Abnormal white and gray matter functional connectivity is associated with cognitive dysfunction in presbycusis.

Presbycusis is characterized by high-frequency hearing loss and is closely associated with cognitive decline. Previous studies have observed functional reorganization of gray matter in presbycusis, but the information transmission between gray matter and white matter remains ill-defined. Using resting-state functional magnetic resonance imaging, we investigated differences in functional connectivity (GM-GM, WM-WM, and GM-WM) between 60 patients with presbycusis and 57 healthy controls. Subsequently, we examined the correlation between these connectivity differences with high-frequency hearing loss as well as cognitive impairment. Our results revealed significant alterations in functional connectivity involving the body of the corpus callosum, posterior limbs of the internal capsule, retrolenticular region of the internal capsule, and the gray matter regions in presbycusis. Notably, disrupted functional connectivity was observed between the body of the corpus callosum and ventral anterior cingulate cortex in presbycusis, which was associated with impaired attention. Additionally, enhanced functional connectivity was found in presbycusis between the internal capsule and the ventral auditory processing stream, which was related to impaired cognition in multiple domains. These two patterns of altered functional connectivity between gray matter and white matter may involve both bottom-up and top-down regulation of cognitive function. These findings provide novel insights into understanding cognitive compensation and resource redistribution mechanisms in presbycusis.

Aberrant auditory metabolite levels and topological properties are associated with cognitive decline in presbycusis patients.

Presbycusis has been reported as related to cognitive decline, but its underlying neurophysiological mechanism is still unclear. This study aimed to investigate the relationship between metabolite levels, cognitive function, and node characteristics in presbycusis based on graph theory methods. Eighty-four elderly individuals with presbycusis and 63 age-matched normal hearing controls underwent magnetic resonance spectroscopy, functional magnetic resonance imaging scans, audiological assessment, and cognitive assessment. Compared with the normal hearing group, presbycusis patients exhibited reduced gamma-aminobutyric acid and glutamate levels in the auditory region, increased nodal characteristics in the temporal lobe and precuneus, as well as decreased nodal characteristics in the superior occipital gyrus and medial orbital. The right gamma-aminobutyric acid levels were negatively correlated with the degree centrality in the right precuneus and the executive function. Degree centrality in the right precuneus exhibited significant correlations with information processing speed and executive function, while degree centrality in the left medial orbital demonstrated a negative association with speech recognition ability. The degree centrality and node efficiency in the superior occipital gyrus exhibited a negative association with hearing loss and speech recognition ability, respectively. These observed changes indicate alterations in metabolite levels and reorganization patterns at the brain network level after auditory deprivation.

Long-Chain Hydrocarbons from Nonthermal Plasma-Driven Biogas Upcycling.

The burgeoning necessity to discover new methodologies for the synthesis of long-chain hydrocarbons and oxygenates, independent of traditional reliance on high-temperature, high-pressure, and fossil fuel-based carbon, is increasingly urgent. In this context, we introduce a nonthermal plasma-based strategy for the initiation and propagation of long-chain carbon growth from biogas constituents (CO2 and CH4). Utilizing a plasma reactor operating at atmospheric room temperature, our approach facilitates hydrocarbon chain growth up to C40 in the solid state (including oxygenated products), predominantly when CH4 exceeds CO2 in the feedstock. This synthesis is driven by the hydrogenation of CO2 and/or amalgamation of CHx radicals. Global plasma chemistry modeling underscores the pivotal role of electron temperature and CHx radical genesis, contingent upon varying CO2/CH4 ratios in the plasma system. Concomitant with long-chain hydrocarbon production, the system also yields gaseous products, primarily syngas (H2 and CO), as well as liquid-phase alcohols and acids. Our finding demonstrates the feasibility of atmospheric room-temperature synthesis of long-chain hydrocarbons, with the potential for tuning the chain length based on the feed gas composition.

Elevated liver enzymes in the first trimester are associated with gestational diabetes mellitus: A prospective cohort study.

AIMS: Previous studies have found that a single liver enzyme may predict gestational diabetes mellitus (GDM), but the results have been inconsistent. This study aimed to explore the associations of liver enzymes in early pregnancy with risk of GDM, as well as to independently rank risk factors. METHODS: This prospective cohort study included 1295 women who underwent liver enzyme measurements during early pregnancy and completed GDM assessment in mid-pregnancy. Logistic regression and restricted cubic spline analyses were conducted to assess the relationship between liver enzymes and risk of GDM. Back-propagation artificial neural network was performed to rank independently risk factors of GDM. RESULTS: Women diagnosed with GDM exhibited significantly higher levels of liver enzymes than those without GDM (all p < 0.05). The highest quartile of liver enzymes was associated with higher risk of GDM compared with the lowest quartile, with adjusted odds ratio (ORs) ranging from 2.76 to 8.11 (all p < 0.05). Moreover, the ORs of GDM increased linearly with liver enzymes level (all P for overall association <0.001). Furthermore, Back-propagation artificial neural network identified γ-gamma-glutamyl transferase (GGT) as accounting for the highest proportion in the ranking of GDM risk prediction weights (up to 20.8%). CONCLUSIONS: Single or total elevations of liver enzymes in early pregnancy could predict the GDM occurrence, in which GGT, alkaline Phosphatase, and aspartate aminotransferase were the three most important independent risk factors.

Wolfberry, Yam, and Chrysanthemum polysaccharides increased intestinal Akkermansia muciniphila abundance and hepatic YAP1 expression to alleviate DILI.

Drug-induced liver injury (DILI) is frequently induced by high dose of acetaminophen (APAP) and is concomitant with disturbances of gut flora. Akkermansia muciniphila is beneficial for the repair of liver injury. Lycium barbarum polysaccharide, yam polysaccharide, and chrysanthemum polysaccharide all have anti-inflammatory and antioxidation effects. The objective of this study is to investigate the potential of lycium barbarum polysaccharide, yam polysaccharide, and chrysanthemum polysaccharide (LYC) in improving DILI by increasing the abundance of A. muciniphila. Initially, screening for the optimal concentrations of wolfberry, yam, and chrysanthemum (WYC) or LYC to promote A. muciniphila proliferation in vitro and validated in antibiotic (ATB)-treated KM mice. Subsequently, APAP-induced DILI model in BALB/c mice were constructed to examine the treatment effects of LYC. Our findings indicate that the optimal concentration ratio of WYC was 2:3:2, and LYC was 1:1:1. WYC increased A. muciniphila proliferation in vitro and in ATB-treated mice under this ratio. Meanwhile, LYC increased A. muciniphila abundance in vitro and the combination LYC with A. muciniphila promoted the proliferation of A. muciniphila in ATB-treated mice. The overdose of APAP resulted in the impairment of the intestinal barrier function and subsequent leakage of lipopolysaccharide (LPS). Moreover, LYC increased A. muciniphila abundance, reduced intestinal inflammation and permeability, and upregulated the expression of the tight junction protein zonula occludens protein 1 (ZO-1) and occludin contents in the gut. Lastly, LYC inhibited LPS leakage and upregulated hepatic YAP1 expression, ultimately leading to the repair of DILI.

Wolfberry enhanced the abundance of Akkermansia muciniphila by YAP1 in mice with acetaminophen-induced liver injury.

Drug-induced liver injury (DILI) by acetaminophen (APAP) was one of the most challenging liver diseases. Wolfberry (Lycium barbarum L.), a traditional Chinese medicinal material and food supplement, has a potential effect on increasing the abundance of Akkermansia muciniphila (A. muciniphila) in mice colons. However, the effect and mechanism of wolfberry remain unclear in APAP-induced DILI. In this study, wolfberry promoted the proliferation of activated-A. muciniphila in vitro and in vivo. For the first time, we detected that the activated-A. muciniphila but not the killed-A. muciniphila increased the expression level of Yes-associated protein 1 (YAP1) in the liver and alleviated liver injury in APAP-induced DILI mice. Mechanically, A. muciniphila improved the intestinal mucosal barrier and reduced lipopolysaccharide (LPS) content in the liver, leading to the increased expression level of YAP1. Furthermore, wolfberry increased the A. muciniphila abundance in the colon and YAP1 expression in the liver from APAP-induced DILI mice, which promoted the recovery of APAP-induced liver injury. Meanwhile, wolfberry combination with A. muciniphila synergistically increased AKK abundance and YAP1 expression in the liver. Our research provides an innovative strategy to improve DILI.

Role of LncRNA H19 in tumor progression and treatment.

As one of the earliest discovered lncRNA molecules, lncRNA H19 is usually expressed in large quantities during embryonic development and is involved in cell differentiation and tissue formation. In recent years, the role of lncRNA H19 in tumors has been gradually recognized. Increasing evidence suggests that its aberrant expression is closely related to cancer development. LncRNA H19 as an oncogene not only promotes the growth, proliferation, invasion and metastasis of many tumors, but also develops resistance to treatment, affecting patients' prognosis and survival. Therefore, in this review, we summarise the extensive research on the involvement of lncRNA H19 in tumor progression and discuss how lncRNA H19, as a key target gene, affects tumor sensitivity to radiotherapy, chemotherapy and immunotherapy by participating in multiple cellular processes and regulating multiple signaling pathways, which provides a promising prospect for further research into the treatment of cancer.

Human umbilical cord mesenchymal stem cells promoted tumor cell growth associated with increased interleukin-18 in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is experiencing a concerning rise in both incidence and mortality rates. Current therapeutic strategies are limited in their effectiveness, largely due to the complex causes of the disease and significant levels of drug resistance. Given the latest developments in human umbilical cord mesenchymal stem cells (hUC-MSCs) research, there is a debate over the continued use of stem cell transplantation for treating tumors. Consequently, this study seeks to explore the role of hUC-MSCs in the management of HCC. METHODS AND RESULTS: HUC-MSCs increased the number (10.75 ± 1.50) in the DEN/TCPOBOP-induced mice hepatoma model, compared with DMSO group (7.25 ± 1.71). Moreover, the liver index in hUC-MSCs group (0.21 ± 0.06) was greater than that in DMSO group (0.09 ± 0.01). Immunohistochemical (IHC) analysis revealed that while hUC-MSCs did not alter Foxp3 expression, they significantly stimulated Ki67 expression, indicative of increased tumor cellular proliferation. Additionally, immunofluorescence (IF) studies showed that hUC-MSCs increased CD8+ T cell counts without affecting macrophage numbers. Notably, granzyme B expression remained nearly undetectable. We observed that serum IL-18 levels were higher in the hUC-MSCs group (109.66 ± 0.38 pg/ml) compared to the DMSO group (91.14 ± 4.37 pg/ml). Conversely, IL-1ß levels decreased in the hUC-MSCs group (63.00 ± 0.53 pg/ml) relative to the DMSO group (97.38 ± 9.08 pg/ml). CONCLUSIONS: According to this study, hUC-MSCs promoted the growth of liver tumors. Therefore, we proposed that hUC-MSCs are not suitable for treating HCC, as they exhibit clinically prohibited abnormalities.

YAP1 suppression inhibits autophagy and improves the efficacy of anti-PD-1 immunotherapy in hepatocellular carcinoma.

Anti-PD-1 immunotherapy is a promising treatment for hepatocellular carcinoma (HCC), but some patients with HCC do not experience clinical benefits. Autophagy promotes tumor progression and participates in drug resistance. Previous studies have revealed that suppressing the expression level of Yes-associated protein 1 (YAP1) improves anti-PD-1 therapy efficacy. Therefore, the relationship between YAP1 expression and autophagy activity during anti-PD-1 treatment was investigated in this study. A positive correlation was found between the expression level of YAP1 and LC3B by analyzing The Cancer Genome Atlas (TCGA), UALCAN databases, and HCC tissue microarray. Meanwhile, YAP1 expression and autophagy constituted positive feedback, in which YAP1 inhibition decreased the autophagy activity in liver tumor cells by hepatocyte-specific Yap1 knockout mice. Further, anti-PD-1 treatment increased autophagy and YAP1 expression levels in the cancer tissues from DEN/TCPOBOP-induced liver cancer mice. Finally, Yap1 knockout suppressed autophagy and improved anti-PD-1 therapy efficacy in hepatocyte-specific Yap1 knockout mice with liver tumors. These results suggested that YAP1 suppression was sensitized to anti-PD-1 treatment and inhibited autophagy activity in liver tumor cells. YAP1 is a promising target for improving the efficacy of anti-PD-1 immunotherapy in HCC.

Direct Fast-Neutron Detection by 2D Perovskite Semiconductor.

Fast-neutrons play a critical role in a range of applications, including medical imaging, therapy, and nondestructive inspection. However, direct detecting fast-neutrons by semiconductors has proven to be challenging due to their weak interaction with most matter and the requirement of high carrier mobility-lifetime (µτ) product for efficient charge collection. Herein, a novel approach is presented to direct fast-neutron detection using 2D Dion-Jacobson perovskite semiconductor BDAPbBr4 . This material features a high fast-neutron caption cross-section, good electrical stability, high resistivity, and, most importantly, a record-high µτ product of 3.3 × 10-4 cm2 V-1 , outperforming most reported fast-neutron detection semiconductors. As a result, BDAPbBr4 detector exhibited good response to fast-neutrons, not only achieving fast-neutron energy spectra in counting mode, but also obtaining linear and fast response in integration mode. This work provides a paradigm-shifting strategy for designing materials that efficiently detect fast-neutrons and paves the way toward exciting applications in fast-neutron imaging and therapy.

Design of Fourier ptychographic illuminator for single full-FOV reconstruction.

Fourier ptychographic microscopy (FPM) is a spatial-temporal-modulation high-throughput imaging technique via a sequential angle-varied LED illumination. Therefore, the illuminator is one of the key components and the design of this illuminator is significant. However, because of the property of spherical wave, partial coherence, and aperture-induced vignetting, the acquired images must be processed in blocks first, and rely on parallel reconstruction via a graphics processing unit (GPU). The high cost makes it unappealing compared with commercial whole slide imaging system via a low-cost central processing unit (CPU). Especially, the vignetting severely destroys the space-invariant model and induces obvious artifacts in FPM, which is the most difficult problem. The conventional method is to divide the field of view (FOV) into many tiles and omit those imperfect images, which is crude and may discards low frequency information. In this paper, we reevaluated the conditions of vignetting in FPM. Through our analysis, the maximum side length of FOV is 0.759 mm for a single full-FOV reconstruction via a 4×/0.1 NA objective and a 4 mm spacing LED array in theory, while almost 1.0 mm can be achieved in practice due to the tolerance of algorithm. We found that FPM system can treat the vignetting coefficient Vf below 0.1 as brightfield images and Vf lager than 0.9 as darkfield images, respectively. We reported an optimized distribution for designing an illuminator without vignetting effect according to the off-the-shelf commercial products, which can reconstruct full FOV in one time via a CPU. By adjusting the distribution of LED units, the system could retrieve the object with the side length of FOV up to 3.8 mm for a single full-FOV reconstruction, which achieves the largest FOV that a typical 4×/0.1 NA objective with the field number of 22 mm can afford.

Redundant information model for Fourier ptychographic microscopy.

Fourier ptychographic microscopy (FPM) is a computational optical imaging technique that overcomes the traditional trade-off between resolution and field of view (FOV) by exploiting abundant redundant information in both spatial and frequency domains for high-quality image reconstruction. However, the redundant information in FPM remains ambiguous or abstract, which presents challenges to further enhance imaging capabilities and deepen our understanding of the FPM technique. Inspired by Shannon's information theory and extensive experimental experience in FPM, we defined the specimen complexity and reconstruction algorithm utilization rate and reported a model of redundant information for FPM to predict reconstruction results and guide the optimization of imaging parameters. The model has been validated through extensive simulations and experiments. In addition, it provides a useful tool to evaluate different algorithms, revealing a utilization rate of 24%±1% for the Gauss-Newton algorithm, LED Multiplexing, Wavelength Multiplexing, EPRY-FPM, and GS. In contrast, mPIE exhibits a lower utilization rate of 19%±1%.

Dihydroartemisinin promoted FXR expression independent of YAP1 in hepatocellular carcinoma.

Loss of FXR, one of bile acid receptors, enlarged livers. Yes-associated protein 1 (YAP1), a dominant oncogene, promotes hepatocellular carcinoma (HCC). However, the relationship between FXR and YAP1 was unspecified in bile acid homeostasis in HCC. Here, we used TIMER2.0, the Cancer Genome Atlas (TCGA) Database, and Kaplan-Meier Plotter Database and discovered that FXR was positively correlated with better prognosis in liver cancer patients. Our previous research showed that dihydroartemisinin (DHA) inhibited cell proliferation in HepG2 and HepG22215 cells. However, the relationship of YAP1 and the bile acid receptor FXR remains elusive during DHA treatment. Furthermore, we showed that DHA improved FXR and reduced YAP1 in the liver cancer cells and mice. Additionally, the expression of nucleus protein FXR was enhanced in Yap1LKO mice with liver cancer. DHA promoted the expression level of whole and nuclear protein FXR independent of YAP1 in Yap1LKO mice with liver cancer. DHA declined cholesterol 7α-hydroxylase, but not sterol 27-hydroxylase, and depressed cholic acid and chenodeoxycholic acid of liver tissue in Yap1LKO mice with liver cancer. Generally, our results suggested that DHA improved FXR and declined YAP1 to suppress bile acid metabolism. Thus, we suggested that FXR acted as a potential therapeutic target in HCC.

A novel prognostic model based on pretreatment serum albumin and ECOG PS for primary CNS lymphoma: an international, multi-center study.

BACKGROUND: Serum albumin has been demonstrated as prognostic parameter in non-Hodgkin lymphoma (NHL). Primary central nervous system lymphoma (PCNSL) is a rare extranodal NHL with highly aggressive behavior. In this study, we aimed at creating a novel prognostic model for PCNSL based on serum albumin levels. METHODS: We compared several commonly used laboratory nutritional parameters for predicting the survival of PCNSL patients using overall survival (OS) for outcome analysis and receiver operating characteristic curve analysis to determine the optimal cut-off values. Parameters associated with OS were evaluated by univariate and multivariate analyses. Independent prognostic parameters for OS were selected for risk stratification, including albumin ≤ 4.1 g/dL, ECOG PS > 1, and LLR > 166.8, which were associated with shorter OS; albumin > 4.1 g/dL, ECOG PS 0-1 and LLR ≤ 166.8, which were associated with longer OS, and five-fold cross-validation was used for evaluating predictive accuracy of identified prognostic model. RESULTS: By univariate analysis, age, ECOG PS, MSKCC score, Lactate dehydrogenase-to-lymphocyte ratio (LLR), total protein, albumin, hemoglobin, and albumin to globulin ratio (AGR) resulted statistically associated with the OS of PCNSL. By multivariate analysis, albumin ≤ 4.1 g/dL, ECOG PS > 1, and LLR > 166.8 were confirmed to be significant predictors of inferior OS. We explored several PCNSL prognostic models based on albumin, ECOG PS and LLR with 1 point assigned to each parameter. Eventually, a novel and effective PCNSL prognostic model based on albumin and ECOG PS successfully classified patients into three risk groups with 5-year survival rates of 47.5%, 36.9%, and 11.9%, respectively. CONCLUSIONS: The novel two-factor prognostic model based on albumin and ECOG PS we propose represents a simple but significant prognostic tool for assessing newly diagnosed patients with PCNSL.

Porphyromonas gingivalis exacerbates alcoholic liver disease by altering gut microbiota composition and host immune response in mice.

AIM: Porphyromonas gingivalis (P. gingivalis), a major periodontal pathogen, increases the risk of systemic diseases. P. gingivalis infection is closely associated with alcoholic liver disease (ALD), but the underlying mechanism remains unclear. We aimed to investigate the role of P. gingivalis in the pathogenesis of ALD. MATERIALS AND METHODS: An ALD mouse model was established using a Lieber-DeCarli liquid diet, and C57BL/6 mice were treated with P. gingivalis to detect the pathological indicators of ALD. RESULTS: Oral administration of P. gingivalis exacerbated alcohol-induced alterations in the gut microbiota, leading to gut barrier dysfunction and inflammatory response and disruption of the T-helper 17 cell/T-regulatory cell ratio in the colon of ALD mice. Furthermore, P. gingivalis worsened liver inflammation in ALD mice by increasing the protein expression of toll-like receptor 4 (TLR4) and p65, increasing the mRNA expression of interleukins-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) and up-regulating the transforming growth factor-beta 1 (TGF-ß1) and galectin-3 (Gal-3) production. CONCLUSIONS: These results indicate that P. gingivalis accelerates the pathogenesis of ALD via the oral-gut-liver axis, necessitating a new treatment strategy for patients with ALD complicated by periodontitis.

Nrf2 affects hydroquinone-induces cell cycle arrest through the p16/pRb signaling pathway and antioxidant enzymes.

Hydroquinone (HQ), a well-known carcinogenic agent, induces oxidative stress, cell cycle arrest, apoptosis, and malignant transformation. As an antioxidant actor, the nuclear factor erythroid 2-related factor 2 (Nrf2) drives adaptive cellular protection in response to oxidative stress. The human lymphoblastoid cell line (TK6 cells) is widely used as a model for leukemia researches. In the present study, we focused on exploring whether Nrf2 regulatory cell cycle in TK6 cells upon HQ treatment and the underlying mechanisms. The results showed that the cell cycle arrest in TK6 cells induced by hydroquinone was accompanied by activation of the Nrf2 signaling pathway. We further clarified that Nrf2 loss accelerated cell cycle progression from G0/G1 to S and G2/M phases and promoted ROS production by downregulating the expression of SOD and GSH. Western blotting analysis indicated that Nrf2 regulated cell cycle progression via p16/pRb signaling pathways. Therefore, we conclude that Nrf2 is engaged in HQ-induced cell cycle arrest as well through p16/pRb and antioxidant enzymes.

JNK1 activated pRb/E2F1 and inhibited p53/p21 signaling pathway is involved in hydroquinone-induced pathway malignant transformation of TK6 cells by accelerating the cell cycle progression.

Hydroquinone (HQ) is an important metabolites of benzene in the body, and it has been found to result in cellular DNA damage, mutation, cell cycle imbalance, and malignant transformation. The JNK1 signaling pathway plays an important role in DNA damage repair. In this study, we focused on whether the JNK1 signaling pathway is involved in the HQ-induced cell cycle abnormalities and the underlying mechanism. The results showed that HQ induced abnormal progression of the cell cycle and initiated the JNK1 signaling pathway. We further confirmed that JNK1 suppression decelerated the cell cycle progression through inhibiting pRb/E2F1 signaling pathway and triggering p53/p21 pathway. Therefore, we concluded that JNK1 might be involved in HQ-induced malignant transformation associated with activating pRb/E2F1 and inhibiting p53/p21 signaling pathway which resulting in accelerating the cell cycle progression.

An electrochemical aptasensor for the detection of chloramphenicol based on ultra-small Au-inserted hollow PCN-222 MOF.

The excessive utilization of antibiotics has led to significant water contamination and posed severe threats to human well-being. Consequently, the pressing imperative to identify antibiotics in the environment arises. In this study, we have successfully synthesized a hollow PCN-222 MOF distinguished by its substantial surface area and abundant functional groups, particularly the porphyrin cores. To augment the electrical conductivity of the hollow PCN-222 (HPCN-222), gold (Au) particles were incorporated within the porphyrin core using a fundamental hydrothermal method. This modification facilitated the effective immobilization of aptamer strands through π-π stacking and electrostatic interactions. As a result, the Au@HPCN-222 composite demonstrated exceptional efficacy as a substrate for immobilizing the aptamer (Apt) onto the GCE surface. By employing differential pulse voltammetry (DPV) we successfully achieved the detection of chloramphenicol (CAP) with a remarkably low limit of detection of 0.0138 ng mL-1 and the peak DPV currents at 0.18 V (vs. Ag/AgCl) were used for calibration. Furthermore, this aptasensor exhibited high selectivity and reproducibility.

An Improved Ambiguity Resolution Algorithm for Smartphone RTK Positioning.

Ambiguity resolution based on smartphone GNSS measurements can enable various potential applications that currently remain difficult due to ambiguity biases, especially under kinematic conditions. This study proposes an improved ambiguity resolution algorithm, which uses the search-and-shrink procedure coupled with the methods of the multi-epoch double-differenced residual test and the ambiguity majority tests for candidate vectors and ambiguities. By performing a static experiment with Xiaomi Mi 8, the AR efficiency of the proposed method is evaluated. Furthermore, a kinematic test with Google Pixel 5 verifies the effectiveness of the proposed method with improved positioning performance. In conclusion, centimeter-level smartphone positioning accuracy is achieved in both experiments, which is greatly improved compared with the float and traditional AR solutions.

Establishment of LC-MS/MS Method for Determination of GMDTC in Rat Plasma and Its Application in Preclinical Pharmacokinetics.

Sodium (S)-2-(dithiocarboxylato((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)-4(methylthio)butanoate (GMDTC) is the first compound to use cadmium repellent as an indication. In this paper, we established and validated a bioanalytical method for the determination of GMDTC in rat plasma, and used it to determine the drug concentrations in the plasma of rats after intravenous dosing in different genders and dosages. After pretreating the plasma samples with an acetonitrile-water-ammonia solution (70:30:1.25, v/v/v), liquid chromatographic separations were efficiently achieved with a XBridge C18 column using a 5 min gradient system of aqueous ammonium bicarbonate and 95% acetonitrile-water solution (95:5, v/v) as the eluent. The GMDTC and metolazone (internal standard, IS) detection were carried out using high-performance liquid chromatography coupled with triple quadrupole mass spectrometry (LC-MS/MS), monitored at m/z 390.06-324.1 (for the GMDTC, tR: 2.03 min) and m/z 366.0-259.2 (for IS, tR: 3.88 min). The GMDTC was stable under various testing conditions, and this analytical method conforms to the verification standard of biological analysis methods. The half-life (t1/2) was determined to be 0.54-0.65 h for the intravenous, mean distribution volume and clearances were 1.08-2.08 L/kg and 1-3 L/h/kg, respectively. The AUC0-t and AUC0-∞ found after increasing the dosage exhibited a linear relationship with the administered dose. There were no statistically significant differences in the values obtained for the different genders at dosages of 50, 100 and 250 mg/kg, respectively (p > 0.05). This is the first report of a bioanalytical method to quantify GMDTC in rat plasma using LC-MS/MS, which provides useful information for the study of its pharmacological effects and clinical applications.