The traditional uses, pharmacology, and phytochemistry of Peucedanum praeruptorum Dunn.

Bai Hua Qian Hu (Qianhu; Peucedanum praeruptorum Dunn) is a classical medicinal plant traditionally prescribed for respiratory ailments, including cough, pulmonary hypertension, and asthma. In this review, we summarize the research progress of the toxicology, pharmacokinetics, pharmacology, phytochemistry, botany, quality control, and traditional uses of P. praeruptorum in order to support future investigations into the scientific and therapeutic promise of this important medicinal plant. Information pertaining to P. praeruptorum was collected from scientific databases (ScienceDirect, Springer, SciFinder, PubMed, Baidu Scholar, Google Scholar, Web of Science), as well as toxicology papers from local conferences, M. Sc. and Ph.D. theses and dissertations, local magazines, classic texts on Chinese botanical drugs, and peer-reviewed journals. The Plant List (www.theplantlist.org) was utilized to verify the taxonomy of P. praeruptorum. P. praeruptorum was found to contain more than 119 distinct phytochemicals, including simple coumarins, pyranocoumarins, furanocoumarins, flavonoids, ketones, organic acids, and sterols, among others (e.g., praeruptorins A and B). Both crude plant extracts and purified metabolites of P. praeruptorum have been reported as treatments for hypertension, osteoporosis, Huntington's disease, and cancer. In addition, extracts of P. praeruptorum are reported to exhibit diverse pharmacological activities, including osteogenic, anti-osteoclastogenic, antidepressant, neuroprotective, antitumor, and anti-inflammatory effects. Research into the pharmacology and phytochemistry of P. praeruptorum partially support both traditional uses and extraction methods. However, further research is required to elucidate the relationships between these metabolites, their molecular mechanisms, their structure-function roles, and their antagonistic and synergistic effects.

Association of previous stillbirth with subsequent perinatal outcomes: a systematic review and meta-analysis of cohort studies.

OBJECTIVE: We conducted a systematic review and meta-analysis to examine the relationship between stillbirth and various perinatal outcomes in subsequent pregnancy. DATA SOURCES: PubMed, the Cochrane Library, Embase, Web of Science, and CNKI databases were searched up to July 2023. STUDY ELIGIBILITY CRITERIA: Cohort studies that reported the association between stillbirth and perinatal outcomes in subsequent pregnancies were included. METHODS: We conducted this systematic review and meta-analysis in accordance with the PRISMA guidelines. Statistical analysis was performed using R and Stata software. We used random-effects models to pool each outcome of interest. We performed a meta-regression analysis to explore the potential heterogeneity. The certainty (quality) of evidence assessment was performed using the GRADE approach. RESULTS: Nineteen cohort studies were included, involving 4,855,153 participants. From these studies, we identified 28,322 individuals with previous stillbirths who met the eligibility criteria. After adjusting for confounders, evidence of low to moderate certainty indicated that compared with women with previous live births, women with previous stillbirths had higher risks of recurrent stillbirth (odds ratio, 2.68; 95% confidence interval, 2.01-3.56), preterm birth (odds ratio, 3.15; 95% confidence interval, 2.07-4.80), neonatal death (odds ratio, 4.24; 95% confidence interval, 2.65-6.79), small for gestational age/intrauterine growth restriction (odds ratio, 1.3; 95% confidence interval, 1.0-1.8), low birthweight (odds ratio, 3.32; 95% confidence interval, 1.46-7.52), placental abruption (odds ratio, 3.01; 95% confidence interval, 1.01-8.98), instrumental delivery (odds ratio, 2.29; 95% confidence interval, 1.68-3.11), labor induction (odds ratio, 4.09; 95% confidence interval, 1.88-8.88), cesarean delivery (odds ratio, 2.38; 95% confidence interval, 1.20-4.73), elective cesarean delivery (odds ratio, 2.42; 95% confidence interval, 1.82-3.23), and emergency cesarean delivery (odds ratio, 2.35; 95% confidence interval, 1.81-3.06) in subsequent pregnancies, but had a lower rate of spontaneous labor (odds ratio, 0.22; 95% confidence interval, 0.13-0.36). However, there was no association between previous stillbirth and preeclampsia (odds ratio, 1.72; 95% confidence interval, 0.63-4.70) in subsequent pregnancies. CONCLUSION: Our systematic review and meta-analysis provide a more comprehensive understanding of adverse pregnancy outcomes associated with previous stillbirth. These findings could be used to inform counseling for couples who are considering pregnancy after a previous stillbirth.

Membrane and Lumen-Compartmentalized Polymersomes for Biocatalysis and Cell Mimics.

Compartmentalization is a crucial feature of a natural cell, manifested in cell membrane and inner lumen. Inspired by the cellular structure, multicompartment polymersomes (MCPs), including membrane-compartmentalized polymersomes and lumen-compartmentalized polymersomes (polymersomes-in-polymersomes), have aroused great expectations for biological applications such as biocatalysis and cell mimics in the past decades. Compared with traditional polymersomes, MCPs have advantages in encapsulating multiple enzymes separately for multistep enzymatic cascade reactions. In this review, first, the design principles and preparation methods of membrane-compartmentalized and lumen-compartmentalized polymersomes are summarized. Next, recent advances of MCPs as nanoreactors and cell mimics to mimic subcellular organelles or artificial cells are discussed. Finally, the future research directions of MCPs are prospected.

Variations in Rhizospheric and Endophytic Root Fungal Communities of Scrophularia ningpoensis in Different Producing Areas.

Few studies have examined the association of factors associated with soil fertility and composition with the structure of microbial communities in the rhizosphere and endosphere. Hence, this study aimed to explore the effects of geographical differences on fungal communities in the roots of Scrophularia ningpoensis and the relationship between the fungal communities and secondary metabolic components in the host plant. We found that there was greater diversity in the fungal communities of the rhizosphere compartment than in endosphere communities. Ascomycota and Basidiomycota were dominant among the endosphere fungi, whereas Mortierellomycota was distributed in the rhizosphere. The composition of bulk soil obtained from different producing areas was significantly different, and the correlation between the rhizospheric and physicochemical compartments of the soil was higher than that observed with the endophytic compartment. Redundancy analysis and canonical correspondence analysis of the rhizospheric and endophytic samples revealed that the organic matter, total organic carbon, total nitrogen, and Hg levels were adequately correlated with the composition of rhizospheric and endophytic fungal communities. Multiple linear regression analyses facilitated the identification of potentially beneficial fungi whose abundance was correlated with levels of secondary metabolites, such as harpagide and harpagoside. These fungi could potentially provide valuable information regarding the use of S. ningpoensis in the medicinal plant industry.

SARS-CoV-2 Spike Protein S1 Exposure Increases Susceptibility to Angiotensin II-Induced Hypertension in Rats by Promoting Central Neuroinflammation and Oxidative Stress.

The SARS-CoV-2 spike S1 subunit (S1) can cross the blood-brain barrier and elicit neuroinflammatory response independent of viral infection. Here we examined whether S1 influences blood pressure (BP) and sensitizes the hypertensive response to angiotensin (ANG) II by enhancing neuroinflammation and oxidative stress in hypothalamic paraventricular nucleus (PVN), a key brain cardiovascular regulatory center. Rats received central S1 or vehicle (VEH) injection for 5 days. One week after injection, ANG II or saline (control) was subcutaneously delivered for 2 weeks. S1 injection induced greater increases in BP, PVN neuronal excitation and sympathetic drive in ANG II rats but had no effects in control rats. One week after S1 injection, mRNA for proinflammatory cytokines and oxidative stress marker were higher but mRNA of Nrf2, the master regulator of inducible antioxidant and anti-inflammatory responses, was lower in the PVN in S1-injected rats than in VEH-injected rats. Three weeks after S1 injection, mRNA for proinflammatory cytokines and oxidative stress marker, microglia activation and reactive oxygen species in the PVN were comparable between S1 and VEH treated control rats but were elevated in two groups of ANG II rats. Notably, ANG II-induced elevations in these parameters were exaggerated by S1. Interestingly, ANG II increased PVN Nrf2 mRNA in VEH-treated rats but not in S1-treated rats. These data suggest that S1 exposure has no effect on BP, but post-S1 exposure increases susceptibility to ANG II-induced hypertension by downregulating PVN Nrf2 to promote neuroinflammation and oxidative stress and augment sympathetic excitation.

Translation and validation of the Pancreatic Cancer Disease Impact score for Chinese patients with pancreatic cancer: A methodological and cross-sectional study.

Objective: We aimed to establish and validate the Chinese version of the Pancreatic Cancer Disease Impact (C-PACADI) score for Chinese patients with pancreatic cancer (PC). Methods: This was a methodological and cross-sectional study. We established the C-PACADI score following Beaton's translation guidelines and then included 209 patients with PC to evaluate C-PACADI's reliability and validity. Results: The Cronbach's alpha coefficient of the C-PACADI score was 0.822. The correlation coefficient between "skin itchiness" score and the total score was 0.224, while the correlation coefficients ranged from 0.515 to 0.688 (P â€‹< â€‹0.001) for all the other items. The item content validity index and the scale content validity index, evaluated by eight experts were 0.875 and 0.98, respectively. Regarding concurrent validity, the total score of the C-PACADI score was moderately correlated with the EuroQol-5D (EQ-5D) index and the EQ-5D VAS score (r â€‹= â€‹-0.738, P â€‹< â€‹0.01; r â€‹= â€‹-0.667, P â€‹< â€‹0.01, respectively); the individual-item scores of C-PACADI on pain/discomfort, anxiety, loss of appetite, fatigue, and nausea were strongly associated with the corresponding symptoms of the Edmonton Symptom Assessment System scale (r ranged from 0.879 to 0.916, P â€‹< â€‹0.01). The known-group validity was demonstrated by C-PACADI's ability to detect significant symptom differences between groups stratified by treatment modalities (P â€‹< â€‹0.05) and health status (P â€‹< â€‹0.001). Conclusions: The C-PACADI score is a suitable disease-specific tool for measuring the prevalence and severity of multiple symptoms in the Chinese population with PC.

Exogenous and Endophytic Fungal Communities of Dendrobium nobile Lindl. across Different Habitats and Their Enhancement of Host Plants' Dendrobine Content and Biomass Accumulation.

Both the biosynthesis and array of bioactive and medicinal compounds in plants can be influenced by interactions with endophytic and exogenous fungi. However, the composition of endophytic and exogenous fungal communities associated with many medicinal plants is unknown, and the mechanism by which these fungi stimulate the secondary metabolism of host plants is unclear. In this study, we conducted a correlative analysis between endophytic and exogenous fungi and dendrobine and biomass accumulation in Dendrobium nobile across five Chinese habitats: wild Danxia rock, greenhouse-associated large Danxia stone, broken Danxia stone, broken coarse sandstone, and wood spile. Across habitats, fungal communities exhibited significant differences. The abundances of Phyllosticta, Trichoderma, and Hydropus were higher in wild habitats than in greenhouse habitats. Wild habitats were host to a higher diversity and richness of exogenous fungi than were greenhouse habitats. However, there was no significant difference in endophytic fungal diversity between habitats. The differences between the fungal communities' effects on the dendrobine content and biomass of D. nobile were attributable to the composition of endophytic and exogenous fungi. Exogenous fungi had a greater impact than endophytic fungi on the accumulation of fresh weight (FW) and dendrobine in D. nobile. Furthermore, D. nobile samples with higher exogenous fungal richness and diversity exhibited higher dendrobine content and FW. Phyllosticta was the only genus to be significantly positively correlated with both FW and dendrobine content. A total of 86 strains of endophytic fungi were isolated from the roots, stems, and leaves of D. nobile, of which 8 strains were found to be symbiotic with D. nobile tissue-cultured seedlings. The strain DN14 (Phyllosticta fallopiae) was found to promote not only biomass accumulation (11.44%) but also dendrobine content (33.80%) in D. nobile tissue-cultured seedlings. The results of this study will aid in the development of strategies to increase the production of dendrobine in D. nobile. This work could also facilitate the screening of beneficial endophytic and exogenous fungal probiotics for use as biofertilizers in D. nobile.

Pharmacokinetics, tissue distribution, and plasma protein binding rate of curcumol in rats using liquid chromatography tandem mass spectrometry.

Objective: Curcumol is one of the major active ingredients isolated from the traditional Chinese medicine Curcumae Rhizoma and is reported to exhibit various bioactivities, such as anti-tumor and anti-liver fibrosis effects. However, studies of curcumol pharmacokinetics and tissue distribution are currently lacking. This study aims to characterize the pharmacokinetics, tissue distribution, and protein binding rate of curcumol. Methods: Pharmacokinetics properties of curcumol were investigated afte doses of 10, 40, and 80 mg/kg of curcumol for rats and a single dose of 2.0 mg/kg curcumol was given to rats via intravenous administration to investigate bioavailability. Tissue distribution was investigated after a single dose of 40 mg/kg of orally administered curcumol. Plasma protein binding of curcumol was studied in vitro via the rapid equilibrium dialysis system. Bound and unbound curcumol in rat plasma were analyzed to calculate the plasma protein binding rate. A UHPLC-MS/MS method was developed and validated to determine curcumol in rat plasma and tissues and applied to study the pharmacokinetics, tissue distribution, and plasma protein binding in rats. Results: After oral administration of 10, 40, and 80 mg/kg curcumol, results indicated a rapid absorption and quick elimination of curcumol in rats. The bioavailability ranging from 9.2% to 13.1% was calculated based on the area under the curves (AUC) of oral and intravenous administration of curcumol. During tissue distribution, most organs observed a maximum concentration of curcumol within 0.5-1.0 h. A high accumulation of curcumol was found in the small intestine, colon, liver, and kidney. Moreover, high protein binding rates ranging from 85.6% to 93.4% of curcumol were observed in rat plasma. Conclusion: This study characterized the pharmacokinetics, tissue distribution, and protein binding rates of curcumol in rats for the first time, which can provide a solid foundation for research into the mechanisms of curcumol's biological function and clinical application.

An Efficient UPLC-MS/MS Method for the Determination of Pyrroloquinoline Quinone in Rat Plasma and Its Application to a Toxicokinetic Study.

Pyrroloquinoline quinone (PQQ) is a powerful antioxidant coenzyme existing in diet, benefiting growth, development, cognition function, and the repair of damaged organs. However, a method for detecting PQQ in vivo was rarely described, limiting the research on the bioanalysis and metabolic properties of PQQ. In this study, a novel, simple, and efficient ultra-high performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to quantify the concentration of PQQ in rat plasma. Detection through mass spectrometry was operated by multiple reaction monitoring (MRM) in negative electrospray ionization mode with ion transitions m/z 328.99→197.05 for PQQ and m/z 280.04→195.04 for the internal standard. The calibration curves were linear up to 10,000 ng/mL, with a lower limit of quantitation of 10 ng/mL. Inter-run and intra-run precision ranged from 1.79% to 10.73% and accuracy ranged from -7.73% to 7.30%. The method was successfully applied to a toxicokinetic study in Sprague-Dawley rats after the oral administration of PQQ disodium salt at doses of 250 mg/kg, 500 mg/kg, and 1000 mg/kg. The toxicokinetic parameters were subsequently analyzed, which may provide valuable references for the toxicokinetic properties and safety evaluation of PQQ.

Laparoscopic vs. open anatomical hepatectomy for intrahepatic cholangiocarcinoma: A retrospective cohort study.

Background: Intrahepatic cholangiocarcinoma is a highly malignant and invasive cancer originating from biliary epithelial cells. The current study was designed to evaluate the feasibility, safety, and clinical outcomes of laparoscopic anatomical hepatectomy in patients with intrahepatic cholangiocarcinoma. Methods: After screening, 95 patients who underwent anatomical hepatectomy for intrahepatic cholangiocarcinoma at our center were enrolled and divided into two groups according to the surgical approach; the baseline characteristics, pathological findings, surgical outcomes, and long-term outcomes were compared. Moreover, univariate and multivariate analyses were performed to identify independent prognostic factors for overall survival (OS) and disease-free survival (DFS). Results: There were no significant differences in baseline characteristics or pathological findings between the two groups. Regarding short-term outcomes, the intraoperative blood loss, incision length, and length of postoperative hospital stay were more favorable in the laparoscopic anatomical hepatectomy group than the open anatomical hepatectomy group (P < 0.05). The two groups differed significantly in the extent of liver resection, with a lower lymph node dissection rate and lymph node yield in the laparoscopic anatomical hepatectomy group (P < 0.05). Furthermore, the postoperative complication rate was similar in the two groups (P > 0.05). The median postoperative follow-up times were 10.7 and 13.8 months in the laparoscopic anatomical hepatectomy and open anatomical hepatectomy groups, respectively. Regarding the long-term follow-up results, OS and DFS were similar in the two groups (P > 0.05). On multivariate analysis, the independent prognostic factors for OS were CA-199, CEA, HGB, tumor diameter, and T stage, and those for DFS were CA-199 (P < 0.05), and T stage (P < 0.05). Conclusion: laparoscopic anatomical hepatectomy for intrahepatic cholangiocarcinoma is safe and feasible when performed by experienced surgeons. Compared with open anatomical hepatectomy, laparoscopic anatomical hepatectomy provides better short-term outcomes and a comparable long-term prognosis.

The phytochemical properties, pharmacological effects and traditional uses of Actinidia eriantha Benth.: A review.

Actinidia eriantha Benth. (Called Maohuamihoutao in China) is a plant that has been utilized as a heat-clearing drug in She ethnic minority group for a long time in China. Specifically, it has been involved in the treatment of stomach cancer, colon cancer, cirrhosis with ascites, chronic hepatitis, leukemia, rectal prolapse, hernia and uterine prolapse. Pharmacological research provides partial evidence for the traditional use of A. eriantha and might have demonstrated the folk utilization of A. eriantha to combat many cancers. Crude extracts and relatively pure components of A. eriantha possess a variety of pharmacological activities, including anti-cancer, immunoregulatory, anti-angiogenic, neuroprotective, anti-inflammatory, and antioxidant activities. In addition, over 104 chemical substances have been determined from A. eriantha, involving terpenoids, alcohols, phenolics, aldehydes, organic acids, flavonoids glycosides, ketones, and glucoside. The existing literature reveals that a large proportion of the therapeutic effects of A. eriantha were rendered by the polysaccharides. However, the mechanisms of action and the structure-function correlations of these compounds, as well as the synergistic and antagonistic effects between them, need to be investigated further. Therefore, we propose that future studies on A. eriantha should focus on comprehensively assessing its medicinal quality, exploring its multi-target nature using network pharmacology approaches, and evaluating its long-term toxicity and efficacy in vivo.

Effects of body mass index and serum albumin on overall survival in patients with cancer undergoing pancreaticoduodenectomy: a single-center retrospective cohort study.

OBJECTIVES: We aimed to explore whether body mass index (BMI) and albumin were associated with overall survival (OS) in individuals who underwent pancreaticoduodenectomy (PD) for cancer. METHODS: Three-hundred twenty-nine consecutive patients who underwent PD for cancer were enrolled from January 2020 to December 2020. All clinicopathological information was extracted based on medical records. The survival follow-ups were regularly performed and ended on June 30, 2021. The Kaplan-Meier survival analysis and univariate and multivariate Cox proportional-hazards models were used to assess the association of BMI and albumin with OS. RESULTS: Of the 329 patients, 186 (56.5%) were male, and median age at admission was 65.0 (56.0-71.0) years. There were 258 patients (78.4%) with BMI < 25.0 kg/m2 and 89 patients (27.05%) with albumin < 35.0 g/L respectively. In overall cohort, BMI < 25.0 kg/m2 was associated with OS (adjusted HR = 3.516, 95% CI = 1.076-11.492, P = 0.037). In contrast, albumin < 35.0 g/L did not affect OS. Subgroup analysis showed, in patients with pancreas lesion, BMI < 25.0 kg/m2 had a higher risk for OS compared to BMI ≥ 25.0 kg/m2 (adjusted HR = 3.209, 95% CI = 0.985-10.451, P = 0.048), while albumin < 35.0 g/L was not linked to OS. In patients with lesion in ampulla of Vater, duodenum, or common bile duct, there was no significant association of BMI and albumin with OS. CONCLUSIONS: BMI, rather than serum albumin, was associated with OS in patients who underwent PD for cancer.

RecQ mediated genome instability 2 (RMI2): a potential prognostic and immunological biomarker for pan-cancers.

BACKGROUND: RecQ mediated genome instability 2 (RMI2) is an essential component of the BLM-TopoIIIa-RMI1-RMI2 (BTR) complex. However, the mysterious veil of the potential immunological relationship of RMI2 in tumorigenesis and development has not been revealed. METHODS: We conducted the differential expression (DE) analysis of the RMI2 in pan-cancer using data onto Oncomine, TIMER, and GEPIA databases. Afterward, survival analysis and clinical-stage correlation analysis were performed via the TCGA database. Subsequently, we used R software to further explore the relationship between the expression level of RMI2 and tumor mutation burden (TMB), microsatellite instability (MSI), tumor microenvironment (TME), tumor immune-infiltrated cells (TILs), immune checkpoints (ICP), mismatch repairs (MMRs) -related genes, m6A-related genes, DNA methylation-related genes. Finally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional networks were also performed for annotation via gene set enrichment analysis (GSEA). RESULTS: The RMI2 expressed remarkably high in most cancer types compared to cancer adjacent normal tissues (P < 0.05). High expression of RMI2 was linked to unfavorable prognosis and advanced stage of disease, especially in LIHC and PAAD. RMI2 expression was related to TMB in 16 cancer types and MSI in 8 cancer types. Furthermore, it is significant positive correlations between RMI2 and stromal and immune cells, ICP-related genes, MMRs-related genes, m6A-related genes, and DNA methylation-related genes. Finally, GSEA analysis revealed that RMI2 was engaged in a variety of signaling pathways in pan-cancers. CONCLUSIONS: RMI2 may serve as a potential biological target and probably assume a crucial part in tumorigenesis and progression.

An immune subtype-related prognostic signature of hepatocellular carcinoma based on single-cell sequencing analysis.

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world and is often associated with a poor prognosis. The main reason for this poor prognosis is that inconspicuous early symptoms lead to delayed diagnosis. Treatment options for advanced HCC remain limited and ineffective. In this context, the exploration of the immune microenvironment in HCC becomes attractive. In this study, we divided HCC into immune cell and non-immune cell subtypes, by single-cell sequencing analysis of GEO dataset GSE146115. We found differentially expressed genes in the two subtypes, which we used to construct a prognostic model for HCC through Cox and Lasso regressions. Our prognostic model can accurately evaluate the prognosis of HCC patients, and provide a reference for the design of immunotherapy for HCC.

Current status and influencing factors of care burden of pancreatic cancer caregivers under COVID-19.

Objective: To explore the level of care burden and its influencing factors of caregivers of pancreatic cancer patients during hospitalization under the background of COVID-19. Methods: From September 2021 to December 2021, in Jiangsu Province Hospital, the convenience sampling method was used to investigate the care burden level of family caregivers of pancreatic cancer patients, and univariate and multivariate analysis methods were used to analyze the influencing factors. The survey tools included the General Information Questionnaire, the Family Caregiver Care Burden Scale, the Hospital Anxiety and Depression Scale, the Benefit Discovery Rating Scale, and the General Self-Efficacy Scale. Results: A total of 100 subjects were included in this study, of which 45% were male and 55% were older than 50 years. In the Context of COVID-19, the care burden of caregivers of pancreatic cancer patients was at a mild level, and the main influencing factors were family economic status (p < 0.001), anxiety and depression level (p < 0.001) and self-efficacy (p < 0.001). Conclusion: Medical staff should pay attention to the caregivers of pancreatic cancer with a heavy family burden, and pay attention to their anxiety and depression, and take corresponding measures to improve the self-efficacy of the caregivers, so as to reduce the care burden.

Restoration of Proresolution Pathway with Exogenous Resolvin D1 Prevents Sevoflurane-Induced Cognitive Decline by Attenuating Neuroinflammation in the Hippocampus in Rats with Type 2 Diabetes Mellitus.

Sevoflurane (SEV), a commonly used volatile anesthetic, has been shown to cause cognitive decline in diabetic rats by aggregating neuroinflammation in the hippocampus, but the underlying mechanisms are unknown. Recent evidence suggests that neuroinflammation could be a consequence of failure to resolve inflammation by specialized pro-resolving lipid mediators including resolvin D1 (RvD1). Here we first examined whether type 2 diabetes mellitus (DM) alters RvD1 proresolution pathway. Diabetic Goto-Kakizaki (GK) rats and non-diabetic Wistar rats received control or 2.6% SEV exposure for 4 h. Seven days after exposure, GK control rats, compared with Wistar control rats, had significantly lower RvD1 levels in plasma and CSF and decreased RvD1 receptor FPR2 expression in the hippocampus. SEV increased RvD1 levels in plasma and CSF and FPR2 expression in the hippocampus in Wistar rats but not in GK rats. We next examined whether RvD1 treatment of GK rats can prevent SEV-induced neuroinflammation and cognitive decline. GK rats received control, SEV or SEV and once-daily treatment with exogenous RvD1 (0.2 ug/kg, ip) for 7 days. RvD1 administration markedly increased RvD1 levels in plasma and CSF and FPR2 expression in the hippocampus in GK rats received SEV. Compared with GK control rats, GK rats received SEV exhibited shorter freezing times in trace fear conditioning task, which was accompanied by increased microglia activity and pro-inflammatory cytokine expression in the hippocampus. RvD1 administration attenuated SEV-induced increases in microglia activity and pro-inflammatory cytokine expression in the hippocampus, preventing cognitive decline in GK rats. Notably, neither SEV nor RvD1 altered metabolic parameters in GK rats. The results suggest that RvD1 proresolution pathway is impaired in the brain of diabetic GK rats. which may enhance the susceptibility to SEV, contributing to neuroinflammation and cognitive decline. Restoration of RvD1 proresolution pathway in diabetic GK rats with exogenous RvD1 can prevent SEV-induced cognitive decline by attenuating neuroinflammation in the hippocampus.

Comparative Pharmacokinetic Study of Forchlorfenuron in Adult and Juvenile Rats.

Forchlorfenuron (CPPU) is a plant growth regulator extensively used in agriculture. However, studies on CPPU pharmacokinetics are lacking. We established and validated a rapid, sensitive, and accurate liquid chromatography-mass spectrometry method for CPPU detection in rat plasma. CPPU pharmacokinetics was evaluated in adult and juvenile rats orally treated with 10, 30, and 90 mg/kg of the compound. The area under the plasma drug concentration-time curve from 0 to 24 h (AUC), at the final time point sampled (AUC0-t), and the maximum drug concentration of CPPU increased in a dose-dependent manner. The pharmacokinetic parameters AUC0-t and absolute bioavailability were higher in the juvenile rats than in adult rats. The mean residence time and AUC0-t of juvenile rats in the gavage groups, except for the 10 mg/kg dose, were significantly higher in comparison to those observed for adult rats (p < 0.001). The plasma clearance of CPPU in juvenile rats was slightly lower than that in the adult rats. Taken together, juvenile rats were more sensitive to CPPU than adult rats, which indicates potential safety risks of CPPU in minors.

Bioreducible, arginine-rich polydisulfide-based siRNA nanocomplexes with excellent tumor penetration for efficient gene silencing.

RNA interference (RNAi) technology has great potential in cancer therapy, e.g., small interfering RNA (siRNA) can be exploited to silence specific oncogenes related to tumor growth and progression. However, it is critical to achieve high transfection efficiency while reducing cytotoxicity. In this paper, we report an siRNA delivery strategy targeting the oncogene KRAS based on arginine-modified poly(disulfide amine)/siRNA nanocomplexes. The poly(disulfide amine) is synthesized via aza-Michael polyaddition followed by the introduction of arginine groups onto its backbone to afford poly((N,N'-bis(acryloyl)cystamine-co-ethylenediamine)-g-Nω-p-tosyl-l-arginine) (PBR) polycations. Thus multiple interactions including electrostatic interaction, hydrogen bonding and a hydrophobic effect are introduced simultaneously between PBR and siRNA or cell membranes to improve transfection efficiency. By optimizing the grafting density of arginine groups, PBR/siRNA nanocomplexes achieve high cellular uptake efficiency, successful endosomal/lysosomal escape, and rapid biodegradation in the presence of high GSH concentration in the cytoplasm, and finally release siRNA to activate the RNAi mechanism. Additionally, compared to commercially available PEI 25K, PBR/siRNA nanocomplexes possess a significantly increased gene silencing effect on human pancreatic cancer cells (PANC-1) with decreased cytotoxicity and enhanced tumor penetration ability in PANC-1 multicellular spheroids in vitro. Overall, with both GSH-responsiveness and excellent tumor penetration, this safe and efficient poly(disulfide amine)-based siRNA delivery system is expected to provide a new strategy for gene therapy of pancreatic cancer and other stromal-rich tumors.

Recent progress on charge-reversal polymeric nanocarriers for cancer treatments.

Nanocarriers (NCs) for delivery anticancer therapeutics have been under development for decades. Although great progress has been achieved, the clinic translation is still in the infancy. The key challenge lies in the biological barriers which lie between the NCs and the target spots, including blood circulation, tumor penetration, cellular uptake, endo-/lysosomal escape, intracellular therapeutics release and organelle targeting. Each barrier has its own distinctive microenvironment and requires different surface charge. To address this challenge, charge-reversal polymeric NCs have been a hot topic, which are capable of overcoming each delivery barrier, by reversing their charges in response to certain biological stimuli in the tumor microenvironment. In this review, the triggering mechanisms of charge reversal, including pH, enzyme and redox approaches are summarized. Then the corresponding design principles of charge-reversal NCs for each delivery barrier are discussed. More importantly, the limitations and future prospects of charge-reversal NCs in clinical applications are proposed.