Prediction and countermeasures of heavy metal copper pollution accident in the Three Gorges Reservoir Area.

In order to mitigate the hazards of water pollution in drinking water source areas (DWSAs), developing applicable models and proposing effective solutions is of paramount significance. The study developed the Heshangshan Drinking Water Source Area (HDWSA) Hydrodynamic Model, integrating Geographic Information System (GIS) into a two-dimensional hydrodynamic water quality model using FORTRAN. TECPLOT360 software (Software Tools for Numerical Simulation with Visualization) visualized contamination transportation and diffusion. The model's relative error is less than 6%, indicating its strong stability and high reliability. The HDWSA in the Three Gorges Reservoir Area (TGRA) was used as a case study, focusing on copper (Cu) as a pollutant. By regulating the flow downstream from the Xiangjiaba Reservoir, Scheduling Group 1 and Scheduling Group 2 respectively increased the flow by 4000 m3/s and 8000 m3/s. The study analyzed the spatio-temporal variations of Cu concentration following pollution accident and flow scheduling. Under accident conditions, it took 71, 61, 49, and 56 min for the Cu concentration in the study area to decrease to below the standard value (1 mg/L) during dry, falling, flood, and storage periods. Scheduling Groups 1 and 2 reduced the pollutant exceedance duration by 19-26 min and 12-18 min across the four water periods.

Synthesis and biological activity assay of novel camptothecin-peptidic conjugates based on PEPT1.

Camptothecin (CPT) and its derivatives are potent candidates for cancer treatment. However, the clinical applications are largely restricted by non-selectivity and severe toxicities. The peptide transporter 1 (PEPT1), which is highly expressed in human intestines, has been found to be overexpressed in several cancer cells. This discovery suggests that PEPT1 has the potential to serve as a therapeutic target for both improving bioavailability and cancer-targeting treatment. Therefore, a prodrug approach for CPT targeting at PEPT1 highly expressed cancer cells was adopted in the present study. Eighteen CPT prodrugs, its peptidic conjugates, were synthesized and the structures were confirmed by NMR and HRMS. The protein expression profiles of PEPT1 in different cell lines were performed using immunofluorescence assay and western blotting analysis. The cytotoxicity of CPT prodrugs and their uptake via competition with Gly-Sar, a typical substrate of PEPT1, were evaluated in both PEPT1-overexpressed and under expressed cells. The results demonstrated that most CPT prodrugs significantly impaired Gly-Sar uptake, suggesting a higher affinity of CPT-peptidic conjugates for PEPT1 and PEPT1 overexpression cells. In addition, these prodrugs demonstrated a higher capability for inhibiting cell growth in PEPT1 highly-expressed cancer cells compared to PEPT1 under expressed cells. These results indicated that this peptidic prodrug strategy might offer great potential for improved tumor selectivity and chemotherapeutic efficacy of CPT.

A Novel Betulinic Acid Analogue: Synthesis, Solubility, Antitumor Activity and Pharmacokinetic Study in Rats.

Betulinic acid (BA) and betulin (BE) are naturally pentacyclic triterpenes with documented biological activities, especially antitumor and anti-inflammatory activity. However, their bioavailability in vivo is not satisfactory in terms of medical applications. Thus, to improve the solubility and bioavailability so as to improve the efficacy, 28-O-succinyl betulin (SBE), a succinyl derivative of BE, was synthesized and its solubility, in vitro and in vivo anti-tumor activities, the apoptosis pathway as well as the pharmacokinetic properties were investigated. The results showed that SBE exhibited significantly higher solubility in most of the tested solvents, and showed a maximum solubility of 7.19 ± 0.66 g/L in n-butanol. In vitro and in vivo anti-tumor activity assays indicated both BA and SBE exhibited good anti-tumor activities, and SBE demonstrated better potential compared to BA. An increase in the ratio of Bad/Bcl-xL and activation of caspase 9 was found in SBE treated Hela cells, suggesting that the intrinsic mitochondrial pathway is involved in SBE induced apoptosis. Compared with BA, SBE showed much-improved absorption and bioavailability in pharmacokinetic studies.

Anatomical and Functional Connectivity of Critical Deep Brain Structures and Their Potential Clinical Application in Brain Stimulation.

Subcortical structures, such as the hippocampus, amygdala, and nucleus accumbens (NAcc), play crucial roles in human cognitive, memory, and emotional processing, chronic pain pathophysiology, and are implicated in various psychiatric and neurological diseases. Interventions modulating the activities of these deep brain structures hold promise for improving clinical outcomes. Recently, non-invasive brain stimulation (NIBS) has been applied to modulate brain activity and has demonstrated its potential for treating psychiatric and neurological disorders. However, modulating the above deep brain structures using NIBS may be challenging due to the nature of these stimulations. This study attempts to identify brain surface regions as source targets for NIBS to reach these deep brain structures by integrating functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI). We used resting-state functional connectivity (rsFC) and probabilistic tractography (PTG) analysis to identify brain surface stimulation targets that are functionally and structurally connected to the hippocampus, amygdala, and NAcc in 119 healthy participants. Our results showed that the medial prefrontal cortex (mPFC) is functionally and anatomically connected to all three subcortical regions, while the precuneus is connected to the hippocampus and amygdala. The mPFC and precuneus, two key hubs of the default mode network (DMN), as well as other cortical areas distributed at the prefrontal cortex and the parietal, temporal, and occipital lobes, were identified as potential locations for NIBS to modulate the function of these deep structures. The findings may provide new insights into the NIBS target selections for treating psychiatric and neurological disorders and chronic pain.

Descending dopaminergic pathway facilitates itch signal processing via activating spinal GRPR+ neurons.

A11 dopaminergic neurons regulate somatosensory transduction by projecting from the diencephalon to the spinal cord, but the function of this descending projection in itch remained elusive. Here, we report that dopaminergic projection neurons from the A11 nucleus to the spinal dorsal horn (dopaminergicA11-SDH ) are activated by pruritogens. Inhibition of these neurons alleviates itch-induced scratching behaviors. Furthermore, chemogenetic inhibition of spinal dopamine receptor D1-expressing (DRD1+ ) neurons decreases acute or chronic itch-induced scratching. Mechanistically, spinal DRD1+ neurons are excitatory and mostly co-localize with gastrin-releasing peptide (GRP), an endogenous neuropeptide for itch. In addition, DRD1+ neurons form synapses with GRP receptor-expressing (GRPR+ ) neurons and activate these neurons via AMPA receptor (AMPAR). Finally, spontaneous itch and enhanced acute itch induced by activating spinal DRD1+ neurons are relieved by antagonists against AMPAR and GRPR. Thus, the descending dopaminergic pathway facilitates spinal itch transmission via activating DRD1+ neurons and releasing glutamate and GRP, which directly augments GRPR signaling. Interruption of this descending pathway may be used to treat chronic itch.

Inflammation in pathogenesis of chronic pain: Foe and friend.

Chronic pain is a refractory health disease worldwide causing an enormous economic burden on individuals and society. Accumulating evidence suggests that inflammation in the peripheral nervous system (PNS) and central nervous system (CNS) is the major factor in the pathogenesis of chronic pain. The inflammation in the early- and late phase may have distinctive effects on the initiation and resolution of pain, which can be viewed as friend or foe. On the one hand, painful injuries lead to the activation of glial cells and immune cells in the PNS, releasing pro-inflammatory mediators, which contribute to the sensitization of nociceptors, leading to chronic pain; neuroinflammation in the CNS drives central sensitization and promotes the development of chronic pain. On the other hand, macrophages and glial cells of PNS and CNS promote pain resolution via anti-inflammatory mediators and specialized pro-resolving mediators (SPMs). In this review, we provide an overview of the current understanding of inflammation in the deterioration and resolution of pain. Further, we summarize a number of novel strategies that can be used to prevent and treat chronic pain by controlling inflammation. This comprehensive view of the relationship between inflammation and chronic pain and its specific mechanism will provide novel targets for the treatment of chronic pain.

Chemokine Receptor CXCR3 in the Spinal Cord Contributes to Chronic Itch in Mice.

Recent studies have shown that the chemokine receptor CXCR3 and its ligand CXCL10 in the dorsal root ganglion mediate itch in experimental allergic contact dermatitis (ACD). CXCR3 in the spinal cord also contributes to the maintenance of neuropathic pain. However, whether spinal CXCR3 is involved in acute or chronic itch remains unclear. Here, we report that Cxcr3 -/- mice showed normal scratching in acute itch models but reduced scratching in chronic itch models of dry skin and ACD. In contrast, both formalin-induced acute pain and complete Freund's adjuvant-induced chronic inflammatory pain were reduced in Cxcr3 -/- mice. In addition, the expression of CXCR3 and CXCL10 was increased in the spinal cord in the dry skin model induced by acetone and diethyl ether followed by water (AEW). Intrathecal injection of a CXCR3 antagonist alleviated AEW-induced itch. Furthermore, touch-elicited itch (alloknesis) after compound 48/80 or AEW treatment was suppressed in Cxcr3 -/- mice. Finally, AEW-induced astrocyte activation was inhibited in Cxcr3 -/- mice. Taken together, these data suggest that spinal CXCR3 mediates chronic itch and alloknesis, and targeting CXCR3 may provide effective treatment for chronic pruritus.

A 3D-QSAR Study on Betulinic Acid Derivatives as Anti-Tumor Agents and the Synthesis of Novel Derivatives for Modeling Validation.

BACKGROUND: Betulinic acid is a lupane-type triterpene firstly extracted from the bark of white birch. It has displayed anti-inflammatory, antioxidant, anti-HIV and selective cytotoxicity. OBJECTIVE: To understand the structure- anti-tumor activity relationship of betulinic acid and betulin derivatives and to synthesize novel anti-tumor derivatives of betulinic acid and betulin. METHOD: The 3D-QSAR methods including CoMFA and CoMSIA methods were performed to study the structureanti- tumor activity relationship of betulinic acid (BA) and betulin (BE) derivatives. RESULTS: According to the models, near the C-3 site, non-bulky, negatively charged electron-donating, hydrophobic, non-hydrogen-bond-donating and hydrogen-bond-accepting groups are favored to the activity. Around the C-28 site, the bulky, positively charged electron-withdrawing and hydrophobic groups are favored, whereas hydrophilic groups may be introduced at the terminal of the side chain. Based on the models, BA and BE were esterified with substituted amino acid derivatives achieving novel derivatives for the modeling validation. CONCLUSION: The experimental results verified the modeling rules, and showed when different rules may apply to the new structures, the steric effects might be more important. The synthesized derivatives were showed promising cytotoxicity against tested cancer cell lines.

The metabolism of salidroside to its aglycone p-tyrosol in rats following the administration of salidroside.

Salidroside is one of the major phenolic glycosides in Rhodiola, which has been reported to possess various biological activities. In the present study the in vivo deglycosylation metabolism of salidroside was investigated and its aglycone p-tyrosol but not the original salidroside was identified as the main form in rat tissues following the administration of salidroside. After the i.v. administration of salidroside at a dose of 50 mg/kg in rats, salidroside was quantified only in the liver, kidney and heart tissues. The highest level of p-tyrosol was detected in the heart, followed by the spleen, kidney, liver and lungs, in order. Salidroside was detected only in the liver, in contrast, p-tyrosol was detectable in most tissues except the brain, and the kidney tissues contained a significant amount of p-tyrosol compared to the other tissues after the i.g. administration of 100 mg/kg salidroside. The excretion behaviour revealed that the administrated salidroside mainly eliminated in the form of salidroside but not its aglycone metabolite p-tyrosol through urine. After i.v. and i.g. administration in rats, 64.00% and 23.80% of the total dose was excreted through urine in the form of salidroside, respectively. In addition, 0.19% and 2.25% of the dose was excreted in the form of p-tyrosol through urine after i.v. and i.g. administration, respectively. The faecal salidroside and p-tyrosol concentrations were 0.3% and 1.48% of the total dose after i.v. administration, respectively. After the i.g. administration of salidroside, trace salidroside and p-tyrosol were quantified in faeces within 72 h. In addition, the biliary excretion levels of salidroside after i.v. and i.g. administration were 2.86% and 0.02% of the dose, respectively. The obtained results show that salidroside was extensively metabolised to its aglycone p-tyrosol and distributed to various organs and the original salidroside was cleared rapidly through urine following the administration of salidroside.