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To clarify the nutritional mechanisms of quercetin mitigation in the digestive and absorptive functions in rats fed protein-oxidized soybean meal, 48 three-week-old male SD rats were randomly allocated into a 2 × 2 factorial design with two soybean meal types (fresh soybean meal or protein-oxidized soybean meal) and two quercetin levels (0 or 400 mg/kg) for a 28-day feeding trial. The protein-oxidized soybean meal treatment decreased (p < 0.05) the relative weights of the pancreas, stomach, and cecum, duodenal villus height, pancreatic and jejunal lipase activities, apparent ileal digestibility of amino acids, and apparent total tract digestibility of dry matter, crude protein, and ether extract. The supplementation of quercetin in the protein-oxidized soybean meal diet reversed (p < 0.05) the decreases in the duodenal length, ileal villus height, lipase activity, apparent ileal digestibility of amino acids, and apparent total tract digestibility of dry matter, crude protein, and ether extract. Transcriptomics revealed that the “alanine transport” and “lipid digestion and absorption” pathways were downregulated by the protein-oxidized soybean meal compared with fresh soybean meal, while the “basic amino acid transmembrane transporter activity” and “lipid digestion and absorption” pathways were upregulated by the quercetin supplementation. Microbiomics revealed that the protein-oxidized soybean meal increased the protein-degrading and inflammation-triggering bacteria in the cecum, while the relative abundances of beneficial bacteria were elevated by the quercetin supplementation.

This study investigated the effects of different doses of rutin on the growth performance, immunity, intestinal barrier, and antioxidant capacity of broilers. A total of two hundred and fifty-six 1-day-old male broilers were divided into 4 groups and fed basal diets supplemented with 0 (control group), 250, 500 and 1,000 mg rutin/kg, respectively, for 42 days. In the starter period (days 1–21) and whole trial period (days 1–42), broilers fed diets containing 500 mg rutin/kg had significantly (p

To investigate the effects of dietary betaine supplementation on the growth performance, digestive function, intestinal integrity, immunity, and antioxidant capacity of yellow-feathered broilers, a total of 400 one-day-old female yellow-feathered broilers were randomly allocated into 5 dietary treatments with 8 replicates of 10 chicks each, and fed a basal diet supplemented with 0 (control group), 125, 250, 500 and 1000 mg/kg betaine for 74 days, respectively. During the 1–37 days and 1–74 days, betaine linearly increased (p

BackgroundDermatitis 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.MethodsAll 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.ResultsAccording 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).ConclusionThe 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.

Abstract Background Dietary structure in ruminants is closely connected with the composition of gastrointestinal microbiota. Merging study has shown that dietary induced SARA causes the alteration of microbial community in the cecum leading to the local inflammation. However, the mechanisms of cecum inflammation elicited by the shift of microbial flora in ruminants are largely unknown, and whether the development of this inflammation is modified by epigenetic modifications. Results Ten multiparous lactating goats were randomly seperated into two groups and received either a low concentrate diet (LC, 40% concentrate, n = 5) or a high concentrate diet (HC, 60% concentrate) to induce subacute ruminal acidosis (SARA). Compared with LC, HC-induced SARA altered the predominant phyla and genera, thereby increasing the concentration of lipopolysaccharide (LPS) and short chain fatty acids (SCFAs). Meanwhile, HC-induced SARA enhanced the mRNA expression of cytokines and chemokines and the expression of mRNA and protein of GPR41, GPR43, p38 and ERK1/2, while HC-induced SARA had no effect on TLR4 and p65. Furthermore, HC-induced SARA decreased the percentage of chromatin compaction and DNA methylation at the area of the promoters of GPR41 and GPR43. Conclusion This study indicated that HC diet induced SARA resulted in the alteration in the composition of cecal microbiota. This alteration increased the concentration of LPS, but failing to activate TLR4 signaling pathway due to the tolerance effect of intestinal epithelial cell to certain level of LPS, as well as elevated the concentration of SCFAs, thereby activating GPR41 and GPR43 signaling pathway to produce cytokines and chemokins and cause the cecal inflammation. And epigenetic mechanisms contributed to the development of this inflammation in the lactating goats suffering from SARA.

The effects of dietary palygorskite (Pal) supplementation on growth performance, oxidative status, and intestinal barrier function in ducks were investigated. In total, 720 one-day-old Cherry Valley ducks were categorized into 4 treatments comprising 6 replicates with 30 ducks each. Ducks were fed a basal diet supplemented with 0, 5, 10, or 20 g/kg Pal for 42 days. Twenty-four ducks (1 male/replicate) were slaughtered at 14 and 42 days and samples were collected for analysis. Pal supplementation quadratically increased weight gain and linearly and quadratically increased feed intake (P

To investigate the effect of betaine supplementation on growth performance, muscle protein deposition, muscle nucleic acid and amino acid contents, and muscle proteome of broilers, 160 one-day-old male partridge shank broiler chickens were randomly divided into 2 groups with 8 replicates of 10 broilers each. Broilers were fed a basal diet alone, or a basal diet supplemented with 1000 mg/kg betaine. Compared with the control group, the betaine group significantly increased (p < 0.05) the broilers average daily gain, the levels of serum insulin-like growth factor-1 (IGF-1), growth hormone (GH), total protein (TP), the contents of muscle absolute protein deposition, RNA, Ser, Glu, Met, and Phe, and the ratio of RNA/DNA, and decreased (p < 0.05) the feed conversion ratio and serum blood urea nitrogen content. Moreover, proteomic analysis revealed 35 differentially abundant proteins (DAPs) in the betaine group compared with the control group, including 27 upregulated proteins and 8 downregulated proteins (p < 0.05). These DAPs were mainly related to cell differentiation, small molecule metabolic process, and tissue development. In conclusion, diets supplemented with 1000 mg/kg betaine improved growth performance and muscle protein deposition of broilers. Increased serum GH, IGF-1, and TP contents, and alterations in muscle nucleic acids, amino acids, and protein abundance levels were involved in this process.

This study was conducted to investigate the effect of hatching weight (HW) on the growth, immunity and oxidative status of broilers for 21 d. Male chicks (Arbor Acres) were divided into 2 groups according to HW (51.30±0.21 and 42.97±0.11 g, respectively), each of which consisted of 8 replicates of 10 birds. Chicks with high HW exhibited heavier body weight in the first two weeks (P

PURPOSE:Epigenetic modifications critically regulate the expression of immune-related genes in response to inflammatory stimuli. It has been extensively reported that a high concentrate (HC) diet can trigger systemic inflammation in dairy cows, yet it is unclear whether epigenetic regulation is involved in the expression of immune genes in the livers of dairy cows. This study aimed to investigate the impact of epigenetic modifications on the expression of immune-related genes. EXPERIMENTAL DESIGN:In eight mid-lactating cows, we installed a rumen cannula and catheters of the portal and hepatic veins. Cows were randomly assigned to either the treatment group fed a high concentrate (HC) diet (60% concentrate + 40% forage, n = 4) or a control group fed a low concentrate (LC) diet (40% concentrate + 60% forage, n = 4). RESULTS:After 10 weeks of feeding, the rumen pH was reduced, and levels of lipopolysaccharide (LPS) in the rumen, and portal and hepatic veins were notably increased in the HC group compared with the LC group. The expression levels of detected immune response-related genes, including Toll-like receptor 4 (TLR4), cytokines, chemokines, and acute phase proteins, were significantly up-regulated in the livers of cows fed a HC diet. Chromatin loosening at the promoter region of four candidate immune-related genes (TLR4, LPS-binding protein, haptoglobin, and serum amyloid A3) was elicited, and was strongly correlated with enhanced expression of these genes in the HC group. Demethylation at the promoter region of all four candidate immune-related genes was accompanied by chromatin decompaction. CONCLUSION:After HC diet feeding, LPS derived from the digestive tract translocated to the liver via the portal vein, enhancing hepatic immune gene expression. The up-regulation of these immune genes was mediated by epigenetic mechanisms, which involve chromatin remodeling and DNA methylation. Our findings suggest that modulating epigenetic mechanisms could provide novel ways to treat systemic inflammatory responses elicited by the feeding of a HC diet.

PURPOSE: The mechanism underlying the decline in milk quality during periods of feeding high-concentrate diets to dairy ruminants is not well documented. The aim of this study was to investigate the metabolic changes in the liver that contribute to the input of substrate precursors to the mammary gland after feeding a high-concentrate diet to lactating goats for a long period. EXPERIMENTAL DESIGN: Eight mid-lactating goats with rumen cannulas were randomly assigned to two groups. For 9 weeks, the treatment group was fed a high-concentrate diet (60% concentrate of dry matter, HC) and the control group was fed a low-concentrate diet (40% concentrate of dry matter, LC). Ruminal fluid, plasma, and liver tissues were sampled, microarray techniques and real-time polymerase chain reaction were used to evaluate metabolic parameters and gene expression in liver. RESULTS: Feeding a 60%-concentrate diet for 9 weeks resulted in a significant decrease in rumen pH. Changes in fat and protein content also occurred, which negatively affected milk quality. Plasma levels of leptin (p = 0.058), non-esterified fatty acid (p = 0.071), and glucose (p = 0.014) increased markedly in HC group. Plasma cortisol concentration was significantly elevated in the treatment group (p

In the 21st century, translation studies has expanded its boundaries and paradigms so that it is now possible to use its tools and methods to research the communication of fashion at textual as well as material levels, as inter-semiotic and cultural translation. Fashion communication, from the perspective of post translation studies, can be viewed as a process of cultural translation with visual symbols as its main text form, visual rhetoric as its core meaning system and a visual designer as its translator. At the intersection of translation, communication and fashion studies, the article takes Kenzo's most successful "tiger icon" as the main research object, through the analysis of different forms of visual text structures throughout the whole process of fashion communication, to explore the semiotic transformation process and strategy of the "tiger icon" by means of visual rhetoric theories. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The mixing within a full depth lock-exchange gravity current was investigated experimentally with planar laser-induced fluorescence PLIF. The scalar edge of the gravity current was identified via an edge detection algorithm. A strong mixing region located along this edge was extracted from the flow field and analyzed. A dimensionless background potential energy was defined to characterize the local mixing rate in this region, which showed a two-stage behavior. In the section near the nose, mixing rate oscillates strongly under the influence of the lobe and cleft shifting, while in the upper part, the mixing rate grows gradually under the mechanism of billows rolling up. [ABSTRACT FROM AUTHOR]

The flapping of a flag in the wind is a classical fluid-structure problem that concerns the interaction of elastic bodies with ambient fluid. We focus on the desirable experimental results of the flow around the flapping flag. By immersing the elastic yet self-supporting heavy flag into water flow, we use particle image velocimetry (PIV) techniques to obtain the whole flow field around the midspan of the flag interacting with a fluid in periodic state. A unique PIV image processing method is used to measure near-wall flow velocities around a moving elastic flag. There exists a thin flow circulation region on the suction side of the flag in periodic state. This observation suggests that viscous flow models may be needed to improve the theoretical predictions of the flapping flag in periodic state, especially in a large amplitude. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This study investigated the effect of magnesium sulfate (MgSO4) on the viability of the human gastric adenocarcinoma (AGS) epithelial cell line. AGS cells were exposed to various concentrations of MgSO4for different time-periods and the effects on cell viability, DNA fragmentation, apoptotic gene expression, and caspase activity were investigated. A range of tests were employed in this study, including a lactate dehydrogenase cell viability assay, annexin V staining, reverse transcription polymerase chain reaction (RT-PCR), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and several caspase activity assays. Expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), Fas ligand (FasL) and Fas receptor (FasR) were analyzed using RT-PCR. These analyses revealed that MgSO4induced a dose-dependent reduction in AGS cell viability. Annexin V staining did not differ between negative control and treated cells, indicating that no apoptotic cells were detected. The TUNEL assay data were consistent with the annexin V staining results. FasL mRNA expression was increased and FasR mRNA expression was decreased in a dose-dependent manner by MgSO4. MgSO4treatment tended to cause an initial (1 h) dose-dependent increase in the activities of caspase-3, -6, -8, and -9; however, these activities were subsequently inhibited (24 h). We deduced that MgSO4exerted an anti-apoptotic effect in AGS cells via caspase activation. [ABSTRACT FROM PUBLISHER]

Background: The effects of feeding a high-grain (HG) diet on lipopolysaccharide (LPS) clearance and innate immune defence responses in the liver remain unclear. Therefore, we conducted the present study in which twelve female goats were randomly assigned to either a treatment group fed a HG diet (60% grain, n = 6) or a control group fed a low grain diet (LG; 40% grain, n = 6) for 6 weeks. Catheters were installed in the mesenteric, portal and hepatic veins, as well as one femoral artery of the goats, for determining blood flow and net clearance rate of LPS in the liver. Plasma and tissue samples were collected in the week 6 for analyzing pro-inflammatory cytokines, acute phase protein and biochemical parameters, as well as expression of genes involved in immune response. Result: HG diet feeding increased blood flow and LPS concentration in the portal vein, hepatic vein and artery. Hepatic net LPS clearance showed that HG diet feeding elevated the rate of hepatic LPS clearance, but decreased the percentage of removed LPS accounting for the total entry of LPS into the liver. Our results demonstrated that the feeding of HG diet increased plasma concentrations of pro-inflammatory cytokines and acute phase proteins and triggered a systemic inflammatory response. In addition, peripheral blood plasma concentrations of alanine aminotransferase, alkaline phosphatase and total bilirubin were increased in the HG group compared to the LG group. This indicated that the impairment of hepatocytes occurred after 6 weeks of HG diet feeding. The expression of genes involved in immune response and Toll-like receptor (TLR)4 protein in the liver was up-regulated in the HG group compared to the LG group, indicating that increased entry of LPS enhanced hepatic immune defence responses and contributed to hepatic inflammatory responses. Conclusion: These results provide insight into the capacity of the liver to clear LPS. The increased entry of LPS into liver enhanced hepatic immune defence responses, thereby elevated the rate of LPS clearance. However, the reduction of the percentage of hepatic LPS clearance could be due to the formation of hepatocyte lesion during HG diet feeding. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to determine whether carnitine was responsible for the increased energy metabolism observed in Sprague-Dawley rats following inclusion of lamb meat in their diet. This was tested by feeding one of the following three diets: a control diet (control) based on a standard formulation (AIN-93G), a carnitine-supplemented control diet (CD) and a lamb meat diet (LD). All diets were isocaloric (15.46 kJ/g DM) and contained 18.3% protein, 7.1% fat and 58.3% carbohydrate. The carnitine concentrations in the control diet, CD and LD were 29, 984 and 953 mg/kg, respectively. The expression of carnitine palmitoyltransferase-I(CPT-I)α and CTP-Iβ genes, Na,K-ATPase activities and the contents of fat, ATP and creatine phosphate (Cr.P) in liver and skeletal muscle tissues were measured on Days 7 and 14. Bodyweights, bodyweight gains and oxygen consumption rates (OCR) of rats were also measured. The rats fed the LD had higher OCR, ATP and Cr.P concentrations, expressions of CPT-I gene, Na,K-ATPase activities, and lower fat contents, bodyweights and bodyweight gains (P < 0.05) than did the control-group rats. However, rats fed the CD were not significantly different from those fed the control diet, except for the higher CPT-Iα expression, ATP concentrations and lower fat contents in liver (P < 0.05). We conclude that carnitine intake from lamb was not the main factor accounting for the significant effects of lamb consumption on energy metabolism. However, it is likely that carnitine intake by consumption of lamb meat in the LD partly contributed to lowering fat contents in liver, compared with the CD and the control diet groups. There is potential for lamb to be promoted as a meat-based functional food. Carnitine from lamb has been found to reduce the liver fat content of rats. Meat-based functional foods are being seen as an opportunity to improve the 'image' of meat as a healthy product. [ABSTRACT FROM AUTHOR]

The free-fall motion of a thin disk with small dimensionless moments of inertia (${I}^{\ast } \lt 1{0}^{- 3} $) was investigated experimentally. The transition from two-dimensional zigzag motion to three-dimensional spiral motion occurs due to the growth of three-dimensional disturbances. Oscillations in the direction normal to the zigzag plane increase with the development of this instability. At the same time, the oscillation of the nutation angle decreases to zero and the angle remains constant. The effects of initial conditions (release angle) were investigated. Two kinds of transition modes, zigzag–spiral transition and zigzag–spiral–zigzag intermittence transition, were observed to be separated by a critical Reynolds number. In addition, the solution of the generalized Kirchhoff equations shows that the small ${I}^{\ast } $ is responsible for the growth of disturbances in the third dimension (perpendicular to the planar motion). [ABSTRACT FROM PUBLISHER]

Provides information on a study investigating the total synthesis of taxane systems focusing on the development of practical route for complete functionalization of the A ring. Methodology used to conduct the study; Information on the consideration of dual activation as a tool for possible introduction of the bridgehead olefinic bond; Success of the dihydroxylation pathway; Findings of the study.

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 IC 50 is 0.23 μ M and 0.17 μ M, respectively. Due to high homology, CsA also had inhibitory effects on SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), and the IC 50 is 3.2 μ M and 2.8 μ M, 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., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

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.