Objective To evaluate the bioequivalence of test product and reference product in a single dose of amoxicillin clavulanate potassium tablet under fasting and fed conditions in healthy volunteers.Methods An open label,randomized,single dose,four-period,crossover bioequivalence study was designed.Fasting and postprandial tests were randomly divided into 2 administration sequence groups according to 1:1 ratio,amoxicillin clavulanate potassium tablet test product or reference product 375 mg,oral administration separately,liquid chromatography tanden mass spectrometry was applied to determine the concentration of amoxicillin and clavulanate potassium in plasma of healthy subjects after fasting or fed administration,while Phoenix WinNonlin 8.2 software were used for pharmacokinetics(PK)parameters calculation and bioequivalence analysis.Results Healthy subjects took the test product and the reference product under fasting condition,the main PK parameters of amoxicillin are as follows:Cmax were(5 075.57±1 483.37)and(5 119.86±1 466.73)ng·mL-1,AUC0_twere(1.32 × 104±2 163.76)and(1.30 × 104±1 925.11)ng·mL-1,AUC0-∞were(1.32 × 104±2 175.40)and(1.31 ×104±1 935.86)ng·mL-1;the main PK parameters of clavulanic acid are as follows:Cmax were(3 298.27±1 315.23)and(3 264.06±1 492.82)ng·mL-1,AUC0-twere(7 690.06±3 053.40)and(7 538.39±3 155.89)ng·mL-1,AUC0-∞were(7 834.81±3 082.61)and(7 671.67±3 189.31)ng·mL-1;the 90％confidence intervals of Cmax,AUC0-tand AUC0-∞ after logarithmic conversion of amoxicillin and clavulanate potassium of the two products were all within 80.00％-125.00％.Healthy subjects took the test and reference product under fed condition,the main PK parameters of amoxicillin are as follows:Cmax were(4 514.08±1 324.18)and(4 602.82±1 366.48)ng·mL-1,AUC0-twere(1.15 × 104±1 637.95)and(1.15 × 104±1 665.69)ng·mL-1,AUC0-∞ were(1.16 × 104±1 646.26)and(1.15 × 104±1 607.20)ng·mL-1;the main PK parameters of clavulanic acid are as follows:Cmax were(2 654.75±1 358.29)and(2 850.51±1 526.31)ng·mL-1,AUC0-twere(5 882.82±2 930.06)and(6 161.28±3 263.20)ng·mL-1,AUC0-∞ were(6 022.70±2 965.05)and(6 298.31±3 287.63)ng·mL-1;the 90％confidence intervals of Cmax,AUC0-t and AUC0-∞ after logarithmic conversion of amoxicillin and clavulanate potassium of the two products were all within 80.00％-125.00％.Conclusion The two formulations were bioequivalent to healthy adult volunteers under fasting and fed conditions.

Objective To observe the pharmacokinetic effect of amoxicillin and clavulanate potassium tablets on amoxicillin in Chinese healthy subjects under fasting and high fat and high calorie diet.Methods 71 healthy subjects were given a single dose of amoxicillin potassium clavulanate tablets(0.375 g)on fasting or high fat diet,and venous blood samples were collected at different time points.The concentrations of amoxicillin in human plasma were determined by HPLC-MS/MS method,and the pharmacokinetic parameters were calculated by non-atrioventricular model using PhoenixWinNonlin 8.0 software.Results The main pharmacokinetic parameters of amoxicillin potassium clavulanate tablets after fasting and high fat diet were(5 105.00±1 444.00),(4 593.00±1 327.00)ng·mL-1,and postprandial-fasting ratio 89.40％,90％confidence interval(79.55％-100.19％);t1/2 were(1.52±0.16),(1.39±0.22)h;AUC0-t were(12 969.00±1 841.00),(11 577.00±1 663.00)ng·mL-1·h,and postdietary/fasting ratio 89.20％,90％confidence interval(83.92％-94.28％);AUC0-∞ were(13 024.00±1 846.00),(11 532.00±1 545.00)ng·mL-1·h,and postprandial-fasting ratio 88.60％,90％confidence interval(83.48％-93.50％).The median Tmax(range)were 1.63(0.75,3.00)and 2.50(0.75,6.00)h,respectively,and the Tmax of postprandial medication was delayed(P＜0.01).Conclusion Compared with fasting condition,amoxicillin Tmax was significantly delayed after high fat diet,while Cmax,AUC0-t and AUC0-∞ were not significantly changed,indicating that food could delay the absorption of amoxicillin,but did not affect the degree of absorption.

Objective To evaluate the bioequivalence of metronidazole tablet and reference formulation in Chinese healthy subjects.Methods A single-dose,two-cycle,randomized,open,self-crossover trial was designed with 48 healthy subjects randomly assigned to fasting or postprandial group.For each group,a single oral dose of metronidazole tablet(200 mg)or a reference preparation(200 mg)per cycle were enrolled.The concentration of metronidazole in plasma was measured by high performance liquid chromatography tandem mass spectrometry(HPLC-MS/MS).The non-compartmental model was applied to calculate the pharmacokinetic parameters for bioequivalence analysis via SAS 9.3 software.Results The main pharmacokinetic parameters of test and reference metronidazole tablets in the fasting group were as follows,the Cmax were(4 855.00±1 383.97)and(4 799.13±1 195.32)ng·h·mL-1;the AUC0-t were(54 834.68±12 697.88)and(55 931.35±11 935.28)ng·h·mL-1;the AUC0-∞ were(56 778.09±13 937.76)and(57 922.83±13 260.54)ng·h·mL-1;the Tmax were respectively 1.17 and 1.00 h;t1/2 were(8.99±1.76)and(9.11±1.73)h,respectively.The ratio of the geometric mean and its 90％confidence intervals(CI)of Cmax,AUC0-t and AUC0-∞ were all within the equivalent interval of 80.00％-125.00％.As for postprandial conditions,the main pharmacokinetic parameters of test and reference metronidazole tablets were as follows,the Cmax were(4 057.08±655.08)and(4 044.17±773.98)ng·h·mL-1;the AUC0-t were(55 956.42±12 228.12)and(55 121.04±11 784.55)ng·h·mL-1;the AUC0-∞ were(58 212.83±13 820.00)and(57 350.38±13 229.46)ng·h·mL-1;the Tmax were 2.50 and 2.25 h;the t1/2 were(9.37±1.68)and(9.37±1.79)h,respectively.The ratio of the geometric mean and 90％CI of Cmax,AUC0-t and AUC0-∞ were all within the equivalent interval of 80.00％-125.00％.Conclusion The two preparations were bioequivalent to Chinese healthy adult volunteers under both fasting and fed conditions.

Cerebral organoids are three-dimensional nerve cultures induced by embryonic stem cells(ESCs)or induced pluripotent stem cells(iPSCs)that mimic the structure and function of human brain.With the continuous optimization of cerebral organoid culture technology and the combination with emerging technologies such as organ transplantation,gene editing and organoids-on-chip,complex brain tissue structures such as functional vascular structures and neural circuits have been produced,which provides new methods and ideas for studying human brain development and diseases.This article reviews the latest advances in brain organoid technology,describes its application in neurological diseases and advances in stroke modeling and transplantation treatment.

Post-stroke cognitive impairment(PSCI)is mainly manifested as learning and memory disorders.Highly enriched RNA m6A methylation modification in mammalian brain is involved in glial cell-mediated neuroinflammation.Given that neuroinflammation is the main mechanism for neural damage and spatial and memory impairment of PSCI,it is speculated that RNA m6A methylation modification can regulate the inflammatory response of glial cells after stroke to improve PSCI.This review summarizes and analyzes the role of RNA m6A methylation modification in the development of PSCI and analyzes its detailed mechanism of regulating glial cell-mediated inflammation,which will provide reference for researchers in this field.

BACKGROUND:Long non-coding RNAs(lncRNAs),as important regulators of the inflammatory response,are involved in the immune-inflammation-brain crosstalk mechanism after ischemic stroke and have the potential to become a therapeutic agent for neurological dysfunction after ischemic stroke. OBJECTIVE:To analyze and summarize the molecular mechanism of lncRNA acting on glial cells involved in the neuroimmuno-inflammatory cascade response after ischemic stroke and the associated signaling pathways,pointing out that lncRNAs have the potential to regulate inflammation after ischemic stroke. METHODS:PubMed was searched using the search terms of"ischemic stroke,long non-coding RNA,neuroinflammation,immune function,signal pathway,microglia,astrocytes,oligodendrocyte,mechanism,"and 63 relevant documents were finally included for review. RESULTS AND CONCLUSION:In the early stage of ischemic stroke,the death of nerve cells due to ischemia and hypoxia activates the innate immune response of the brain,promoting the secretion of inflammatory factors and inducing blood-brain barrier damage and a series of inflammatory cascades responses.As an important pathogenesis factor in ischemic stroke,the neuroimmuno-inflammatory cascade has been proved to seriously affect the prognosis of patients with ischemic stroke,and it needs to be suppressed promptly in the early stage.Neuroinflammation after ischemic stroke usually induces abnormal expression of a large number of lncRNAs that mediate a series of neuro-immune-inflammatory crosstalk mechanisms through regulating the polarization of microglia,astrocytes and oligodendrocytes to exert post-stroke neuroprotective effects.LncRNAs,as important regulatory factors of the inflammatory response,inhibit the neuroimmuno-inflammatory cascade response after ischemic stroke through regulating nuclear factor-κB,lncRNA-miRNA-mRNA axis,Rho-ROCK,MAPK,AKT,ERK and other signaling pathways to effectively improve neurological impairment after ischemic stroke.Most of experimental studies on the interaction between lncRNAs and ischemic stroke are based on a middle cerebral artery occlusion model or a cerebral ischemia-reperfusion injury model,but no clinical trials have been conducted.Therefore,it remains to be further explored about whether lncRNAs can be safely applied in clinical practice.At present,there are many therapeutic drugs for the treatment of ischemic stroke,but there are relatively few studies on the application of lncRNAs,exosomes and other transplantation technologies for the treatment of ischemic stroke using tissue engineering technology,which need to be further explored.lncRNA has become an important target for the treatment of ischemic stroke with its relative stability and high specificity.In future studies,more types of inflammatory lncRNAs that function under ischemic-hypoxia conditions should continue to be explored,in order to provide new research directions for the treatment of neuroinflammation after ischemic stroke.

Post-stroke cognitive impairment(PSCI)is a common complication after stroke,which significantly affects quality of life.However,the pathogenesis has not been fully explained.Increasing evidence has shown that the mechanism of programmed cell death(PCD)is related to PSCI,including apoptosis,necroptosis,pyroptosis,PANoptosis,parthanatos,and ferroptosis.Therefore,it is crucial to clearly understand the various mechanisms of PCD and their relationship with PSCI,and to elucidate the role of PCD in PSCI pathogenesis.The article reviews six PCD pathways related to PSCI,summarizes their mechanisms of action in PSCI,and elucidates the possible crosstalk among pathways to provide a basis for clinical targeting of regulatory factors in the PCD pathway for PSCI treatment.

OBJECTIVE: To investigate the effect of Yinlai Decoction (YD) on the microstructure of colon, and activity of D-lactic acid (DLA) and diamine oxidase (DAO) in serum of pneumonia mice model fed with high-calorie and high-protein diet (HCD). METHODS: Sixty male Kunming mice were randomly divided into 6 groups by the random number table method: normal control, pneumonia, HCD, HCD with pneumonia (HCD-P), YD (229.2 mg/mL), and dexamethasone (15.63 mg/mL) groups, with 10 in each group. HCD mice were fed with 52% milk solution by gavage. Pneumonia mice was modeled with lipopolysaccharide inhalation and was fed by gavage with either the corresponding therapeutic drugs or saline water, twice daily, for 3 days. After hematoxylin-eosin staining, the changes in the colon structure were observed under light microscopy and transmission electron microscope, respectively. Enzyme-linked immunosorbent assay was used to detect the protein levels of DLA and DAO in the serum of mice. RESULTS: The colonic mucosal structure and ultrastructure of mice in the normal control group were clear and intact. The colonic mucosal goblet cells in the pneumonia group tended to increase, and the size of the microvilli varied. In the HCD-P group, the mucosal goblet cells showed a marked increase in size with increased secretory activity. Loose mucosal epithelial connections were also observed, as shown by widened intercellular gaps with short sparse microvilli. These pathological changes of intestinal mucosa were significantly reduced in mouse models with YD treatment, while there was no significant improvement after dexamethasone treatment. The serum DLA level was significantly higher in the pneumonia, HCD, and HCD-P groups as compared with the normal control group (P<0.05). Serum DLA was significantly lower in the YD group than HCD-P group (P<0.05). Moreover, serum DLA level significantly increased in the dexamethasone group as compared with the YD group (P<0.01). There was no statistical significance in the serum level of DAO among groups (P>0.05). CONCLUSIONS YD can protect function of intestinal mucosa by improving the tissue morphology of intestinal mucosa and maintaining integrity of cell connections and microvilli structure, thereby reducing permeability of intestinal mucosa to regulate the serum levels of DLA in mice.
Mice ; Male ; Animals ; Lactic Acid/pharmacology* ; Intestinal Mucosa ; Colon/pathology* ; Dexamethasone/pharmacology* ; Diet, High-Protein ; Pneumonia/pathology*

Objective To evaluate the effects of fasting and high-fat diet on the pharmacokinetics of moxifloxacin in Chinese healthy adult subjects.Methods A single-center,randomized,open,single-dose trial design was used in this study,healthy subjects were assigned to receive single dose of moxifloxacin tablets 0.4 g in either fasting or high-fat diet state,and blood samples were taken at different time points,respectively.The concentrations of moxifloxacin in plasma were determined by liquid chromatography-tandem mass spectrometry.Results The main pharmacokinetic parameters of moxifloxacin in fasting state and high-fat diet states were as follows:Cmax were(2 286.09±802.64)and(1 963.33±474.99)ng·mL-1;t1/2 were(12.32±1.42)and(13.56±1.38)h;AUC0-twere(2.70±0.51)×104 and(2.60±0.55)×104 ng·mL-1·h;AUC0-∞ were(2.88±0.54)×104 and(2.85±0.63)×104 ng·mL-1·h;tmax were 1.50 and 2.00 h.After high-fat diet,the AUC was not significantly changed,Cmax was decreased by 14.12％,and tmax was indistinctively delayed(all P＞0.05).Conclusion Food had no effects on the absorption rate and degree of moxifloxacin.

Investigation on how nature produces natural compounds with chemical and biological diversity at the genetic level offers inspiration for the discovery of new natural products and even their biological targets. The polyketide rumbrin ( 1) is a lipid peroxide production and calcium accumulation inhibitor, which contains a chlorinated pyrrole moiety that is a rare chemical feature in fungal natural products. Here, we identify the biosynthetic gene cluster (BGC) rum of 1 and its isomer 12E-rumbrin ( 2) from Auxarthron umbrinum DSM3193, and elucidate their biosynthetic pathway based on heterologous expression, chemical complementation, and isotopic labeling. We show that rumbrins are assembled by a highly reducing polyketide synthase (HRPKS) that uniquely incorporates a proline-derived pyrrolyl-CoA starer unit, and followed by methylation and chlorination. Sequent precursor-directed biosynthesis was able to yield a group of rumbrin analogues. Remarkably, inspired by the presence of a human immunodeficiency virus (HIV)-Nef-associated gene in the rum cluster, we predicted and pharmacologically demonstrated rumbrins as potent inhibitors of HIV at the nanomolar level. This work enriches the recognition of unconventional starter units of fungal PKSs and provides a new strategy for genome mining-guided drug discovery.