Dual function of quercetin as an MMP inhibitor and crosslinker in preventing dentin erosion and abrasion: An in situ/in vivo study.

OBJECTIVE: The aim of the present study was to evaluate the in situ/in vivo effect of quercetin on dentin erosion and abrasion. METHODS: Human dentin blocks (2 × 2 × 2 mm) were embedded and assigned to 6 groups: 75 µg/mL, 150 µg/mL and 300 µg/mL quercetin (Q75, Q150, Q300); 120 µg/mL chlorhexidine (CHX, positive control); and deionized water and ethanol (the negative controls). The specimens were treated with the respective solutions for 2 min and then subjected to in situ/in vivo erosive/abrasive challenge for 7 d as follows: in vivo erosion 4 times a day and then in vivo toothbrush abrasion after the first and last erosive challenges of each day. Dentin loss was assessed by profilometry. An additional dentin specimen was used to evaluate the penetration depth of quercetin into dentin by tracking the spatial distribution of its characteristic Raman peak. Moreover, dentin blocks (7 × 1.7 × 0.7 mm) were used to detect the impact of quercetin on dentin-derived matrix metalloproteinase (MMP) inhibition by in situ zymography, and the inhibition percentage (%) was calculated. Additionally, the potential collagen crosslinking interactions with quercetin were detected by Raman spectroscopy, and the crosslinking degree was determined with a ninhydrin assay. Fully demineralized dentin beams (0.5 × 0.5 × 10 mm) were used to evaluate the impact of quercetin on the mechanical properties of dentin collagen fibre by the ultimate micro-tensile strength test (µUTS). The data were analysed by one-way analysis of variance and Tukey's test (α = 0.05). RESULTS: Compared to the negative controls, all treatment solutions significantly reduced dentin loss. The dentin loss of Q150 and Q300 was significantly less than that of CHX (all P < 0.05). The amount of quercetin decreased with increasing dentin depth, and the maximum penetration depth was approximately 25-30 µm. In situ zymography showed that quercetin significantly inhibited the activities of dentin-derived MMPs. The inhibitory percentages of Q75 and Q150 were significantly lower than that of CHX (all P < 0.05), but no significant difference was found between Q300 and CHX (P = 0.58). The collagen crosslinking interactions with quercetin primarily involved hydrogen bonding and the degree of crosslinking increased in a concentration-dependent manner. Statistically significant increases in µUTS values were observed for demineralized dentin beams after quercetin treatment compared with those of the control treatments (all P < 0.05). SIGNIFICANCE: This study provides the first direct evidence that quercetin could penetrate approximately 25-30 µm into dentin and further prevent dentin erosion and abrasion by inhibiting dentin-derived MMP activity as well as crosslinking collagen of the demineralized organic matrix.

Danshen-Chuanxiongqin Injection attenuates cerebral ischemic stroke by inhibiting neuroinflammation via the TLR2/ TLR4-MyD88-NF-κB Pathway in tMCAO mice.

Danshen-Chuanxiongqin Injection (DCI) is a commonly used traditional Chinese medicine for the treatment of cerebral ischemic stroke in China. However, its underlying mechanisms remain completely understood. The current study was designed to explore the protective mechanisms of DCI against cerebral ischemic stroke through integrating whole-transcriptome sequencing coupled with network pharmacology analysis. First, using a mouse model of cerebral ischemic stroke by transient middle cerebral artery occlusion (tMCAO), we found that DCI (4.10 mL·kg-1) significantly alleviated cerebral ischemic infarction, neurological deficits, and the pathological injury of hippocampal and cortical neurons in mice. Next, the whole-transcriptome sequencing was performed on brain tissues. The cerebral ischemia disease (CID) network was constructed by integrating transcriptome sequencing data and cerebrovascular disease-related genes. The results showed CID network was imbalanced due to tMCAO, but a recovery regulation was observed after DCI treatment. Pathway analysis of the key genes with recovery efficiency showed that the neuroinflammation signaling pathway was highly enriched, while the TLR2/TLR4-MyD88-NF-κB pathway was predicted to be affected. Consistently, the in vivo validation experiments confirmed that DCI exhibited protective effects against cerebral ischemic stroke by inhibiting neuroinflammation via the TLR2/TLR4-MyD88-NF-κB pathway. More interestingly, DCI markedly suppressed the neutrophils infiltrated into the brain parenchyma via the choroid plexus route and showed anti-neuroinflammation effects. In conclusion, our results provide dependable evidence that inhibiting neuroinflammation via the TLR2/TLR4-MyD88-NF-κB pathway is the main mechanism of DCI against cerebral ischemic stroke in mice.

Exposure to hot temperatures during lactation in Swiss mice stunts offspring growth and decreases future reproductive performance of female offspring.

Exposure to high temperatures (heatwaves) is rapidly emerging as an important issue of climate change, in particular for female mammals during lactation. High temperatures adversely affect the ability to dissipate heat, which has negative effects on reproductive output. The cumulative effects on growth of F1 offspring after weaning, and future reproductive performance of offspring, remain uncertain. In this study, F1 mice weaned from mothers lactating at 21 and 32.5°C were housed at 21°C from day 19 until day 56 of age, during which food intake and body mass were measured. The F1 adult females that were weaned at the two temperatures were bred and then exposed to 32.5°C during lactation. Energy intake and milk output, and litter size and mass, were determined. The F1 adults weaned at 32.5°C consumed less food and had lower body mass than their counterparts weaned at 21°C. Several visceral organs or reproductive tissues were significantly lower in mass in F1 weaned at 32.5°C than at 21°C. The exposure to 32.5°C significantly decreased energy intake, milk output and litter mass in F1 adult females during lactation. The F1 adult females weaned at 32.5°C produced less milk and raised lighter pups than those previously weaned at 21°C. The data suggest that transient exposure to hot temperatures during lactation has long-lasting impacts on offspring, including stunted growth and decreases in future reproductive performance when adult. This indicates that the offspring of females previously experiencing hot temperatures have a significant fitness disadvantage.

Exposure to hot temperatures during lactation stunted offspring growth and decreased the future reproductive performance of female offspring.

Among the important aspects of climate change, exposure to high temperatures (heat waves) is rapidly emerging as an important issue, in particular for female mammals during lactation. High temperatures adversely impact ability to dissipate heat, which has negative effects on reproductive output. The cumulative effects on growth of F1 offspring after weaning and future reproductive performance of offspring remain uncertain. In this study, the F1 mice that weaned from mothers lactating at 21°C and 32.5°C were housed at 21°C from day 19 till 56 of age; during which food intake and body mass were measured. The F1 adult females that had been weaned at the two temperatures were bred and then both exposed to 32.5°C during lactation. Energy intake, milk output and litter size and mass were determined. The F1 adults weaned at 32.5°C consumed less food and had lower body mass than their counterparts weaned at 21°C. Several visceral organs or reproductive tissues were significantly lower in mass in F1 weaned at 32.5°C than at 21°C. The exposure to 32.5°C significantly decreased energy intake, milk output and litter mass in F1 adult females during lactation. The F1 adult females weaned at 32.5°C produced less milk and raised lighter pups than those previously weaned at 21°C. The data suggest that transient exposure to hot temperature during lactation has long-lasting impacts on the offspring, including stunted growth and decreases in future reproductive performance when adult. This indicates that the offspring of females previously experiencing hot temperatures have a significant fitness disadvantage.

Promoting neurogenesis in hippocampal dentate gyrus of chronic unpredictable stress-induced depressive-like rats with paeoniflorin.

Hippocampal neurogenesis plays an important role in the onset and treatment of depressive disorders. Previous studies suggest that paeoniflorin could be used as an antidepressant for treating rats subjected to chronic unpredictable stress. In this study, the effects of paeoniflorin on neurogenesis in the hippocampus dentate gyrus and potential mechanism of action are further investigated in chronic unpredictable stress-induced rat. Results suggest that paeoniflorin markedly increased both sucrose consumption and the number of 5-bromo-2-deoxyuridine-positive cells in the dentate gyrus of chronic unpredictable stress-induced rats, and the ratio of co-expressed 5-bromo-2-deoxyuridine and glial fibrillary acidic protein-positive cells, but exerted no significant effect on the ratio of co-expressed 5-bromo-2-deoxyuridine and neuronal nuclei-positive cells. Compared with the vehicle group, a significant increase was detected in the number of brain-derived neurotrophic factor-positive cells and the expression of brain-derived neurotrophic factor mRNA in the hippocampus of the paeoniflorin-treated group. According to the results, paeoniflorin promoted neural stem cell proliferation, their differentiation into astrocytes, and neurogenesis in the hippocampal dentate gyrus of chronic unpredictable stress-induced rats. Apart from enhancing the protein expression and gene transcription of brain-derived neurotrophic factor, it also activated the expression of tropomyosin receptor kinase B (a high-affinity receptor of brain-derived neurotrophic factor). This suggests that paeoniflorin might promote neurogenesis in the hippocampus dentate gyrus of chronic unpredictable stress-induced rats and act as an antidepressant by regulating the brain-derived neurotrophic factor-tropomyosin receptor kinase B signaling pathway.

Leptin resistance was involved in susceptibility to overweight in the striped hamster re-fed with high fat diet.

Food restriction (FR) is the most commonly used intervention to prevent the overweight. However, the lost weight is usually followed by "compensatory growth" when FR ends, resulting in overweight. The present study was aimed to examining the behavior patterns and hormones mechanisms underpinning the over-weight. Energy budget and body fat content, and several endocrine markers related to leptin signals were examined in the striped hamsters under 20% FR refed by either low-fat diet (LF group) or high-fat diet (HF group). Body mass and fat content significantly regained when FR ended, and the hamsters in HF group showed 49.1% more body fat than in LF group (P < 0.01). Digestive energy intake was higher by 20.1% in HF than LF group, while metabolic thermogenesis and behavior patterns did not differed between the two groups. Gene expression of leptin receptor and anorexigenic peptides of pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript in hypothalamus were significantly up-regulated in LF group, but down-regulated in HF group. It suggests that effective leptin signals to the brain were involved in attenuation of hyperphagia in hamsters refed with LF. However, "leptin resistance" probably occurred in hamsters refed with HF, which impaired the control of hyperphagia, resulting in development of over-weight.

Safety and tolerability of iopromide in patients undergoing cardiac catheterization: real-world multicenter experience with 17,513 patients from the TRUST trial.

To assess the incidence of and risk factors for acute adverse drug reactions (ADRs) (occurring within 1 h) following iopromide administration in cardiac catheterization in Chinese 'real-world' practice. Acute ADRs following iopromide administration during coronary angiography or percutaneous coronary intervention (PCI) have not been systematically evaluated in China. TRUST was a prospective, multicenter, observational study conducted at 63 centers in China. Patients received iopromide (300 or 370 mgI/mL) during coronary angiography or PCI (n = 17,513). Acute ADRs occurred in 66 patients (0.38%); ADRs were mild in 58 patients (0.33%) and severe in two patients (0.01%). Most acute ADRs manifested as allergy-like symptoms such as nausea/vomiting [39 patients (0.22%)] and/or rash [15 patients (0.09%)]. The rate of acute ADRs was lower among patients who received premedication (6/3349; 0.18 %) than those who did not (60/14,164; 0.42%; p = 0.0379), and among those who did receive pre-procedural hydration (10/7993; 0.13%) compared with those who did not (56/9520; 0.59%; p < 0.0001). Age <50 years, left main coronary disease and history of ADRs to contrast media increased the risk of ADRs, while premedication with corticosteroids, pre-procedural hydration and contrast volume <100 mL versus ≥100 mL reduced the risk. Contrast quality was rated as 'Excellent' in 99.1% of patients. The incidence of acute ADRs was very low with iopromide in cardiac catheterization in China. The risk of acute ADRs increased in patients <50 years and in those with a history of ADRs to contrast media. Premedication with corticosteroids and pre-procedural hydration may prevent acute ADRs in at-risk patients.

[Novel method for the evaluation of the synchronicity of the chemomic release/dissolution of multi-component traditional Chinese medicines].

Due to the diversity of components within the traditional Chinese medicines (TCMs), the release profiles of the components in the TCM dosage forms vary dramatically and no quantification method is available to determine the variance yet. Based upon the principles of Kalman filter method, the authors defined a new parameter, relative chemomic error (epsilon), to evaluate the asynchronous nature of the components in TCMs, and a derivative parameter as synchronization factor (SF) to quantify the synchronicity of the chemome of the TCMs. The average synchronization factor (SF(av)) was accordingly derived to simultaneously quantify the release/dissolution profiles of the multi-components in TCMs. Randomly generated simulation data were processed to demonstrate the chemomic data processing and the methodology. The results indicated that the novel parameter epsilon was well correlated (r = 0.996 8) with the coefficient of variation from the conventional release profiles of all the components. As the asynchronicity was the intrinsic characteristics of the multi-component TCMs, the synchronicity might be a new target of quality control of TCMs. The methods established by this report can be used a quantitative tool for the evaluation of the chemomic release synchronization of TCMs.

[Application of the theories of materiomic release kinetics to the evaluation of the sustained release kinetics and synchronicity of yinqiaojiedu honeyed pills].

Yinqiaojiedu honeyed pills were equally divided into 1/4, 1/8, 1/12, and 1/16 parts. The materiomics release rates within 12 h of the intact Yinqiaojiedu honeyed pills and the divided granules were determined by the paddle method with a rotate speed at 100 r x min(-1), and the materiome was quantified by UV-scan and Kalman filter methods. The intact Yinqiaojiedu honeyed pills behaved typical sustained release profiles, while the well-divided portions also maintained a sustained release profile over 2-4 h. The release rates were well correlated with the extents for the divisions of the pills. The Weibull distribution parameters, Td and T50, were reduced in line with the particle size, indicating that the ways of administration of the pills may play a role in the in vivo pharmacokinetics of the pills. The visualization results showed obvious difference of materiomic release synchronicities between the intact pills and the equally divided particles, and the divisions enhanced the asynchronization. Therefore the novel theory of materiomic release/dissolution kinetics of traditional Chinese medicines (TCMs) quantitatively proved the traditional dosage form, namely, honeyed pills, as a prototype of the sustained-release dosage form with a visualization of the scientific connotation to the old saying in the classics of TCM, Pills, the moderate ones in action. In terms of materiome increase for each period of the release profiles, the materiomic release synchronicity was visually demonstrated. The novel theories provided methodological basis for the evaluation of traditional dosage forms and the design of the modern drug delivery systems for TCMs.

Hypertonic perfusion reduced myocardial injury during subsequent ischemia and reperfusion in normal and hypertensive rats.

AIM: To determine the effects of hypertonic solution on myocardial ischemia and reperfusion injury in normal and stroke-prone hypertensive rat hearts in vitro. METHODS: Hearts were perfused in an isolated-perfused Langendorff apparatus and perfused with normal or hypertonic solution (360 mOsm/L, by addition of NaCl to the normal perfusate of 300 mOsm/L) before subjected to 30 min ischemia followed by 40 min isotonic reperfusion. Heart function, myocardial creatine kinase leakage, norepinephrine release, and ventricular calcium content were determined. RESULTS: Normal rat hearts with hypertonic perfusion showed higher recovery rate of spontaneous beating than control hearts after ischemia. Hypertensive rat hearts perfused with hypertonic solution also had better recovery in diastolic function and less creatine kinase leakage than hypertensive controls. Concomitantly, myocardial release of norepinephrine was also reduced from hypertensive hearts perfused with hypertonic solution. There was no significant difference in myocardial calcium content between normal and hypertonic perfused hypertensive hearts. CONCLUSION: Hypertonic perfusion may precondition the hearts and protect them from ischemia and reperfusion injury in both normal and hypertensive rats. The modulation of hypertonic perfusion on myocardial norepinephrine release and its role in cardioprotection needs further investigation.