on VCR-resistant therapy) together with VCR.

Bioactive Diterpenoids from the Stems of Euphorbia antiquorum.

A total of 18 diterpenoids, including 10 new analogues (1-10), were isolated from Euphorbia antiquorum. The structures were characterized by spectroscopic techniques, and circular dichroism data analysis was adopted to confirm the absolute configurations of 1-10. Compounds 1-9 were classified as ent-atisane diterpenoids, and 10 was assigned as an ent-kaurane diterpenoid. The biological evaluation of nitric oxide (NO) production inhibition was conducted, and all of these isolates showed the property of inhibiting NO generation in lipopolysaccharide-induced BV-2 cells. Further research on molecular docking disclosed the affinities between the diterpenoids obtained and inducible nitric oxide synthase.

Nitric oxide inhibitory limonoids as potential anti-neuroinflammatory agents from Swietenia mahagoni.

Recent studies have revealed that there is a close relationship between neuroinflammation and Alzheimer's disease (AD) and compounds with anti-neuroinflammatory effects are potentially useful for the treatment of AD. A phytochemical investigation to obtain new neuroinflammatory inhibitors resulted in the isolation of four new and three known limonoids from Swietenia mahagoni. The structures of these limonoids were established by NMR, MS, and electronic circular dichroism (ECD) data analysis. Compounds 1-3 feature complicated polycyclic caged structures of limonoid orthoester and represent new examples of phragmalin-type limonoids. All of the isolates showed anti-neuroinflammatory activities by inhibiting nitric oxide (NO) release in LPS-induced murine microglial BV-2 cells with compounds 1 and 3-6 having IC50 values of 26.8, 26.1, 26.0, 37.1, and 16.5 µM, respectively. The possible mechanism of NO inhibition of some bioactive compounds was also investigated using molecular docking, which revealed the interactions of bioactive compounds with the inducible nitric oxide synthase (iNOS) protein.

NO inhibitory constituents as potential anti-neuroinflammatory agents for AD from Blumea balsamifera.

Our continuous search for new nitric oxide (NO) inhibitory substances as anti-neuroinflammatory agents for AD resulted in the isolation of one new labdane diterpenoid and three new guaiane sesquiterpenoids, as well as ten known compounds from Blumea balsamifera. Their structures were elucidated by NMR spectroscopic data analysis and the time-dependent density functional theory (TDDFT) electronic circular dichroism (ECD) calculations. The anti-neuroinflammatory effects were examined by inhibiting NO release in LPS-induced murine microglial BV-2 cells. The possible mechanism of NO inhibition of some bioactive compounds was also investigated using molecular docking, which revealed the interactions of bioactive compounds with the iNOS protein.