Targeting Cyclophilin A and CD147 to Inhibit Replication of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and SARS-CoV-2-Induced Inflammation.

Identification and development of effective therapeutics for coronavirus disease 2019 (COVID-19) are still urgently needed. The CD147-spike interaction is involved in the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 invasion process in addition to angiotensin-converting enzyme 2 (ACE2). Cyclophilin A (CyPA), the extracellular ligand of CD147, has been found to play a role in the infection and replication of coronaviruses. In this study, our results show that CyPA inhibitors such as cyclosporine A (CsA) and STG-175 can suppress the intracellular replication of SARS-CoV-2 by inhibiting the binding of CyPA to the SARS-CoV-2 nucleocapsid C-terminal domain (N-CTD), and the IC50 is 0.23 µM and 0.17 µM, respectively. Due to high homology, CsA also had inhibitory effects on SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), and the IC50 is 3.2 µM and 2.8 µM, respectively. Finally, we generated a formulation of phosphatidylserine (PS)-liposome-CsA for pulmonary drug delivery. These findings provide a scientific basis for identifying CyPA as a potential drug target for the treatment of COVID-19 as well as for the development of broad-spectrum inhibitors for coronavirus via targeting CyPA. Highlights: 1) SARS-CoV-2 infects cells via the binding of its S protein and CD147; 2) binding of SARS-CoV-2 N protein and CyPA is essential for viral replication; 3) CD147 and CyPA are potential therapeutic targets for SARS-CoV-2; and 4) CsA is a potential therapeutic strategy by interrupting CD147/CyPA interactions. SIGNIFICANCE STATEMENT: New severe acute respiratory syndrome coronavirus (SARS-CoV)-2 variants and other pathogenic coronaviruses (CoVs) are continually emerging, and new broad-spectrum anti-CoV therapy is urgently needed. We found that binding sites of cyclophilin A/cyclosporin A (CyPA/CsA) overlap with CyPA/N-CTD (nucleocapsid C-terminal domain), which shows the potential to target CyPA during SARS-CoV-2 infection. Here, we provide new evidence for targeting CyPA in the treatment of coronavirus disease 2019 (COVID-19) as well as the potential of developing CyPA inhibitors for broad-spectrum inhibition of CoVs.

Global Burden, Incidence and Disability-Adjusted Life-Years for Dermatitis: A Systematic Analysis Combined With Socioeconomic Development Status, 1990-2019.

Background: Dermatitis is an important global health problem that not only affects social interaction and physical and mental health but also causes economic burden. Health problems or distress caused by dermatitis may be easily overlooked, and relevant epidemiological data are limited. Therefore, a better understanding of the burden of dermatitis is necessary for developing global intervention strategies. Methods: All data on dermatitis, including atopic dermatitis (AD), contact dermatitis (CD) and seborrhoeic dermatitis (SD), were obtained from the Global Burden of Disease 2019 (GBD2019) database. The extracted age-standardized incidence rates (ASIR) and disability-adjusted life-years (DALYs) rates (ASDR) data were analysed by stratification, including by sex, country or region, and sociodemographic index (SDI) indicators. Finally, we analysed the correlation between the global burden of dermatitis and socioeconomic development status. Results: According to the GBD 2019 estimate, the ASIR and ASDR for the three major types of dermatitis in 2019 were 5244.3988 (95% CI 4551.7244-5979.3176) per 100,000 person-years and 131.6711 (95% CI 77.5876-206.8796) per 100,000 person-years. The ASIR and ASDR of atopic dermatitis, contact dermatitis and seborrhoeic dermatitis are: Incidence (95%CI,per 100,000 person-years), 327.91 (312.76-343.67), 3066.04 (2405.38-3755.38), 1850.44 (1706.25- 1993.74); DALYs (95%CI, per 100,000 person-years), 99.69 (53.09-167.43), 28.06 (17.62-41.78), 3.93 (2.24-6.25). In addition, among the three dermatitis types, the greatest burden was associated with AD. According to the ASDR from 1990 to 2019, the burden of dermatitis has exhibited a slow downward trend in recent years. In 2019, the ASIR showed that the USA had the greatest burden, while the ASDR showed that Asian countries (such as Japan, Mongolia, Kazakhstan, and Uzbekistan) and some European countries (France, Estonia) had the greatest burden. According to SDI stratification and the three major dermatitis types, high ASIR and ASDR corresponded to high SDI areas (especially for AD). Conclusion: The burden of dermatitis is related to socioeconomic development status, especially for AD, which is positively correlated with the SDI. The results based on GBD2019 data are valuable for formulating policy, preventing and treating dermatitis and reducing the global burden of dermatitis.

Application of deterministic networking for reducing network delay in urological telesurgery: A retrospective study.

BACKGROUND: Deterministic Networking (DetNet) is a new technology that can effectively control network delay and may promote the revolution of telemedicine. This study verified the feasibility and advantage of deterministic networking in telesurgery. METHODS: All telesurgeries employed the 'MicroHand S' surgical robot system. The network mode adopted fixed-line and 5G wireless networks, while the network configuration scheme adopted DetNet and general networking. The telesurgery data of three patients using DetNet and four patients using a general network were collected, and the time-delay, packet loss rate and delay jitter were compared during the operations. RESULTS: Compared with a general network, DetNet can effectively control data transmission during the telesurgery process for both fixed-line and 5G wireless networks, further reducing network latency, minimising data fluctuations, and improving surgery security. CONCLUSION: The DetNet meets the requirements of deterministic delay, low jitter and high bandwidth for telesurgery, which may provide effective network guarantee for developing the telemedicine system.

Efficacy and safety of Chinese herbal medicine Long Dan Xie Gan Tang in insomnia: A systematic review and meta-analysis.

BACKGROUND: Insomnia is a global public problem, which has a significant negative impact on both physical and mental health, while increasing the economic burden placed on both sufferers and society. Western medicine has a fast treatment on sleep, but it leads to side effects and strong dependence. Long Dan Xie Gan Tang(LDXGT) is a representative Chinese herbal medicine for the treatment of insomnia especially which has a bad-tempered symptom, and its effectiveness and safety has been validated clinically. However, there is yet to be any evidence-based medicine. Therefore, the effectiveness and safety of LDXGT in the treatment of insomnia are studied and systematically evaluated in this study. It will provide a theoretical support for the treatment of insomnia compared to western medicine. OBJECTIVE: The study is purposed to evaluate the effectiveness and safety of LDXGT for the treatment of insomnia. METHODS: Search was conducted for various databases including Pubmed, Chinese Biomedicine Database(CBM), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP), and Wan-fang. Randomized-controlled trials (RCTs) were identified for insomnia treatment involving LDXGT and LDXGT combined with ordinary Western medicine. The quality of literature was evaluated by Cochrane assessing tool to reduce the risk of bias. RevMan 5.3 software and STATA 12.0 software were applied to perform the meta-analysis. RESULTS: Thirteen studies involving 1181 participants were identified in this systematic review. Few studies described the details of random principle. No placebo was involved in treatment. LDXGT was compared with ordinary Western medicine in 11 trials and with LDXGT combined with conventional Western medicine in 2 trials. The results of our meta-analysis showed the relative benefits in effective rates compared with conventional western medicine. (Odds Ratio [OR]= 4.32, I = 0%,95% confidence interval CI [3.05 to 6.13], P < .00001) and recovery rate was (Odds Ratio [OR] = 2.67, I = 0%,95% confidence interval CI [2.04 to 3.48], P < .00001). In two trials, adverse events were reported, but no serious adverse effects were reported. CONCLUSION: Our systematic evaluation will provide evidence for the clinical effectiveness and safety of LDXGT in the treatment of insomnia, and the side effects of western medicine are addressed. Further trials are necessary to collect the evidence for the use of LDXGT.

Characterization of the Anti-HCV Activities of the New Cyclophilin Inhibitor STG-175.

Shortened current direct-acting antiviral (DAA) therapies while less expensive, have not provided satisfactory efficacy in naïve cirrhotics, treatment experienced non-cirrhotics or even genotype-3 (GT3)-infected patients. Since DAA regimens consist of the same classes of inhibitors-NS5A (NS5Ai) and NS5B (NS5Bi) +/- NS3 (NS3i) inhibitors-it is likely that their costs will be high and will provide similar degrees of protection. Integrating drugs with distinct mechanisms of action (MoA) into DAA regimens could provide the solution for shortening the period of treatment. One such class of agents is the cyclophilin inhibitors (CypI), which has shown efficacy in patients. Resistance-associated variants persist for years post-treatment in patients exposed to NS5Ai or NS5Bi who fail to achieve a sustained virologic response, impairing their chance for cure on retreatment with existing DAA combinations. Because of their high barrier to resistance, CypI may be particularly useful as a rescue therapy for patients who have relapsed with DAA resistance-associated variants. In this study, we analyzed the anti-HCV properties of the novel cyclosporine A (CsA) derivate-STG-175. The non-immunosuppressive STG-175 possesses a high (EC50 11.5-38.9 nM) multi-genotypic (GT1a to 4a) anti-HCV activity. STG-175 clears cells from HCV since no viral replication rebound was observed after cessation of drug treatment. It presents a higher barrier to resistance than other CypI or selected DAAs. HCV variants, which emerged under STG-175 pressure, are only ~2-fold resistant to the drug. No cross-resistance was observed with DAAs STG-175 was efficacious against DAA-resistant HCV variants. Drug combination studies revealed that STG-175 provides additive and synergistic effects against GT1a to 4a. STG-175 inhibits the infection of HCV, HIV-1 and HBV in mono-, dual- and triple-infection settings. Altogether these results suggest that the new CypI STG-175 represents an attractive drug partner for IFN-free DAA regimens for the treatment of HCV and co-infections.

[Effects of acute cold exposure on pulmonary proinflammatory cytokine of rat].

OBJECTIVE: To study the effects of acute cold exposure on the inflammation and pathologic injuries in pulmonary of rats, and explore the mechanism induced by cold stress. METHODS: Forty male Wistar rats were randomly divided into five groups(n = 8): control group (23 ± 2) °C 2.5 h, -25°C 0.5 h group, -25°C 1 h group, -25°C 2 h group and -25°C 2.5 h group. Rats were exposed to cold at -25°C and no wind by keeping them in a low temperature chamber except control group. Rectal temperatures of the rats were measured before and after cold exposure. The morphological changes of pulmonary were observed by the optics microscope. The levels of tumer necrosis factor-α(TNF- α), interleukin-6 (IL-6) and interleukin-ß (IL-1ß) in lung tissue homogenate were measured by ELISA. RESULTS: Compared to the control group, body core temperatures of the -25°C 1 h group, -25°C2 h group and -25°C 2.5 h group were decreased significantly, and the D-values of rectal temperature were increased before and after cold exposure (P < 0.05). The infiltration of inflammatory cells and alveolar edema fluid appeared in the lung tissue of the -25°C 2.5 h group. The concentrations of tumor necrosis factor-α (TNF α), interleukin-6 (IL-6) and inter- leukin-1ß (IL-1ß) in lung tissue homogenate were increased significantly in -25°C l h group, -25°C 2 h group and -25C° 2.5 h group (P < 0. 05). CONCLUSION: The infiltration of inflammatory cells and the increase in proinflammatory cytokine from pulmonary may lead to the lung tissue injury after acute cold exposure.

[Effect of Electroacupuncture Stimulation of "Neiguan" (PC 6) on Expression of Myocardial Chloride Channel-related Genes, PKC and PKG Proteins in Myocardial Ischemia Rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulation of "Neiguan" (PC 6), etc. on expression levels of myocardial chloride (CL-) channel-related genes and intracellular protein kinase C (PKC) protein in myocardial ischemia (M) rats. METHODS: Seventy SD rats were randomly divided into control group (n = 10), model group (n = 15) , Neiguan (PC 6) group (n = 15), Lieque (LU 7) group (n = 15) and non-acupoint group (n = 15). The MI model was established by i. p. of isoproterenol (ISO, a sympathomimetic beta adrenergic agonist). Electroacupuncture stimulation was applied to bilateral "Neiguan" (PC 6), "Lieque" (LU 7), or non-acupoint [the mid-point between "Tianshu" (ST 25) and "Shenque" (CV 8)] for 15 min, once a day for 7 days. Quantitative RT-PCR was employed to detect the expression levels of cystic fibrosis transmembrane conductance regulator (CFTR, a CL-channel) mRNA and chloride channel calcium-activated 1 (CLCa 1, a member of the family of calcium-activated chloride channels, CLCa) mRNA in the left cardiac ventricle tissue, and Western blot was used to detect the expression level of myocardial PKC protein of the left ventricle. RESULTS: Compared with the control group, the expression levels of myocardial PKC protein, and CLCa 1 and CFTR genes were significantly increased in the model group (P<0.05). In comparison with the model group, the expression levels of myocardial PKC protein, and CFTR mRNA and CLCa 1 mRNA in the Neiguan group, and PKC protein and CLCa 1 mRNA in the Lieque and non-acupoint groups, as well as CFTR mRNA in the Lieque group were notably down-regulated (P<0.05). No significant change was found in the expression of CFTR mRNA in the non-acupoint group (P>0.05), and no significant differences were found between Neiguan and Lieque groups in the expression levels of PKC protein (P>0.05). The effects of "Neiguan" (PC 6) were obviously superior to those of non-acupoint in down-regulating myocardial PKC protein, CLCa 1 mRNA and CFTR mRNA (P<0.05). CONCLUSION: EA stimulation of "Neiguan" (PC 6) can down-regulate the expression of myocardial PKC protein, CFTR and CLCa 1 genes in Ml rats, which may contribute to its effect in protecting rnyocardium from ischemic injury.

[Analysis of clinical data of 16 595 pediatric burn patients during fifteen years].

OBJECTIVE: To analyze the epidemiological characteristics of pediatric burn in the midwest region of Inner Mongolia and the related areas, and to provide reference for seeking pertinent measures of prevention and treatment. METHODS: Medical records of patients hospitalized in the 253rd Hospital of PLA, the 322nd Hospital of PLA, and the Inner Mongolia Autonomous Region Hospital from January 1996 to December 2010 were collected. Patients were divided into pediatric burn group with specific reason (group SF, with scald resulted from construction defect of Guo-lian-kang--a heatable brick bed linked to a cooking pot), and burn control group with other causes (group C) according to the main injury cause. Clinical data of patients in both groups, including general condition, family background, occurrence regularity, and outcome, were analyzed. The epidemiological trend of variation before and after taking preventive measures (1996 to 2001 and 2002 to 2010) was compared. Data were processed with chi-square test and rank sum test. RESULTS: (1) General condition: out of 16 595 pediatric burn patients, 15 816 cases (95.3%) suffered scald due to liquids with high temperature, and 779 cases (4.7%) suffered burns due to other causes. Patients in group SF (scald due to specific cause--Guo-lian-kang) accounted for 32.2% (5089/15 816) of the total suffered scald by liquids with high temperature, and 30.7% (5089/16 595) of all the inpatients the cause of burn was related to Guo-lian-kang (group SF). The patients in group SF admitted to the 322nd Hospital of PLA accounted for 34.2% of all the inpatients admitted to this hospital (1803/5267), more than the other two hospitals in this study. The number of patients in group C was 11 506, accounted for 69.3% of all the inpatients. The age of patients ranged from 8 months to 5 years in group SF and 1 month to 12 years in group C. The age of the majority of patients ranged from 1 to 3 years in both groups. The ratio of male to female was 2.1:1.0 in group SF and 1.4:1.0 in group C. The incidence of scald involving multiple body parts in group SF (3590 cases accounting for 70.5%) was obviously higher than that of group C (6311 cases accounting for 54.8%, χ(2) = 361.138, P < 0.01). In both group SF and group C, the incidence in different sites was ranked from high to low as follows: upper limbs, lower limbs, the head-face-neck region, and the trunk. The degree of injury in group SF was much more severe than that of group C (Z = 27.770, P < 0.01). The rate of patients without pre-hospital treatment was 31.2% (1588/5089) in group SF, which was obviously higher than that of group C (24.8%, 2857/11 506, χ(2) = 73.010, P < 0.01). The rate of patients treated with cryotherapy was obviously lower in group SF (14.7%, 747/5089) than in group C (19.6%, 2255/11 506, χ(2) = 57.636, P < 0.01). The rate of patients treated with delayed resuscitation (6 hours after injury) in group SF (31.5%, 1601/5089) was obviously higher than that of group C (7.8%, 897/11 506, χ(2) = 1545.234, P < 0.01). (2) Family background and occurrence regularity: in group SF, 67.3% (3424/5089) of the patients came from farming area, 22.1% (1123/5089) from villages and towns, and 10.7% (542/5089) from urban areas. In group C, 32.4% (3727/11 506) of the patients came from farming area, 48.4% (5570/11 506) from villages and towns, and 19.2% (2209/11 506) from urban areas. Most of the patients in group SF (77.8%, 3958/5089) were injured between October and March, while most of the patients in group C (58.2%, 6697/11 506) were injured between May and October. (3) Outcome and epidemiological variation: the cure rate of patients in group SF was 32.3% (1645/5089), which was obviously lower than that of group C (44.7%, 5143/11 506, χ(2) = 215.615, P < 0.01). The mortality of patients in group SF was 1.6% (79/5089), and it was obviously higher than that of group C (0.4%, 46/11 506, χ(2) = 62.700, P < 0.01). From 1996 to 2001, patients in group SF accounted for 42.5% (2213/5212), while patients in group C accounted for 57.5% (2999/5212) of the inpatients scalded by hot liquid. After taking preventive measures against injury due to Guo-lian-kang, incidence of scald injury in group SF was lowered to 27.1% (2876/10 604), while the incidence in group C remained at 72.9% (7728/10 604) of the inpatients with hot liquid scald from 2002 to 2010. The difference between the two periods was statistically significant (χ(2) = 376.695,P < 0.01). CONCLUSIONS: The defect of construction of Guo-lian-kang is one of the main factors that lead to a high incidence of pediatric burn in the midwest of Inner Mongolia. Installation of a protective bannister between the cooking pot and the "kang (heatable brick bed)" can obviously reduce the incidence of scald injury. Special injury-causing factors, unprofessional pre-hospital treatment of the wound, delayed resuscitation after shock are the main causes of increasing mortality and disability, and they constitute the key targets of prevention and treatment of such injury in future.

[The application of undermining orbicularis oculi muscle from orbital rim for the correction of tear trough deformity and palabromalar groove in lower blepharoplasty].

OBJECTIVE: To evaluate the role of undermining orbicularis oculi muscle from Orbital rim for the correction of tear trough deformity and palabromalar groove in lower blepharoplasty. METHODS: 56 cases of lower eye baggy deformity with tear trough deformity and palabromalar groove were treated with the procedure of stripping eye orbicularis oculi muscle from orbital rim by a transcutaneous approach in lower blepharoplasty. The orbital septum was opened along the arcus marginalis for releasing the orbital fat. Some orbital fat was removed if necessary. Then the inferior edge of the orbital septum fat was reset over the orbital rim so as to smooth the infraorbital groove. RESULTS: 56 patients were available for 6 to 18 month's follow-up. 54 patients were quite satisfied with the cosmetic result. One developed lower eyelid retraction and another one showed asymmetrical subcutaneous local uneven after 1 month's. They were all corrected by the second operation after 3 months. CONCLUSIONS: Stripping orbicularis oculi muscle from orbital rim plays an important role for the correction of tear trough deformity and palabromalar groove in lower blepharoplasty.

The application of undermining orbicularis oculi muscle from orbital rim for the correction of tear trough deformity and palabromalar groove in lower blepharoplasty / 中华整形外科杂志

<p><b>OBJECTIVE</b>To evaluate the role of undermining orbicularis oculi muscle from Orbital rim for the correction of tear trough deformity and palabromalar groove in lower blepharoplasty.</p><p><b>METHODS</b>56 cases of lower eye baggy deformity with tear trough deformity and palabromalar groove were treated with the procedure of stripping eye orbicularis oculi muscle from orbital rim by a transcutaneous approach in lower blepharoplasty. The orbital septum was opened along the arcus marginalis for releasing the orbital fat. Some orbital fat was removed if necessary. Then the inferior edge of the orbital septum fat was reset over the orbital rim so as to smooth the infraorbital groove.</p><p><b>RESULTS</b>56 patients were available for 6 to 18 month's follow-up. 54 patients were quite satisfied with the cosmetic result. One developed lower eyelid retraction and another one showed asymmetrical subcutaneous local uneven after 1 month's. They were all corrected by the second operation after 3 months.</p><p><b>CONCLUSIONS</b>Stripping orbicularis oculi muscle from orbital rim plays an important role for the correction of tear trough deformity and palabromalar groove in lower blepharoplasty.</p>

A calcineurin-independent mechanism of angiogenesis inhibition by a nonimmunosuppressive cyclosporin A analog.

Cyclosporin A (CsA) is a widely used immunosuppressant drug. Its immunosuppressive activity occurs through the inhibition of the protein phosphatase calcineurin via formation of a ternary complex with cyclophilin A (CypA). CsA also inhibits endothelial cell proliferation and angiogenesis. This has been thought to occur through calcineurin inhibition as well. However, CsA is also a potent inhibitor of cyclophilins, a class of prolyl isomerases. Because calcineurin inhibition requires binding, and therefore inhibition of CypA, the relative contributions of calcineurin and cyclophilin inhibition in antiangiogenesis have not been addressed. We have taken a chemical biology approach to explore this question by dissociating the two activities of CsA at the molecular level. We have identified a nonimmunosuppressive analog of CsA that does not inhibit calcineurin but maintains inhibition of endothelial cell proliferation and in vivo angiogenesis. The same analog also maintains inhibition of all cyclophilin isoforms tested. We also show that a second, structurally distinct, cyclophilin inhibitor is sufficient to block endothelial cell proliferation. These results suggest that the inhibition of cyclophilins may play a larger role in the antiangiogenic activity of CsA than previously believed, and that cyclophilins may be potential antiangiogenic drug targets.

The role of small molecular weight compounds to increase vacuolation induced by VacA toxin in vitro.

VacA is a vacuolation protein toxin secreted by Helicobacter pylori. Many compounds have been implicated in the regulation of VacA toxin activity. In this study, regulation of cell vacuolation induced by VacA was observed with the addition of glycine, glycine hydrochloride, xylitol, and taurine by neutral red dye uptake assay using gastric human epithelial cell cultures. Glycine, xylitol, and taurine increased cell vacuolation significantly after 48h (p<0.05), with their effect apparent in a wide concentration range (0.2mM to about 100mM). Changes were sharp in respect of concentration and showed little dose-response characteristics. In contrast, upregulation of glycine hydrochloride on cell vacuolation in weak acidic extracellular pH was much retarded with VacA activity not initiated until 72h. In addition, our results showed that cell vacuolation was highest when the pH was 6.8. The increase in vacuolation was gentle in weak acidic extracellular pH and the increase dose-dependent with a Pearson correlation coefficient (r) of 0.986 from 0.2 to 6.25mM. In this concentration range and at the same time point, the pH decrease was negatively correlated with vacuolating activity (r=0.922, p<0.01). In conclusion, our study showed that three small molecular compounds can increase vacuolation induced by VacA toxin in vitro.

[Distribution of C and N in different particle fractions of meadow brown soil in lower reach of Liaohe River Plain].

The study of meadow brown soil with different reclamation history in the lower reach of Liaohe River Plain showed that in 0 approximately 20 and 20 approximately 40 cm soil layers, <0.002 mm fraction had the highest content of organic carbon, followed by < 0.02 and < 0.2 mm fractions. The distribution pattern of total nitrogen was similar to that of organic carbon. There was no obvious correlation between the distribution of organic carbon and total nitrogen in different soil particle fractions and the history of reclamation, but the correlation between organic carbon and total nitrogen in different soil particle fractions was highly significant, with the correlation coefficients 0.74, 0.94 and 0.91 in fractions< 0.2, < 0.02 and < 0.002 mm, respectively.