OBJECTIVE To study the effects of methimazole on the urinary metabolomics of hyperthyroidism rats， and to preliminarily investigate its possible mechanism. METHODS Thirty SD rats were randomly divided into control group， model group and methimazole group， with 10 rats in each group. Except for the control group， the rats in the other two groups were given Levothyroxine sodium tablets 160 mg/kg by intragastric administration for 15 days； at the same time， methimazole group was additionally given methimazole 3.6 mg/kg daily by intragastric administration every day. The basic condition of the rats was observed， and the body weight and anal temperature were measured. After the last medication， the serum levels of triiodothyronine （T3）， tetraiodothyronine （T4）， free triiodothyronine （FT3）， free tetraiodothyronine （FT4）， and thyroid stimulating hormone （TSH） were determined； 24-hour urine was collected on the 15th day after administration. UPLC-TOF-MS was used to analyze the urine metabolomics of rats. Principal component analysis and orthogonal partial least squares-discriminant analysis were used to screen out related differential metabolites， and potential metabolic pathways were analyzed by using HMDB and KEGG. RESULTS Compared with the control group， the rectal temperature， serum levels of T3， T4， FT3 and FT4， the expressions of differential metabolites sebacic acid， cholic acid 3-O-glucuronic acid and N6， N6， N6-trimethyl-L-lysine in urine were significantly up-regulated， while body weight， serum level of TSH， the expressions of deoxycytidine and 2-oxo-4-methylthiobutanoic acid in urine were significantly down-regulated （P＜0.01）. Compared with model group， above indexes of rats were reversed significantly in methimazole group （P＜0.01 or P＜0.05）. Above five differential metabolites were mainly involved in four signaling pathways: pentose and glucuronate interaction， lysine degradation， cysteine and methionine metabolism， and pyrimidine metabolism. CONCLUSIONS Methimazole might improve hyperthyroidism by modulating the four pathways of pentose and glucuronate interaction， lysine degradation， cysteine and methionine metabolism， and pyrimidine metabolism.

Precise orchestration of cell fate determination underlies the success of scaffold-based skeletal regeneration.Despite extensive studies on mineralized parenchymal tissue rebuilding,regenerating and maintaining undifferentiated mesenchyme within calvarial bone remain very challenging with limited advances yet.Current knowledge has evidenced the indispensability of rebuilding suture mesenchymal stem cell niches to avoid severe brain or even systematic damage.But to date,the absence of promising therapeutic biomaterials/scaffolds remains.The reason lies in the shortage of fundamental knowledge and methodological evidence to understand the cellular fate regulations of scaffolds.To address these issues,in this study,we systematically investigated the cellular fate determinations and transcriptomic mechanisms by distinct types of commonly used calvarial scaffolds.Our data elucidated the natural processes without scaffold transplantation and demonstrated how different scaffolds altered in vivo cellular responses.A feasible scaffold,polylactic acid electrospinning membrane(PLA),was next identified to precisely control mesenchymal ingrowth and self-renewal to rebuild non-osteogenic suture-like tissue at the defect center,meanwhile supporting proper osteointegration with defect bony edges.Especially,transcriptome analysis and cellular mechanisms underlying the well-orchestrated cell fate determination of PLA were deciphered.This study for the first time cellularly decoded the fate regulations of scaffolds in suture-bony composite defect healing,offering clinicians potential choices for regenerating such complicated injuries.

Vascular calcification is a highly regulated process of ectopic calcification in cardiovascular system while no effective intervention can be clinically performed up to date.As vascular calcification undergoes a common regulatory mechanism within bone formation,bone morphogenetic protein 7(BMP-7)main-tains contractile phenotype of vascular smooth muscle cells and further inhibits vascular calcification via promoting the process of osteoblast differentiation,reducing ectopic calcification pressure by increasing bone formation and reducing bone resorption.This work systematically reviews the role of BMP-7 in vascular calcifi-cation and the possible mechanism,and their current clinical application as well.The current proceedings may help develope early diagnostic strategy and therapeutic treatment with BMP-7 as a new molecular marker and potential drug target.The expec-tation could achieve early prevention and intervention of vascular calcification and improve poor prognosis on patients.

Objective:To compare the efficacy and safety of red light and daylight photodynamic therapy in the treatment of facial common acne.Methods:From March 2019 to November 2019, 52 patients with facial common acne who received 5-aminolevulinic acid photodynamic therapy in the Department of Dermatology, Chongqing Hospital of Traditional Chinese Medicine were enrolled, including 34 males and 18 females, aged 18-35 years, with an average age of 23.2 years. A 5% concentration of 5-aminolevulinic acid was applied to the entire face, with the right side of the face being exposed to red light for 20 minutes and the left side to daylight for 2 hours. The treatment was administered once a week for a total of 4 sessions. After the treatment, the acne remission, adverse reactions, and patient satisfaction on both sides of the face were compared.Results:Compared with before treatment, the number of inflammatory and non-inflammatory lesions on both sides of the face in the enrolled patients decreased, and there was no significant difference in the clearance rate of skin lesions between the two sides [53.7% (28/52) vs 59.1% (31/52), χ 2=0.89, P>0.05]. The overall effective rate on the red light side was 88.5% (46/52), and 82.7% (43/52) on the daylight side, with no significant difference between the two (χ 2=0.38, P>0.05). In terms of adverse reactions, mild erythema was common, and it was less on the daylight side than on the red light side [34.6% (18/52) vs 19.2% (10/52), χ 2=5.98, P<0.05]. During the treatment period, the pain score on the daylight side decreased compared to the red light side [(7.6±2.3) vs (4.1±1.3), t=13.10, P<0.001]. Overall satisfaction with the daylight side was reported in 49 cases (94.2%), and with the red light side in 37 cases (71.2%), with the daylight side being higher than the red light side, and the difference was statistically significant (χ 2=9.60, P<0.05). Conclusion:Daylight photodynamic therapy is as effective as red light photodynamic therapy for common acne, but it produces fewer adverse reactions and higher patient satisfaction.

COVID-19 epidemic continues to spread around the world till these days, and it is urgent to develop more safe and effective new drugs. Due to the limited P3 biosafety laboratories for directly screening inhibitors of virulent viruses with high infectivity, it is necessary to develop rapid and efficient screening methods for viral proteases and other related targets. The main protease (M^pro), which plays a key role in the replication cycle of SARS-CoV-2, is highly conserved and has no homologous proteases in humans, making it an ideal target for drug development. From two different levels, namely, molecular level and cellular level, this paper summarizes the reported screening methods of SARS-CoV-2 M^pro inhibitors through a variety of representative examples, expecting to provide references for further development of SARS-CoV-2 M^pro inhibitors.

ObjectiveTo investigate the detoxification mechanism of Chebulae Fructus， Glycyrrhizae Radix et Rhizoma and Prepared Aconiti Kusnezoffii Radix Cocta， and their effective components ellagic acid， liquiritin and aconitine based on cardiac cytochrome P450 （CYP450） system. MethodIn in vivo experiments， rats were randomly divided into control group， prepared Aconiti Kusnezoffii Radix Cocta group （0.25 g·kg^-1）， Chebulae Fructus group （0.252 g·kg^-1）， Glycyrrhizae Radix et Rhizoma group （0.25 g·kg^-1） and combination group （0.25 g·kg^-1 Chebulae Fructus+0.25 g·kg^-1 Glycyrrhizae Radix et Rhizoma+0.25 g·kg^-1 prepared Aconiti Kusnezoffii Radix Cocta， with prepared Aconiti Kusnezoffii Radix Cocta as standard）. After 8 days of administration， creatine kinase （CK） and lactate dehydrogenase （LDH） in rats were detected to observe the pathological changes of heart tissue. Real-time PCR and Western blot were performed to detect the mRNA and protein expressions of CYP2J3， respectively. In in vitro experiments， control group， aconitine group， ellagic acid group， liquiritin group and combination group （aconitine+ellagic acid+liquiritin） were set， and their effects on cell number， DNA content， reactive oxygen species （ROS） and mitochondrial membrane potential （MMP） were detected by high content analysis. The changes in the mRNA and protein expressions of CYP2J3 were also observed. ResultIn vivo experiments， compared with the control group， the prepared Aconiti Kusnezoffii Radix Cocta group had increased CK and LDH in serum （P<0.05， P<0.01）， while the combination group had decreased activities of CK and LDH. Additionally， pathological staining results showed that Chebulae Fructus and Glycyrrhizae Radix et Rhizoma reduced the cardiac toxicity caused by prepared Aconiti Kusnezoffii Radix Cocta. Real-time PCR found that compared with the control group， prepared Aconiti Kusnezoffii Radix Cocta down-regulated the mRNA level of CYP2J3 （P<0.05）， while up-regulated that expression when used in combination with Chebulae Fructus and Glycyrrhizae Radix et Rhizoma （P<0.01）. The protein and mRNA translation levels were basically consistent. In vitro experiments， high content analysis revealed that there was a decrease in the cell number， DNA content and MMP fluorescence value of the aconitine group （P<0.01） and the combination group （P<0.05， P<0.01）， and the fluorescence value of the combination group was higher than that of the aconitine group. Moreover， aconitine down-regulated the mRNA level of CYP2J3 （P<0.05）， but the down-regulating ability of aconitine was reversed in the combination group （P<0.05）. ConclusionThe detoxification mechanism of combined Chebulae Fructus， Glycyrrhizae Radix et Rhizoma and prepared Aconiti Kusnezoffii Radix Cocta is mainly that the combination of ellagic acid， liquiritin and aconitine can up-regulate the expression of CYP2J3， and promote the metabolism of arachidonic acid （AA） to produce epoxyeicosatrienoic acids （EETs）， thus reducing the cardiac toxicity， and this effect may start from the transcriptional link.

OBJECTIVE: To observe the effects of electroacupuncture at "Siguan" points on behavior, colonic 5-hydroxytryptamine (5-HT) and fecal short-chain fatty acids (SCFAs) in rats with post-stroke depression (PSD), and explore the effect mechanism of electroacupuncture at Siguan points on PSD. METHODS: Fifty SD rats were randomly divided into a sham-operation group, a stroke group, a PSD group, a drug group and an electroacupuncture group, with 10 rats in each one. The stroke model was established by middle cerebral artery occlusion (MCAO) method in the stroke group; except for the sham-operation group, the rats in the other groups were intervened with MCAO combined with solitary and chronic unpredictable mild stress (CUMS) to establish PSD model. In the electroacupuncture group, electroacupuncture was delivered at "Hegu" (LI 4) and "Taichong" (LR 3), with disperse-dense wave, 2 Hz/10 Hz in frequency, for 30 min in each intervention, once daily, for consecutive 21 days. Simultaneously, distilled water (0.01 L•kg^-1•d^-1) was administrated intragastrically. Fluoxetine solution (2.33 mg•kg^-1•d^-1) was given by gavage , once a day and for 21 days in the drug group. The same procedure of fixation and gavage with distilled water were adopted in the sham-operation group, the stroke group and the PSD group. Separately, before stroke modeling, after PSD modeling and after 21-day intervention, the consumption of sugar water and the scores of horizontal movement and vertical movement in open-field test were observed. After 21-day intervention, the content of colonic 5-HT was detected by immunohistochemical method, and that of fecal SCFAs was determined by gas chromatography mass spectrometry. RESULTS: After PSD modeling, compared with the stroke group, the sugar water consumption, the horizontal movement scores and vertical movement scores of the open-field test were all reduced in the PSD group, the drug group and the electroacupuncture group (P<0.05). After 21-day intervention, the sugar water consumption and the scores of horizontal movement and vertical movement of the open-field test were increased in the drug group and the electroacupuncture group (P<0.05) when compared with the PSD group; and the horizontal movement score in the electroacupuncture group was lower than that of the drug group (P<0.05). Compared with the sham-operation group, the contents of total fecal SCFAs and acetic acid were lower in the stroke group (P<0.05), and the contents of colonic 5-HT and total fecal SCFAs, acetic acid, propionic acid and butyric acid were reduced in the PSD group (P<0.05). In comparison with the PSD group, the contents of colonic 5-HT and total fecal SCFAs, acetic acid and propionic acid were increased in the drug group and the electroacupuncture group (P<0.05); and the content of colonic 5-HT in the electroacupuncture group was lower than that of the drug group (P<0.05). The level of colonic 5-HT was positively correlated with the contents of total fecal SCFAs and propionic acid (r=0.424, P=0.005; r=0.427, P=0.004). CONCLUSION Electroacupuncture at "Siguan" points can relieve the depression-like behavior of PSD rats, and its underlying mechanism may be related to the regulation of fecal SCFAs, which affects the release of colonic 5-HT.
Animals ; Rats ; Rats, Sprague-Dawley ; Propionates ; Serotonin ; Depression/therapy* ; Electroacupuncture ; Fatty Acids, Volatile ; Stroke/complications* ; Acetic Acid ; Butyric Acid ; Water

As a common protease with high similarity among coronavirus species, the main protease (M^pro) of SARS-CoV-2 is responsible for the catalytic hydrolysis of viral precursor proteins into functional proteins, which is essential for coronavirus replication and is one of the ideal targets for the development of broad-spectrum antiviral drugs. This paper reviews the main protease inhibitors of SARS-CoV-2, including their molecular structures, potencies and drug-like profiles, binding modes and structure-activity relationships, etc.

Objective:To investigate the effects of Guiling Gao on body temperature, gastrointestinal motility, gastrointestinal hormones, Th1/Th2 cytokines and water metabolism in rats with damp-heat syndrome.Methods:Totally 60 SD rats were randomly divided into control group, model group, mosapride group, Guiling Gao low dose group (3.4 g/kg), medium dose group (6.8 g/kg) and high dose group (13.6 g/kg) according to random number table method, with 10 rats in each group. Except for the blank group, the other groups adopted the method of "environmental factors + fat and sweet diet + biological factors" to prepare the rat model of damp heat syndrome of febrile diseases. After modeling, they were administered by gavage for 7 days. During the experiment, the general state, body weight and body temperature were observed, the gastric residue rate of rats was calculated by weighing method, the intestinal propulsion rate of rats was calculated by charcoal propulsion method, and the levels of serum motilin (MTL), gastrin (GAS), somatostatin (SS), substance P (SP),IL-4 and interferon-γ (IFN-γ) were detected by ELISA, and the changes of aquaporin 3 (AQP3) mRNA transcription level were detected by real-time PCR.Results:Compared with the model group, the weight of rats in Guiling Gao high dose group increased after experiment of 22 days ( P<0.05), and body temperature of rats in Guiling Gao medium and high dose group decreased in 19-20 day ( P<0.01); and the gastric emptying rate and the small intestine propulsion rate of small intestine in Guiling Gao medium and high dose group increased significantly ( P<0.01 or P<0.05); the serum MTL, GAS and SP levels increased ( P<0.01 or P<0.05), and SS decreased ( P<0.01 or P<0.05) in the Guiling Gao medium and high dose groups; The levels of IL-4, IFN-γ and IFN-γ/IL-4 ratio decreased ( P<0.01); The expression of AQP3 mRNA (1.16 ± 0.25 vs. 0.23 ± 0.01) in the Guiling Gao high dose group was up-regulated ( P<0.01). Conclusions:Guiling Gao can effectively improve the activity state of damp-heat syndrome model rats caused by complex factors. This mechanism may be related to enhancing gastrointestinal movement, increasing gastrointestinal hormone secretion, restoring the dynamic balance of immune system Th1/Th2 and promoting the transport of water from intestinal cavity.

OBJECTIVE: To explore the effects of prognostic nutritional index (PNI) combined with D-dimer on the prognosis of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). METHODS: The clinical data of 73 DLBCL patients at initial diagnosis were retrospectively evaluated, and the optimal cut-off point of PNI and D-dimer were determined by ROC curve. The overall survival (OS) rate and progression-free survival (PFS) rate in different subgroups were compared using Kaplan-Meier survival curves. Univariate and multivariate Cox regression analysis was performed to identify the factors associated with OS. RESULTS: Compared with the low PNI group (PNI<44.775), the high PNI group (PNI≥44.775) had better OS (P =0.022) and PFS (P =0.029), the 2-year OS rates of the two groups were 55.6% and 78.3% respectively (P =0.041). Compared with the high D-dimer group (D-dimer≥0.835), the low D-dimer group (D-dimer<0.835) had better OS (P <0.001) and PFS (P <0.001), the 2-year OS rates of the two groups were 51.4% and 86.8% respectively (P =0.001). Meanwhile, patients in the high PNI+ low D-dimer group had better OS (P =0.003) and PFS (P <0.001) than the other three groups, the 2-year OS rate was statistically different from the other three groups (P <0.05). The multivariate analysis revealed that NCCN-IPI (HR =2.083, 95%CI : 1.034-4.196, P =0.040), PNI (HR =0.267, 95%CI : 0.076-0.940, P =0.040) and PNI+D-dimer (HR =9.082, 95%CI : 1.329-62.079, P =0.024) were the independent risk factors affecting OS in patients with DLBCL. Subgroup analysis showed that PNI, D-dimer, and PNI combined with D-dimer could improve the prognostic stratification in low and low-intermediate risk DLBCL patients. CONCLUSION High PNI, low D-dimer and combination of high PNI and low D-dimer at initial diagnosis suggest a better prognosis in DLBCL patients.
Humans ; Prognosis ; Nutrition Assessment ; Retrospective Studies ; Lymphoma, Large B-Cell, Diffuse/pathology*