Effect of perioperative chemotherapy on resection of isolated pulmonary metastases from colorectal cancer: A single center experience.

BACKGROUND: Numerous studies have assessed surgical resection as a standard treatment option for patients with colorectal cancer (CRC) and resectable pulmonary metastases (PM). However, the role of perioperative chemotherapy after complete resection of isolated PM from patients with CRC patients remains controversial. We hypothesize that perioperative chemotherapy does not provide significant survival benefits for patients undergoing resection of PM from CRC. AIM: To determine whether perioperative chemotherapy affects survival after radical resection of isolated PM from CRC. METHODS: We retrospectively collected demographic, clinical, and pathologic data on patients who underwent radical surgery for isolated PM from CRC. Cancer-specific survival (CSS) and disease-free survival were calculated using Kaplan-Meier analysis. Inter-group differences were compared using the log-rank test. For multivariate analysis, Cox regression was utilized when indicated. RESULTS: This study included 120 patients with a median age of 61.6 years. The 5-year CSS rate was 78.2%, with 36.7% experiencing recurrence. Surgical resection for isolated PM resulted in a 5-year CSS rate of 50.0% for second metastases. Perioperative chemotherapy (P = 0.079) did not enhance survival post-resection. Factors associated with improved survival included fewer metastatic lesions [hazard ratio (HR): 2.51, P = 0.045], longer disease-free intervals (HR: 0.35, P = 0.016), and wedge lung resections (HR: 0.42, P = 0.035). Multiple PM predicted higher recurrence risk (HR: 2.22, P = 0.022). The log-rank test showed no significant difference in CSS between single and repeated metastasectomy (P = 0.92). CONCLUSION: Perioperative chemotherapy shows no survival benefit post-PM resection in CRC. Disease-free intervals and fewer metastatic lesions predict better survival. Repeated metastasectomy is warranted for eligible patients.

The establishment and severity assessment of ultrasound-guided prenatal bronchopulmonary dysplasia model in rat.

To study a new method for establishing animal models of prenatal bronchopulmonary dysplasia (BPD), we used lung ultrasound score (LUS) to semi-quantitatively assess the severity of lung lesions in model rats. Lipopolysaccharide (LPS) was injected into the right lung of the fetus of the rat under ultrasound-guided, and the right lung of the neonates were scanning for LUS. Specimens were collected for pathological scoring and detection of pulmonary surfactant-associated glycoprotein (SP)-C and vascular endothelial growth factor (VEGF) expression quantity. The correlation between LUS and pathological scores was analyzed. (1) The animal models were consistent with the pathological manifestations of BPD. (2) It showed a strong positive correlation between LUS and pathological scores in animal models (r = 0.84, P < 0.005), and the expression quantity of SP-C and VEGF in lung tissue were decreased (both P < 0.05). Animal models established by ultrasound-guided puncture of the lung of rats and injection of LPS were consistent with the manifestation of BPD. This method could be used to establish animal models of BPD before birth, and the severity of BPD could be assessed by using LUS.

Pre-electroacupuncture Ameliorates Cerebral Ischemia-reperfusion Injury by Inhibiting Microglial RhoA/pyrin/GSDMD Signaling Pathway.

Cerebral ischemia reperfusion injury is a severe neurological impairment that occurs after blood flow reconstruction in stroke, and microglia cell pyroptosis is one of its important mechanisms. Electroacupuncture has been shown to be effective in mitigating and alleviating cerebral ischemia reperfusion injury by inhibiting neuroinflammation, reducing cellular pyroptosis, and improving neurological function. In this experiment, we divided the rats into three groups, including the sham operation (Sham) group, the middle cerebral artery occlusion/reperfusion (MCAO/R) group, and the pre-electroacupuncture (EAC) group. Pre-electroacupuncture group was stimulated with electroacupuncture of a certain intensity on the Baihui (GV 20) and Dazhui (GV 14) of the rat once a day from the 7th day to the 1st day before the MCAO/R operation. The extent of cerebral infarction was detected by TTC staining. A modified Zea-Longa five-point scale scoring system was used to determine neurologic function in MCAO rats. The number of neurons and morphological changes were accessed by Nissl staining and HE staining. The cellular damage was detected by TUNEL staining. In addition, the expression levels of RhoA, pyrin, GSDMD, Caspase1, cleaved-Caspase1, Iba-1, CD206, and ROCK2 were examined by western blotting and immunofluorescence. The results found that pre-electroacupuncture significantly attenuated neurological impairment and cerebral infarction compared to the post-MCAO/R rats. In addition, pre-electroacupuncture therapy promoted polarization of microglia to the neuroprotective (M2) phenotype. In addition, pre-electroacupuncture inhibited microglia pyroptosis by inhibiting RhoA/pyrin/GSDMD signaling pathway, thereby reducing neuronal injury and increasing neuronal survival in the MCAO/R rats. Taken together, these results demonstrated that pre-acupuncture could attenuate cerebral ischemia-reperfusion injury by inhibiting microglial pyroptosis. Therefore, pre-electroacupuncture might be a potential preventive strategy for ischemic stroke patients.

Metformin improves cognitive dysfunction through SIRT1/NLRP3 pathway-mediated neuroinflammation in db/db mice.

Diabetes mellitus (DM), an important public health problem, aggravates the global economic burden. Diabetic encephalopathy (DE) is a serious complication of DM in the central nervous system. Metformin has been proven to improve DE. However, the mechanism is still unclear. In this study, the db/db mice, a common model used for DE, were employed to explore and study the neuroprotective effect of metformin and related mechanisms. Behavioral tests indicated that metformin (100 or 200 mg/kg/day) could significantly improve the learning and memory abilities of db/db mice. The outcomes from the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) demonstrate that metformin effectively modulates glucose and insulin signaling pathways in db/db mice. The results of body weight and blood lipid panel (total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol) show that metformin promotes the level of lipid metabolism in db/db mice. Furthermore, data from oxidative stress assays, which measured levels of malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase, suggest that metformin suppresses oxidative stress-induced brain damage in db/db mice. In addition, western blot, Nissl staining, and immunofluorescence results showed that metformin increased the expressions of nerve growth factor and postsynaptic density 95 and repaired neuronal structural damage. For the mechanism study, metformin activated SIRT1 and inhibited the expression of NLRP3 inflammasome (NLRP3, ASC, caspase-1, IL-1ß, and IL-18) and inflammatory cytokines (TNFα and IL-6). In conclusion, metformin could ameliorate cognitive dysfunction through the SIRT1/NLRP3 pathway, which might be a promising mechanism for DE treatment.

Melatonin attenuates scopolamine-induced cognitive dysfunction through SIRT1/IRE1α/XBP1 pathway.

BACKGROUND: The prevalence of dementia around the world is increasing, and these patients are more likely to have cognitive impairments, mood and anxiety disorders (depression, anxiety, and panic disorder), and attention deficit disorders over their lifetime. Previous studies have proven that melatonin could improve memory loss, but its specific mechanism is still confused. METHODS: In this study, we used in vivo and in vitro models to examine the neuroprotective effect of melatonin on scopolamine (SCOP)-induced cognitive dysfunction. The behavioral tests were performed. 18F-FDG PET imaging was used to assess the metabolism of the brain. Protein expressions were determined through kit detection, Western blot, and immunofluorescence. Nissl staining was conducted to reflect neurodegeneration. MTT assay and RNAi transfection were applied to perform the in vitro experiments. RESULTS: We found that melatonin could ameliorate SCOP-induced cognitive dysfunction and relieve anxious-like behaviors or HT22 cell damage. 18F-FDG PET-CT results showed that melatonin could improve cerebral glucose uptake in SCOP-treated mice. Melatonin restored the cholinergic function, increased the expressions of neurotrophic factors, and ameliorated oxidative stress in the brain of SCOP-treated mice. In addition, melatonin upregulated the expression of silent information regulator 1 (SIRT1), which further relieved endoplasmic reticulum (ER) stress by decreasing the expression of phosphorylate inositol-requiring enzyme (p-IRE1α) and its downstream, X-box binding protein 1 (XBP1). CONCLUSIONS: These results indicated that melatonin could ameliorate SCOP-induced cognitive dysfunction through the SIRT1/IRE1α/XBP1 pathway. SIRT1 might be the critical target of melatonin in the treatment of dementia.

Taohong Siwu decoction alleviates cognitive impairment by suppressing endoplasmic reticulum stress and apoptosis signaling pathway in vascular dementia rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Taohong Siwu Decoction (TSD), a classic traditional Chinese medicine formula, is used for the treatment of vascular diseases, including vascular dementia (VD). However, the mechanisms remain unclear. AIM OF STUDY: This study aimed to investigate whether TSD has a positive effect on cognitive impairment in VD rats and to confirm that the mechanism of action is related to the Endoplasmic Reticulum stress (ERs) and cell apoptosis signaling pathway. MATERIALS AND METHODS: A total of 40 male adult Sprague-Dawley rats were divided into four groups: sham-operated group (Sham), the two-vessel occlusion group (2VO), the 2VO treated with 4.5 g/kg/d TSD group (2VO + TSD-L), the 2VO treated with 13.5 g/kg/d TSD group (2VO + TSD-H). The rats underwent either 2VO surgery or sham surgery. Postoperative TSD treatment was given for 4 consecutive weeks. Behavioral tests were initiated at the end of gastrulation. Open-field test (OFT) was used to detect the activity level. The New Object Recognition test (NOR) was used to test long-term memory. The Morris water maze (MWM) test was used to examine the foundation of spatial learning and memory. As a final step, the hippocampus was taken for molecular testing. The protein levels of GRP78 (Bip), p-PERK, PERK, IRE1α, p-IRE1α, ATF6, eIF2α, p-eIF2α, ATF4, XBP1, Bcl-2 and Bax were determined by Western blot. Immunofluorescence visualizes molecular expression. RESULTS: In the OFT, residence time in the central area was significantly longer in both TSD treatment groups compared to the 2VO group. In the NOR, the recognition index was obviously elevated in both TSD treatment groups. The 2VO group had a significantly longer escape latency and fewer times in crossing the location of the platform compared with the Sham group in MWM. TSD treatment reversed this notion. Pathologically, staining observations confirmed that TSD inhibited hippocampal neuronal loss and alleviated the abnormal reduction of the Nissl body. In parallel, TUNEL staining illustrated that TSD decelerated neuronal apoptosis. Western Blot demonstrated that TSD reduces the expression of ERs and apoptotic proteins. CONCLUSION: In this study, the significant ameliorative effect on cognitive impairment of TSD has been determined by comparing the behavioral data of the 4 groups of rats. Furthermore, it was confirmed that this effect of TSD was achieved by suppressing the ERs-mediated apoptosis signaling pathway.

Ethanol extract of Evodia lepta Merr. ameliorates cognitive impairment through inhibiting NLRP3 inflammasome in scopolamine-treated mice.

Evodia lepta Merr. (Evodia lepta) is a well-known traditional Chinese medicine, which has been widely used in herbal tea. We previously reported that the coumarin compounds from the root of Evodia lepta exhibited neuroprotective effects. However, whether Evodia lepta could inhibit NLRP3 inflammasome in dementia was still unknown. In this study, the components of the Evodia lepta extract were identified by HPLC-Q-TOF HRMS. We employed a scopolamine-treated mouse model. Evodia lepta extract (10 or 20 mg/kg) and donepezil were treated by gavage once a day for 14 consecutive days. Following the behavioral tests, oxidative stress levels were measured. Then, Western blot and immunofluorescence analysis were used to evaluate the expressions of NLRP3 inflammasome. 14 major components of the Evodia lepta extract were identified by HPLC-Q-TOF HRMS. The results of Morris water maze, object recognition task and open field test indicated that Evodia lepta extract could ameliorate cognitive impairment in scopolamine-treated mice. Evodia lepta extract improved cholinergic system. Moreover, Evodia lepta extract improved the expressions of PSD95 and BDNF. Evodia lepta extract suppressed neuronal oxidative stress and apoptosis. In addition, Evodia lepta extract inhibited NLRP3 inflammasome in the hippocampus of scopolamine-treated mice. Evodia lepta extract could protect against cognitive impairment by inhibiting NLRP3 inflammasome in scopolamine-treated mice.

Evaluation of extravascular lung water and cardiac function in normal vaginal delivery by intrapartum bedside ultrasound.

BACKGROUND: Healthy parturients may experience pulmonary edema and disturbed cardiac function during labor. We aimed to evaluate the extravascular lung water (EVLW), intravascular volume, and cardiac function of normal parturients during spontaneous vaginal delivery by bedside ultrasound. And to explore the correlation between EVLW and intravascular volume, cardiac function. METHODS: This was a prospective observational study including 30 singleton-term pregnant women undergoing spontaneous vaginal delivery. Bedside ultrasound was performed at the early labor, the end of the second stage of labor, 2 and 24 h postpartum, and 120 scanning results were recorded. EVLW was evaluated by the echo comet score (ECS) obtained by the 28-rib interspaces technique. Inferior vena cava collapsibility index (IVC-CI), left ventricle ejection fraction, right ventricle fractional area change, left and right ventricular E/A ratio, and left and right ventricular index of myocardial performance (LIMP and RIMP) were measured. Measurements among different time points were compared, and the correlations between ECS and other measurements were analyzed. RESULTS: During the spontaneous vaginal delivery of healthy pregnant women, 2 had a mild EVLW increase at the early labor, 8 at the end of the second stage of labor, 13 at 2 h postpartum, and 4 at 24 h postpartum (P < 0.001). From the early labor to 24 h postpartum, ECS first increased and then decreased, reaching its peak at 2 h postpartum (P < 0.001). IVC-CI first decreased and then increased, reaching its minimum at the end of the second stage of labor (P < 0.001). RIMP exceeded the cut-off value of 0.43 at the end of the second stage of labor. ECS was weakly correlated with IVC-CI (r=-0.373, P < 0.001), LIMP (r = 0.298, P = 0.022) and RIMP (r = 0.211, P = 0.021). CONCLUSIONS: During spontaneous vaginal delivery, the most vital period of perinatal care is between the end of the second stage of labor and 2 h postpartum, because the risk of pulmonary edema is higher and the right ventricle function may decline. IVC-CI can be used to evaluate maternal intravascular volume. The increase in EVLW may be related to the increase in intravascular volume and the decrease in ventricular function.

Tanshinone IIA, the key compound in Salvia miltiorrhiza, improves cognitive impairment by upregulating Aß-degrading enzymes in APP/PS1 mice.

In Alzheimer's disease (AD), amyloid-beta (Aß) plays a crucial role in pathogenesis. Clearing Aß from the brain is considered as a key therapeutic strategy. Previous studies indicated that Salvia miltiorrhiza (Danshen) could protect against AD. However, the main anti-AD components in Danshen and their specific mechanisms are not clear. In this study, pharmacological network analysis indicated that Tanshinone IIA (Tan IIA) was identified as the key active compound in Danshen contributing to protect against AD. Then, APP/PS1 double transgenic mice were employed to examine the neuroprotective effect of Tan IIA. APP/PS1 mice (age, 6 months) were administered (10 and 20 mg/kg) for 8 weeks. Tan IIA improved learning and anxiety behaviors in APP/PS1 mice. Furthermore, Tan IIA reduced oxidative stress, inhibited neuronal apoptosis, improved cholinergic nervous system and decreased endoplasmic reticulum stress in the brain of APP/PS1 mice. Moreover, Tan IIA treatment reduced the level of Aß. Molecular docking result showed that Tan IIA might block AD by upregulating Aß-degrading enzymes. Western blot results confirmed that the expressions of insulin degrading enzymes (IDE) and neprilysin (NEP) were significantly increased after Tan IIA treatment, which demonstrated that Tan IIA improved AD by increasing Aß-degrading enzymes.

The Right Ventricular Fetal Tricuspid Annular Plane Systolic Excursion Index Is a New Index for Evaluating Fetal Cardiac Function of Gestational Hypertension.

ABSTRACT: The right ventricular fetal tricuspid annular plane systolic excursion index (FTI) can be used to evaluate right ventricular systolic function. The purpose of this study was to establish the reference range of the FTI in normal fetuses and evaluate its diagnostic value in hypertensive disorders during pregnancy. In this prospective observational study, the right ventricular FTI was measured in 208 normal single-gestation fetuses between 20 and 40 weeks. With the increase in gestational age, the right ventricular FTI did not significantly fluctuate. With the increase in the severity of HDCP, the right ventricular FTI decreased gradually. Compared with the normal group, the low right ventricular FTI group had a higher incidence of premature delivery and emergency delivery due to continuous abnormal fetal heart monitoring, but there were no significant differences in low birth weight, new born Apgar score less than 7 in 5 minutes, or admission to the neonatal intensive care unit. The FTI of the right ventricle of normal fetuses is relatively constant at different gestational weeks. The right ventricular FTI can be used to evaluate fetal cardiac function changes in pregnant women with HDCP.

Phloroglucinol derivatives, coumarins and an alkaloid from the roots of Evodia lepta Merr.

Two previously undescribed phloroglucinol derivatives [(±) evolephloroglucinols A and B], five unusual coumarins [evolecoumarins A and B and (±) evolecoumarins C-E], and one novel enantiomeric quinoline-type alkaloid [(±) evolealkaloid A], along with 20 known compounds, were isolated from the EtOH extract of the roots of Evodia lepta Merr. Their structures were elucidated by extensive spectroscopic analyses. The absolute configurations of the undescribed compounds were determined by X-ray diffraction or computational calculations. Their anti-neuroinflammatory effects were assayed. Among the identified compounds, compound 5a effectively reduced nitric oxide (NO) production with an EC50 value of 22.08 ± 0.46 µM. Hence, it could indeed inhibit the lipopolysaccharide (LPS)-induced Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome.

Fingerprint of parity anomaly for localized magnetic states in quantum anomalous Hall systems.

We investigate the local magnetic states of impurities in quantum anomalous Hall (QAH) systems and observe that with an increasing band gap, the magnetic region of impurities expands in the QAH phase, while it contracts in the ordinary insulator (OI) phase. During the transition between the QAH and the OI phase, the magnetization area undergoes a significant transformation from a broad region to a narrow strip, which serves as a distinctive characteristic of the parity anomaly in the localized magnetic states. Furthermore, the presence of the parity anomaly leads to notable alterations in the dependence of the magnetic moment and magnetic susceptibility on the Fermi energy. Additionally, we analyze the spectral function of the magnetic impurity as a function of Fermi energy for both the QAH and OI phases.

Huang-Lian-Jie-Du decoction alleviates depressive-like behaviors in dextran sulfate sodium-induced colitis mice via Trem2/Dap12 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Huang-Lian-Jie-Du decoction (HLJD), a traditional Chinese medicine prescription, has been implicated as effective in treating colitis, depression and inflammation-related diseases. Whether HLJD decoction could ameliorate colitis-induced depression was still unknown and the underlying mechanism was needed to be clarified. AIM OF THE STUDY: Our study aimed to explore the effect and the underlying mechanism of HLJD treatment on colitis-induced depression and the involvement of the inflammatory factors and microglial-activated related genes. MATERIALS AND METHODS: The chronic colitis model was established by treating male mice with 1% dextran sulfate sodium (DSS) for 8 weeks. One week after DSS-treated, HLJD decoction was administered orally with 2 and 4 g/kg daily for 7 weeks. Behavior tests (Open field/Elevated plus maze/Novel object recognition) and TUNEL staining were then assessed. The expression of inflammatory-related genes and microglial dysregulation were measured by RT-PCR and the expression of Trem2, Danp12 and Iba1 were assessed by immunofluorescence methods. RESULTS: Depressive-like behaviors were observed in mice treated with DSS, which suffered colitis. Compared to normal control (NC-V) mice, the density of TUNEL + cells in the habenula (Hb), hippocampus (HIP), and cortex were significantly higher in colitis (DSS-V) mice, especially in Hb. Compared to NC-V and several brain regions, the expression levels of the Il-1ß, Il-10 and Dap12 mRNA were significantly increased in the lateral habenula (LHb) of colitis mice. Moreover, the expression of Trem2, Dap12 and Iba1 were increased in LHb of DSS-V mice. HLJD treatment could alleviate depressive-like behaviors, reduce the density of TUNEL + cells in Hb and the expression of Il-6, Il-10 and Dap12 mRNA in LHb of DSS-V mice. The overexpression of Trem2, Dap12 and Iba1 in LHb of DSS-V mice were reversed after HLJD treatment. CONCLUSION: These results reveal LHb is an important brain region during the process of colitis-induced depression. HLJD treatment could alleviates depressive-like behaviors in colitis mice via inhibiting the Trem2/Dap12 pathway in microglia of LHb, which would contribute to the precise treatment. It provides a potential mechanistic explanation for the effectiveness of HLJD treatment in colitis patients with depression.

Taohong siwu decoction ameliorates cognitive dysfunction through SIRT6/ER stress pathway in Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: A growing number of people suffer from Alzheimer's disease (AD), but there is currently no effective treatment yet. Taohong Siwu Decoction (TSD) has been proved to take strong neuropharmacological activity on dementia, but the effect and mechanism of TSD against AD are still elusive. AIM OF STUDY: To investigate whether TSD could be effective in ameliorating cognitive deficits through SIRT6/ER stress pathway. MATERIALS AND METHODS: Herein, the APP/PS1 mice, an AD model, and HT-22 cell lines were utilized. Different dosages of TSD (4.25, 8.50 and 17.00 g/kg/d) were administered to the mice for 10 weeks by gavage. Following the behavioral tests, oxidative stress levels were measured using malondialdehyde (MDA) and superoxide dismutase (SOD) kits. Nissl staining and Western blot analyses were used to detect the neuronal function. Then, immunofluorescence and Western blot analysis were applied to evaluate silent information regulator 6 (SIRT6) and ER Stress related protein levels in APP/PS1 mice and HT-22 cells. RESULTS: Behavioral tests revealed that APP/PS1 mice administered with TSD orally took more time in the target quadrant, crossed more times in the target quadrant, had a higher recognition coefficient, and spent more time in the central region. In addition, TSD could ameliorate oxidative stress and inhibit neuronal apoptosis in APP/PS1 mice. Furthermore, TSD could up-regulate the SIRT6 protein expression and inhibit ER sensing proteins expressions, such as p-PERK and ATF6, in APP/PS1 mice and Aß1-42-treated HT22 cells. CONCLUSION: According to the abovementioned findings, TSD could alleviate cognitive dysfunction in AD by modulating the SIRT6/ER stress pathway.

Kai-Xin-San Improves Cognitive Impairment via Wnt/ß-Catenin and IRE1/XBP1s Signalings in APP/PS1 Mice.

Alzheimer's disease (AD) is the most common type of dementia with an insidious onset and slow progression. Kai-Xin-San (KXS) has been reported to be effective in improving cognitive impairment in AD. However, the mechanism is still confused. In this study, we employed APP/PS1 mice to explore the neuroprotective mechanism of KXS. Forty-eight male APP/PS1 mice were randomly divided into model group, KXS groups (0.7, 1.4, and 2.8 g/kg/d, p.o.) and the wild-type mice were assigned to the normal control group (n = 12 in each group). Y-maze and novel object recognition tests were carried out after continuous intragastric administration for 2 months. The abilities of learning, memory, and new object recognition in the APP/PS1 mice were enhanced significantly after KXS treatment. KXS can reduce the deposition of Aß40 and Aß42 in APP/PS1 mice brain. KXS decreased the levels of serum inflammatory cytokines, tumor necrosis factor-α, interleukin-1ß, and interleukin-6. KXS increased the activities of superoxide dismutase and glutathione peroxidase significantly, whereas it inhibited the contents of reactive oxygen species and malondialdehyde significantly. In addition, we also detected Wnt/ß-catenin signaling related proteins, such as Wnt7a, ß-catenin, low-density lipoprotein receptor-related protein 6 (LRP6), glycogen synthase kinase-3ß (GSK-3ß), nuclear factor kappa-B (NF-κB), postsynaptic density 95 (PSD95), microtubule associated protein-2 (MAP-2), and endoplasmic reticulum stress (IRE1 pathway) related proteins, such as inositol-requiring enzyme 1 (IRE1), phosphorylated IRE1(p-IRE1), spliced X-box-binding protein 1 (XBP1s), immunoglobulin binding protein (BIP), and protein disulfide isomerase (PDI) in the hippocampus. Results showed that KXS decreased the expression of GSK-3ß, NF-kB, p-IRE1/IRE1 ratio, XBP1s, and BIP; increased the expression of Wnt7a, ß-catenin, LRP6, PSD95, MAP2, and PDI. In conclusion, KXS improved cognitive impairment by activating Wnt/ß-catenin signaling, inhibiting the IRE1/XBP1s pathway in APP/PS1 mice.

Comparative Study on the Pharmacokinetics of Paeoniflorin, White Peony Root Water Extract, and Taohong Siwu Decoction After Oral Administration in Rats.

BACKGROUND AND OBJECTIVE: Taohong Siwu Decoction (TSD) is a classic traditional Chinese medicine (TCM) compound with pharmacological effects such as vasodilation and hypolipidemia. Paeoniflorin (PF) is one of the active ingredients of TSD. The aim of this study was to evaluate the pharmacokinetics of PF in herbal extracts and their purified forms in rats. METHOD: A sensitive and rapid high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) method for the determination of PF in rat plasma was developed. Rats were divided into three groups, and given PF solution, water extract of white peony root (WPR), or TSD by gavage. At different predetermined timepoints after gavage, blood was collected from the orbital vein. The pharmacokinetic parameters of PF in the plasma of rats in the three groups was determined. RESULTS: The pharmacokinetic studies showed that the time to reach maximum concentration (Tmax) of PF in the purified forms group was relatively high, while the half-lives (T½) of PF in the TSD and WPR groups were longer. Among the three groups, PF in the purified forms group had the maximum area under the concentration-time curve (AUC0-t = 732.997 µg/L·h) and the largest maximum concentration (Cmax = 313.460 µg/L), which showed a significant difference compared with the TSD group (P < 0.05). Compared with the purified group, the clearance (CLz/F = 86.004 L/h/kg) and the apparent volume of distribution (Vz/F = 254.787 L/kg) of PF in the TSD group increased significantly (P < 0.05). CONCLUSIONS: A highly specific, sensitive, and rapid HPLC-MS-MS method was developed and applied for the determination of PF in rat plasma. It was found that TSD and WPR can prolong the action time of paeoniflorin in the body.

Hydroxysafflor Yellow A Exerts Neuroprotective Effect by Reducing Aß Toxicity Through Inhibiting Endoplasmic Reticulum Stress in Oxygen-Glucose Deprivation/Reperfusion Cell Model.

Ischemia stroke is thought to be one of the vascular risks associated with neurodegenerative diseases, such as Alzheimer's disease (AD). Hydroxysafflor yellow A (HSYA) has been reported to protect against stroke and AD, while the underlying mechanism remains unclear. In this study, SH-SY5Y cell model treated with oxygen-glucose deprivation/reperfusion (OGD/R) was used to explore the potential mechanism of HSYA. Results from cell counting kit-8 (CCK-8) showed that 10 µM HSYA restored the cell viability after OGD 2 hours/R 24 hours. HSYA reduced the levels of malondialdehyde and reactive oxygen species, while improved the levels of superoxide dismutase and glutathione peroxidase. Furthermore, apoptosis was inhibited, and the expression of brain-derived neurotrophic factor was improved after HSYA treatment. In addition, the expression levels of amyloid-ß peptides (Aß) and BACE1 were decreased by HSYA, as well as the expression levels of binding immunoglobulin heavy chain protein, PKR-like endoplasmic reticulum (ER) kinase pathway, and activating transcription factor 6 pathway, whereas the expression level of protein disulfide isomerase was increased. Based on these results, HSYA might reduce Aß toxicity after OGD/R by interfering with apoptosis, oxidation, and neurotrophic factors, as well as relieving ER stress.

Tanshinone IIA ameliorates Aß transendothelial transportation through SIRT1-mediated endoplasmic reticulum stress.

BACKGROUND: The disruption of blood-brain barrier (BBB), predominantly made up by brain microvascular endothelial cells (BMECs), is one of the characteristics of Alzheimer's disease (AD). Thus, improving BMEC function may be beneficial for AD treatment. Tanshinone IIA (Tan IIA) has been proved to ameliorate the cognitive dysfunction of AD. Herein, we explored how Tan IIA affected the function of BMECs in AD. METHODS: Aß1-42-treated brain-derived endothelium cells.3 (bEnd.3 cells) was employed for in vitro experiments. And we performed molecular docking and qPCR to determine the targeting molecule of Tan IIA on Sirtuins family. The APPswe/PSdE9 (APP/PS1) mice were applied to perform the in vivo experiments. Following the behavioral tests, protein expression was determined through western blot and immunofluorescence. The activities of oxidative stress-related enzymes were analyzed by biochemically kits. Nissl staining and thioflavin T staining were conducted to reflect the neurodegeneration and Aß deposition respectively. RESULTS: Molecular docking and qPCR results showed that Tan IIA mainly acted on Sirtuin1 (SIRT1) in Sirtuins family. The inhibitor of SIRT1 (EX527) was employed to further substantiate that Tan IIA could attenuate SIRT1-mediated endoplasmic reticulum stress (ER stress) in BMECs. Behavioral tests suggested that Tan IIA could improve the cognitive deficits in APP/PS1 mice. Tan IIA administration increased SIRT1 expression and alleviated ER stress in APP/PS1 mice. In addition, LRP1 expression was increased and RAGE expression was decreased after Tan IIA administration in both animals and cells. CONCLUSION: Tan IIA could promote Aß transportation by alleviating SIRT1-mediated ER stress in BMECs, which ameliorated cognitive deficits in APP/PS1 mice.

Efficacy and safety of hypoglycemic drugs in improving cognitive function in patients with Alzheimer's disease and mild cognitive impairment: A systematic review and network meta-analysis.

Objective: The purpose of this study was to compare the effects of oral hypoglycaemic drugs (HDs) on cognitive function and biomarkers of mild cognitive impairment (MCI) and Alzheimer's disease (AD) through a network meta-analysis of randomized controlled trials (RCTs). Methods: We conducted systematic searches for English- and Chinese-language articles in the PubMed, Medline, Embase, Cochrane Library and Google Scholar databases, with no date restrictions. We performed a network meta-analysis, which we report here according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The 16 studies included a total of 3,081 patients. We selected the Mini-Mental State Examination (MMSE), the Alzheimer's Disease Assessment Scale-Cognitive section (ADAS-Cog), the Alzheimer's Disease Cooperative Study Activities of Daily Living section (ADCS-ADL) and amyloid beta (Aß) 42 as the outcome measures for analysis and comparison. Result: We selected seven treatments and assessed the clinical trials in which they were tested against a placebo control. Of these treatments, intranasal insulin 20 IU (ITSN20), glucagon-like peptide-1 (GLP-1), and dipeptidyl peptidase 4 inhibitor (DPP-4) were associated with significantly improved MMSE scores (7 RCTs, 333 patients, 30≥MMSE score≥20: mild) compared with placebo [standardized mean difference (SMD) 1.11, 95% confidence interval (CI) (0.87, 1.35); SMD 0.75, 95% CI (0.04, 1.41); and SMD 4.08, 95% CI (3.39, 4.77), respectively]. Rosiglitazone 4 mg (RLZ4), rosiglitazone 10 mg (RLZ10), intranasal insulin 40 IU (ITSN40), and ITSN20 significantly decreased ADAS-Cog scores (11 RCTs, 4044 patients, 10 ≤ ADAS-Cog scores ≤ 30: mild and moderate) compared with placebo [SMD -1.40, 95% CI (-2.57, -0.23), SMD -3.02, 95% CI (-4.17, -1.86), SMD -0.92, 95% CI (-1.77, -0.08), SMD -1.88, 95% CI (-3.09, -0.66)]. Additionally, ITSN20 and ITSN40 significantly improved ADCS-ADL scores (2 RCTs, 208 patients, ADCS-ADL scale score ≤ 10: mild) compared with placebo [SMD 0.02, 95% CI (0.01, 0.03), and SMD 0.04, 95% CI (0.03, 0.05), respectively]. In the 16 included studies, the degree of AD was classified as mild or moderate. For mild cognitive impairment, DPP-4 performed best, but for mild to moderate impairment, ITSN40 had excellent performance. Conclusion: Various HDs can improve the cognitive function of MCI and AD patients. Different drug regimens brought different degrees of improvement, which may be related to their dosage, duration, and mechanism of action. Systematic review registration: www.crd.york.ac.uk/prospero.

The safety and efficacy of melatonin in the treatment of COVID-19: A systematic review and meta-analysis.

BACKGROUND: As an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the common signs of coronavirus disease 2019 (COVID-19) are respiratory symptoms, fever, cough, shortness of breath, and dyspnea, with multiple organ injuries in severe cases. Therefore, finding drugs to prevent and treat COVID-19 is urgently needed and expected by the public. Several studies suggested beneficial effects of melatonin for the relevant prevention and treatment. To explore the effect and safety of melatonin in the treatment and provide theoretical support and reference for seeking the most suitable drug for COVID-19, the meta-analysis was carried out accordingly. METHODS: It included randomized clinical trials of patients with COVID-19 treated with melatonin. Total effective rate was the primary outcome, while C-reactive protein (CRP), arterial oxygen saturation (SaO2), white blood cell count (WBC) were the secondary measures. Random-effect and fixed-effect models were used to evaluate the effect size of some indicators in this meta-analysis. RESULTS: Six eligible studies with 338 participants were included. One hundred seventy subjects were treated with melatonin adjuvant therapy and 168 subjects were assigned to the control group, with total excellent effective rate in subjects treated with melatonin [odds ratio = 3.05, 95 % confidence interval (CI) = 1.47, 6.31, P = .003]. Homogeneity was analyzed by fixed effect model (I2 = 0%). There was no significant difference in CRP between the melatonin group and the control group (weighted mean difference [WMD] = -0.36, 95% CI = -3.65, 2.92, P = .83). Significant difference was not existed in SaO2 between the melatonin treatment group and the control group (WMD = 1, 95% CI = -1.21, 3.22, P = .37). In terms of WBC, there was no significant difference between the 2 groups (WMD = -1.07, 95% CI = -2.44, 0.30, P = .13). CONCLUSIONS: The meta-analysis showed that melatonin had the beneficial effects for COVID-19 prevention and treatment as an adjunctive agent in combination with basic treatment for the treatment.