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Ten acridones isolated from Atalantia monophylla were evaluated for effects on Alzheimer’s disease pathogenesis including antioxidant effects, acetylcholinesterase (AChE) inhibition, prevention of beta-amyloid (Aβ) aggregation and neuroprotection. To understand the mechanism, the type of AChE inhibition was investigated in vitro and binding interactions between acridones and AChE or Aβ were explored in silico. Drug-likeness and ADMET parameters were predicted in silico using SwissADME and pKCSM programs, respectively. All acridones showed favorable drug-likeness and possessed multifunctional activities targeting AChE function, Aβ aggregation and oxidation. All acridones inhibited AChE in a mixed-type manner and bound AChE at both catalytic anionic and peripheral anionic sites. In silico analysis showed that acridones interfered with Aβ aggregation by interacting at the central hydrophobic core, C-terminal hydrophobic region, and the key residues 41 and 42. Citrusinine II showed potent multifunctional action with the best ADMET profile and could alleviate neuronal cell damage induced by hydrogen peroxide and Aβ1-42 toxicity.
Pitchayakarn Takomthong; Pornthip Waiwut; Chavi Yenjai; Aonnicha Sombatsri; Prasert Reubroycharoen; Luo Lei; Ren Lai; Suchada Chaiwiwatrakul; Chantana Boonyarat. Multi-Target Actions of Acridones from Atalantia monophylla towards Alzheimer’s Pathogenesis and Their Pharmacokinetic Properties. Pharmaceuticals 2021, 14, 888 .
AMA StylePitchayakarn Takomthong, Pornthip Waiwut, Chavi Yenjai, Aonnicha Sombatsri, Prasert Reubroycharoen, Luo Lei, Ren Lai, Suchada Chaiwiwatrakul, Chantana Boonyarat. Multi-Target Actions of Acridones from Atalantia monophylla towards Alzheimer’s Pathogenesis and Their Pharmacokinetic Properties. Pharmaceuticals. 2021; 14 (9):888.
Chicago/Turabian StylePitchayakarn Takomthong; Pornthip Waiwut; Chavi Yenjai; Aonnicha Sombatsri; Prasert Reubroycharoen; Luo Lei; Ren Lai; Suchada Chaiwiwatrakul; Chantana Boonyarat. 2021. "Multi-Target Actions of Acridones from Atalantia monophylla towards Alzheimer’s Pathogenesis and Their Pharmacokinetic Properties." Pharmaceuticals 14, no. 9: 888.
Soy diet is thought to help prevent cardiovascular diseases in humans. Isoflavone, which is abundant in soybean and other legumes, has been reported to possess antiplatelet activity and potential antithrombotic effect. Our study aims to elucidate the potential target of soy isoflavone in platelet. The anti-thrombosis formation effect of genistein and daidzein was evaluated in ex vivo perfusion chamber model under low (300 s−1) and high (1800 s−1) shear forces. The effect of genistein and daidzein on platelet aggregation and spreading was evaluated with platelets from both wildtype and GPIbα deficient mice. The interaction of these soy isoflavone with 14-3-3ζ was detected by surface plasmon resonance (SPR) and co-immunoprecipitation, and the effect of αIIbβ3-mediated outside-in signaling transduction was evaluated by western blot. We found both genistein and daidzein showed inhibitory effect on thrombosis formation in perfusion chamber, especially under high shear force (1800 s−1). These soy isoflavone interact with 14-3-3ζ and inhibited both GPIb-IX and αIIbβ3-mediated platelet aggregation, integrin-mediated platelet spreading and outside-in signaling transduction. Our findings indicate that 14-3-3ζ is a novel target of genistein and daidzein. 14-3-3ζ, an adaptor protein that regulates both GPIb-IX and αIIbβ3-mediated platelet activation is involved in soy isoflavone mediated platelet inhibition.
Ming Liu; Gan Wang; Runjia Xu; Chuanbin Shen; Heyu Ni; Ren Lai. Soy Isoflavones Inhibit Both GPIb-IX Signaling and αIIbβ3 Outside-In Signaling via 14-3-3ζ in Platelet. Molecules 2021, 26, 4911 .
AMA StyleMing Liu, Gan Wang, Runjia Xu, Chuanbin Shen, Heyu Ni, Ren Lai. Soy Isoflavones Inhibit Both GPIb-IX Signaling and αIIbβ3 Outside-In Signaling via 14-3-3ζ in Platelet. Molecules. 2021; 26 (16):4911.
Chicago/Turabian StyleMing Liu; Gan Wang; Runjia Xu; Chuanbin Shen; Heyu Ni; Ren Lai. 2021. "Soy Isoflavones Inhibit Both GPIb-IX Signaling and αIIbβ3 Outside-In Signaling via 14-3-3ζ in Platelet." Molecules 26, no. 16: 4911.
Glioma is the most common form of malignant brain cancer. It is very difficult to cure malignant glioma because of the presence of glioma stem cells, which are a barrier to cure, have high tumorigenesis, associated with drug resistance, and responsible for relapse by regulating stemness genes. In this study, our results demonstrated that anticarin β, a natural compound from Antiaris toxicaria, can effectively and selectively suppress proliferation and cause apoptosis in glioma cells, which has an IC50 that is 100 times lower than that in mouse normal neural stem cells. Importantly, cell sphere formation assay and real time-quantitative analysis reveal that anticarin β inhibits cancer stemness by modulating related stemness gene expression. Additionally, anticarin β induces DNA damage to regulate the oncogene expression of signal transducer and activator of transcription 3 (STAT3), Akt, mitogen-activated protein kinases (MAPKs), and eventually leading to apoptosis. Furthermore, anticarin β effectively inhibits glioma growth and prolongs the lifts pan of tumor-bearing mice without systemic toxicity in the orthotopic xenograft mice model. These results suggest that anticarin β is a promising candidate inhibitor for malignant glioma.
Min Zhang; Zhi Dai; Xudong Zhao; Gan Wang; Ren Lai. Anticarin β Inhibits Human Glioma Progression by Suppressing Cancer Stemness via STAT3. Frontiers in Oncology 2021, 11, 1 .
AMA StyleMin Zhang, Zhi Dai, Xudong Zhao, Gan Wang, Ren Lai. Anticarin β Inhibits Human Glioma Progression by Suppressing Cancer Stemness via STAT3. Frontiers in Oncology. 2021; 11 ():1.
Chicago/Turabian StyleMin Zhang; Zhi Dai; Xudong Zhao; Gan Wang; Ren Lai. 2021. "Anticarin β Inhibits Human Glioma Progression by Suppressing Cancer Stemness via STAT3." Frontiers in Oncology 11, no. : 1.
Summary Temperature sensing is essential for the survival of living organisms. Some reptile embryos can reposition themselves within the egg to seek optimal temperatures, but the molecular sensors involved in this temperature detection remain unknown. Here, we show that such thermotaxic behavior is directly determined by the activation of two heat-sensitive ion channels of the turtle: the transient receptor potential ankyrin 1 (MrTRPA1) and transient receptor potential vanilloid-1 (MrTRPV1). These two TRP channels were found to exhibit distinctive distributions among turtle dorsal root ganglion (DRG) neurons. Additionally, our laser irradiation assays illustrated that the heat activation thresholds of MrTRPA1 and MrTRPV1 are consistent with the mild (28–33°C) and noxious (>33°C) heat determined by behavioral tests, respectively. Further pharmacological studies have demonstrated that ligand-induced intervention of MrTRPA1 or MrTRPV1 is sufficient to mimic heat stimuli or block temperature signaling, causing changes in embryo movement. These findings indicate that the initiation of thermotaxic response in turtle embryos relies on a delicate functional balance between the heat activation of MrTRPA1 and MrTRPV1. Our study reveals, for the first time, a unique molecular mechanism underlying thermal detection: the two TRP channels act as a physiological tandem to control the thermotaxic behavior of turtle embryos.
Yin-Zi Ye; Hao Zhang; Jiameng Li; Ren Lai; Shilong Yang; Wei-Guo Du. Molecular sensors for temperature detection during behavioral thermoregulation in turtle embryos. Current Biology 2021, 31, 2995 -3003.e4.
AMA StyleYin-Zi Ye, Hao Zhang, Jiameng Li, Ren Lai, Shilong Yang, Wei-Guo Du. Molecular sensors for temperature detection during behavioral thermoregulation in turtle embryos. Current Biology. 2021; 31 (14):2995-3003.e4.
Chicago/Turabian StyleYin-Zi Ye; Hao Zhang; Jiameng Li; Ren Lai; Shilong Yang; Wei-Guo Du. 2021. "Molecular sensors for temperature detection during behavioral thermoregulation in turtle embryos." Current Biology 31, no. 14: 2995-3003.e4.
Wenliang Zhou; Shilong Yang; Ren Lai; Fuwen Wei. How two sesquiterpenes drive horse manure rolling behavior in wild giant pandas. Chemoecology 2021, 1 -3.
AMA StyleWenliang Zhou, Shilong Yang, Ren Lai, Fuwen Wei. How two sesquiterpenes drive horse manure rolling behavior in wild giant pandas. Chemoecology. 2021; ():1-3.
Chicago/Turabian StyleWenliang Zhou; Shilong Yang; Ren Lai; Fuwen Wei. 2021. "How two sesquiterpenes drive horse manure rolling behavior in wild giant pandas." Chemoecology , no. : 1-3.
Background and Purpose Itching is the most frequent pathology in dermatology which has grievous impacts on people’s mental health and social life. Transient receptor potential vanilloid 3 (TRPV3) channel is a promising target for treating pruritus. However, few specific and potent antagonists have been reported. This study was designed to identify selective TRPV3 antagonist and elucidate its anti‐pruritus pharmacology. Experimental Approach Flexstation and calcium fluorescence imaging were conducted to track the functional compounds. Whole‐cell patch clamp was used to record itch‐related ion channel currents. Homologous recombination and site‐directed mutagenesis were employed to construct TRPV3 channel chimeras and point mutations for exploring pharmacological mechanism. Mouse models were used for in vivo anti‐pruritus assay. Key Results An acridone alkaloid (citrusinine‐II) was purified and characterized from Atalantia monophylla. It directly interacts with Y564 within S4 helix of TRPV3 to selectively inhibit the channel with a half maximal inhibitory concentration (IC50) of 12.43 μM. Citrusinine‐II showed potential efficacy to attenuate both chronic and acute itch. Intradermal administration of citrusinine‐II (143 ng/skin site) nearly completely inhibited itch behaviors. It also shows significant analgesic effects. Little side effects of the compound are observed. Conclusion and Implications By acting as a specific and potent inhibitor of TRPV3 channel, citrusinine‐II shows valuable therapeutic effects in pruritus animal models and is a promising candidate drug and/or lead molecule for the development of anti‐pruritus drugs.
Yalan Han; Anna Luo; Peter Muiruri Kamau; Pitchayakarn Takomthong; Jingmei Hu; Chantana Boonyarat; Lei Luo; Ren Lai. A plant‐derived TRPV3 inhibitor suppresses pain and itch. British Journal of Pharmacology 2021, 178, 1669 -1683.
AMA StyleYalan Han, Anna Luo, Peter Muiruri Kamau, Pitchayakarn Takomthong, Jingmei Hu, Chantana Boonyarat, Lei Luo, Ren Lai. A plant‐derived TRPV3 inhibitor suppresses pain and itch. British Journal of Pharmacology. 2021; 178 (7):1669-1683.
Chicago/Turabian StyleYalan Han; Anna Luo; Peter Muiruri Kamau; Pitchayakarn Takomthong; Jingmei Hu; Chantana Boonyarat; Lei Luo; Ren Lai. 2021. "A plant‐derived TRPV3 inhibitor suppresses pain and itch." British Journal of Pharmacology 178, no. 7: 1669-1683.
Attraction to feces in wild mammalian species is extremely rare. Here we introduce the horse manure rolling (HMR) behavior of wild giant pandas (Ailuropoda melanoleuca). Pandas not only frequently sniffed and wallowed in fresh horse manure, but also actively rubbed the fecal matter all over their bodies. The frequency of HMR events was highly correlated with an ambient temperature lower than 15 °C. BCP/BCPO (beta-caryophyllene/caryophyllene oxide) in fresh horse manure was found to drive HMR behavior and attenuated the cold sensitivity of mice by directly targeting and inhibiting transient receptor potential melastatin 8 (TRPM8), an archetypical cold-activated ion channel of mammals. Therefore, horse manure containing BCP/BCPO likely bestows the wild giant pandas with cold tolerance at low ambient temperatures. Together, our study described an unusual behavior, identified BCP/BCPO as chemical inhibitors of TRPM8 ion channel, and provided a plausible chemistry-auxiliary mechanism, in which animals might actively seek and utilize potential chemical resources from their habitat for temperature acclimatization.
Wenliang Zhou; Shilong Yang; Bowen Li; Yonggang Nie; Anna Luo; Guangping Huang; Xuefeng Liu; Ren Lai; Fuwen Wei. Why wild giant pandas frequently roll in horse manure. Proceedings of the National Academy of Sciences 2020, 117, 32493 -32498.
AMA StyleWenliang Zhou, Shilong Yang, Bowen Li, Yonggang Nie, Anna Luo, Guangping Huang, Xuefeng Liu, Ren Lai, Fuwen Wei. Why wild giant pandas frequently roll in horse manure. Proceedings of the National Academy of Sciences. 2020; 117 (51):32493-32498.
Chicago/Turabian StyleWenliang Zhou; Shilong Yang; Bowen Li; Yonggang Nie; Anna Luo; Guangping Huang; Xuefeng Liu; Ren Lai; Fuwen Wei. 2020. "Why wild giant pandas frequently roll in horse manure." Proceedings of the National Academy of Sciences 117, no. 51: 32493-32498.
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic worldwide. Currently, however, no effective drug or vaccine is available to treat or prevent the resulting coronavirus disease 2019 (COVID-19). Here, we report our discovery of a promising anti-COVID-19 drug candidate, the lipoglycopeptide antibiotic dalbavancin, based on virtual screening of the FDA-approved peptide drug library combined with in vitro and in vivo functional antiviral assays. Our results showed that dalbavancin directly binds to human angiotensin-converting enzyme 2 (ACE2) with high affinity, thereby blocking its interaction with the SARS-CoV-2 spike protein. Furthermore, dalbavancin effectively prevents SARS-CoV-2 replication in Vero E6 cells with an EC50 of ~12 nM. In both mouse and rhesus macaque models, viral replication and histopathological injuries caused by SARS-CoV-2 infection are significantly inhibited by dalbavancin administration. Given its high safety and long plasma half-life (8–10 days) shown in previous clinical trials, our data indicate that dalbavancin is a promising anti-COVID-19 drug candidate.
Gan Wang; Meng-Li Yang; Zi-Lei Duan; Feng-Liang Liu; Lin Jin; Cheng-Bo Long; Min Zhang; Xiao-Peng Tang; Ling Xu; Ying-Chang Li; Peter Muiruri Kamau; Lian Yang; Hong-Qi Liu; Jing-Wen Xu; Jie-Kai Chen; Yong-Tang Zheng; Xiao-Zhong Peng; Ren Lai. Dalbavancin binds ACE2 to block its interaction with SARS-CoV-2 spike protein and is effective in inhibiting SARS-CoV-2 infection in animal models. Cell Research 2020, 31, 17 -24.
AMA StyleGan Wang, Meng-Li Yang, Zi-Lei Duan, Feng-Liang Liu, Lin Jin, Cheng-Bo Long, Min Zhang, Xiao-Peng Tang, Ling Xu, Ying-Chang Li, Peter Muiruri Kamau, Lian Yang, Hong-Qi Liu, Jing-Wen Xu, Jie-Kai Chen, Yong-Tang Zheng, Xiao-Zhong Peng, Ren Lai. Dalbavancin binds ACE2 to block its interaction with SARS-CoV-2 spike protein and is effective in inhibiting SARS-CoV-2 infection in animal models. Cell Research. 2020; 31 (1):17-24.
Chicago/Turabian StyleGan Wang; Meng-Li Yang; Zi-Lei Duan; Feng-Liang Liu; Lin Jin; Cheng-Bo Long; Min Zhang; Xiao-Peng Tang; Ling Xu; Ying-Chang Li; Peter Muiruri Kamau; Lian Yang; Hong-Qi Liu; Jing-Wen Xu; Jie-Kai Chen; Yong-Tang Zheng; Xiao-Zhong Peng; Ren Lai. 2020. "Dalbavancin binds ACE2 to block its interaction with SARS-CoV-2 spike protein and is effective in inhibiting SARS-CoV-2 infection in animal models." Cell Research 31, no. 1: 17-24.
Envenomation by viperid snakes may lead to severe bleeding, consumption coagulopathy, and thrombotic microangiopathy symptoms. The exact etiology or toxins responsible for thrombotic microangiopathy symptoms after snake envenomation remain obscure. Snake C-type lectin-like proteins (snaclecs) are one of the main non-enzymatic protein constituents in viper venoms, of which a majority are considered as modulators of thrombosis and hemostasis. In this study, we demonstrated that two snaclecs (mucetin and stejnulxin), isolated and identified from Protobothrops mucrosquamatus and Trimeresurus stejnegeri venoms, directly induced platelet degranulation and clot-retraction in vitro, and microvascular thrombosis has been confirmed in various organs in vivo. These snaclecs reduced cerebral blood flow and impaired motor balance and spatial memories in mice, which partially represent the thrombotic microangiopathy symptoms in some snakebite patients. The functional blocking of these snaclecs with antibodies alleviated the viper venom induced platelet activation and thrombotic microangiopathy-like symptoms. Understanding the pathophysiology of thrombotic microangiopathy associated with snake envenoming may lead to emerging therapeutic strategies.
Chengbo Long; Ming Liu; Huiwen Tian; Ya Li; Feilong Wu; James Mwangi; Qiumin Lu; Tarek Mohamed Abd El-Aziz; Ren Lai; Chuanbin Shen. Potential Role of Platelet-Activating C-Type Lectin-Like Proteins in Viper Envenomation Induced Thrombotic Microangiopathy Symptom. Toxins 2020, 12, 749 .
AMA StyleChengbo Long, Ming Liu, Huiwen Tian, Ya Li, Feilong Wu, James Mwangi, Qiumin Lu, Tarek Mohamed Abd El-Aziz, Ren Lai, Chuanbin Shen. Potential Role of Platelet-Activating C-Type Lectin-Like Proteins in Viper Envenomation Induced Thrombotic Microangiopathy Symptom. Toxins. 2020; 12 (12):749.
Chicago/Turabian StyleChengbo Long; Ming Liu; Huiwen Tian; Ya Li; Feilong Wu; James Mwangi; Qiumin Lu; Tarek Mohamed Abd El-Aziz; Ren Lai; Chuanbin Shen. 2020. "Potential Role of Platelet-Activating C-Type Lectin-Like Proteins in Viper Envenomation Induced Thrombotic Microangiopathy Symptom." Toxins 12, no. 12: 749.
Angiotensin-converting enzyme 2 (ACE2) has been suggested as a receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry to cause coronavirus disease 2019 (COVID-19). However, no ACE2 inhibitors have shown definite beneficiaries for COVID-19 patients, applying the presence of another receptor for SARS-CoV-2 entry. Here we show that ACE2 knockout dose not completely block virus entry, while TfR directly interacts with virus Spike protein to mediate virus entry and SARS-CoV-2 can infect mice with over-expressed humanized transferrin receptor (TfR) and without humanized ACE2. TfR-virus co-localization is found both on the membranes and in the cytoplasma, suggesting SARS-CoV-2 transporting by TfR, the iron-transporting receptor shuttling between cell membranes and cytoplasma. Interfering TfR-Spike interaction blocks virus entry to exert significant anti-viral effects. Anti-TfR antibody (EC50 ∼16.6 nM) shows promising anti-viral effects in mouse model. Collectively, this report indicates that TfR is another receptor for SARS-CoV-2 entry and a promising anti-COVID-19 target.
Ren Lai; Xiaopeng Tang; Mengli Yang; Zilei Duan; Zhiyi Liao; Lei Liu; Ruomei Cheng; Mingqian Fang; Gan Wang; Hongqi Liu; Jingwen Xu; Peter Kamau; Zhiye Zhang; Lian Yang; Xudong Zhao; Xiaozhong Peng. Transferrin receptor is another receptor for SARS-CoV-2 entry. 2020, 1 .
AMA StyleRen Lai, Xiaopeng Tang, Mengli Yang, Zilei Duan, Zhiyi Liao, Lei Liu, Ruomei Cheng, Mingqian Fang, Gan Wang, Hongqi Liu, Jingwen Xu, Peter Kamau, Zhiye Zhang, Lian Yang, Xudong Zhao, Xiaozhong Peng. Transferrin receptor is another receptor for SARS-CoV-2 entry. . 2020; ():1.
Chicago/Turabian StyleRen Lai; Xiaopeng Tang; Mengli Yang; Zilei Duan; Zhiyi Liao; Lei Liu; Ruomei Cheng; Mingqian Fang; Gan Wang; Hongqi Liu; Jingwen Xu; Peter Kamau; Zhiye Zhang; Lian Yang; Xudong Zhao; Xiaozhong Peng. 2020. "Transferrin receptor is another receptor for SARS-CoV-2 entry." , no. : 1.
Angiotensin-converting enzyme 2 (ACE2) has been suggested as a receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry to cause coronavirus disease 2019 (COVID-19). However, no ACE2 inhibitors have shown definite beneficiaries for COVID-19 patients, applying the presence of another receptor for SARS-CoV-2 entry. Here we show that ACE2 knockout dose not completely block virus entry, while TfR directly interacts with virus Spike protein to mediate virus entry and SARS-CoV-2 can infect mice with over-expressed humanized transferrin receptor (TfR) and without humanized ACE2. TfR-virus co-localization is found both on the membranes and in the cytoplasma, suggesting SARS-CoV-2 transporting by TfR, the iron-transporting receptor shuttling between cell membranes and cytoplasma. Interfering TfR-Spike interaction blocks virus entry to exert significant anti-viral effects. Anti-TfR antibody (EC50 16.6 nM) shows promising anti-viral effects in mouse model. Collectively, this report indicates that TfR is another receptor for SARS-CoV-2 entry and a promising anti-COVID-19 target.
Xiaopeng Tang; Mengli Yang; Zilei Duan; Zhiyi Liao; Lei Liu; Ruomei Cheng; Mingqian Fang; Gan Wang; Hongqi Liu; Jingwen Xu; Peter M Kamau; Zhiye Zhang; Lian Yang; Xudong Zhao; Xiaozhong Peng; Ren Lai. Transferrin receptor is another receptor for SARS-CoV-2 entry. 2020, 1 .
AMA StyleXiaopeng Tang, Mengli Yang, Zilei Duan, Zhiyi Liao, Lei Liu, Ruomei Cheng, Mingqian Fang, Gan Wang, Hongqi Liu, Jingwen Xu, Peter M Kamau, Zhiye Zhang, Lian Yang, Xudong Zhao, Xiaozhong Peng, Ren Lai. Transferrin receptor is another receptor for SARS-CoV-2 entry. . 2020; ():1.
Chicago/Turabian StyleXiaopeng Tang; Mengli Yang; Zilei Duan; Zhiyi Liao; Lei Liu; Ruomei Cheng; Mingqian Fang; Gan Wang; Hongqi Liu; Jingwen Xu; Peter M Kamau; Zhiye Zhang; Lian Yang; Xudong Zhao; Xiaozhong Peng; Ren Lai. 2020. "Transferrin receptor is another receptor for SARS-CoV-2 entry." , no. : 1.
Rationale: Epidemiological studies have identified an associate between iron deficiency (ID) and the use of oral contraceptives (CC) and ischemic stroke (IS). To date, however, the underlying mechanism remains poorly understood. Both ID and CC have been demonstrated to upregulate the level and iron-binding ability of Tf (transferrin), with our recent study showing that this upregulation can induce hypercoagulability by potentiating FXIIa/thrombin and blocking antithrombin-coagulation proteases interactions. Objective: To investigate whether Tf mediates IS associated with ID or CC and the underlying mechanisms. Methods and Results: Tf levels were assayed in the plasma of IS patients with a history of ID anemia, ID anemia patients, venous thromboembolism patients using CC, and ID mice, and in the cerebrospinal fluid of some IS patients. Effects of ID and estrogen administration on Tf expression and coagulability and the underlying mechanisms were studied in vivo and in vitro. High levels of Tf and Tf-thrombin/FXIIa complexes were found in patients and ID mice. Both ID and estrogen upregulated Tf through hypoxia and estrogen response elements located in the Tf gene enhancer and promoter regions, respectively. In addition, ID, administration of exogenous Tf or estrogen, and Tf overexpression promoted platelet-based thrombin generation and hypercoagulability and thus aggravated IS. In contrast, anti-Tf antibodies, Tf knockdown, and peptide inhibitors of Tf-thrombin/FXIIa interaction exerted anti-IS effects in vivo. Conclusions: Our findings revealed that certain factors (ie, ID and CC) upregulating Tf are risk factors of thromboembolic diseases decipher a previously unrecognized mechanistic association among ID, CC, and IS and provide a novel strategy for the development of anti-IS medicine by interfering with Tf-thrombin/FXIIa interactions.
Xiaopeng Tang; Mingqian Fang; Ruomei Cheng; Zhiye Zhang; Yuming Wang; Chuanbin Shen; Yajun Han; Qiumin Lu; Yingrong Du; Yingying Liu; Zhaohui Sun; Liping Zhu; James Mwangi; Min Xue; Chengbo Long; Ren Lai. Iron-Deficiency and Estrogen Are Associated With Ischemic Stroke by Up-Regulating Transferrin to Induce Hypercoagulability. Circulation Research 2020, 127, 651 -663.
AMA StyleXiaopeng Tang, Mingqian Fang, Ruomei Cheng, Zhiye Zhang, Yuming Wang, Chuanbin Shen, Yajun Han, Qiumin Lu, Yingrong Du, Yingying Liu, Zhaohui Sun, Liping Zhu, James Mwangi, Min Xue, Chengbo Long, Ren Lai. Iron-Deficiency and Estrogen Are Associated With Ischemic Stroke by Up-Regulating Transferrin to Induce Hypercoagulability. Circulation Research. 2020; 127 (5):651-663.
Chicago/Turabian StyleXiaopeng Tang; Mingqian Fang; Ruomei Cheng; Zhiye Zhang; Yuming Wang; Chuanbin Shen; Yajun Han; Qiumin Lu; Yingrong Du; Yingying Liu; Zhaohui Sun; Liping Zhu; James Mwangi; Min Xue; Chengbo Long; Ren Lai. 2020. "Iron-Deficiency and Estrogen Are Associated With Ischemic Stroke by Up-Regulating Transferrin to Induce Hypercoagulability." Circulation Research 127, no. 5: 651-663.
Animal venoms are powerful, highly evolved chemical weapons for defense and predation. While venoms are used mainly to lethally antagonize heterospecifics (individuals of a different species), nonlethal envenomation of conspecifics (individuals of the same species) is occasionally observed. Both the venom and target specifications underlying these two forms of envenomation are still poorly understood. Here, we show a target-switching mechanism in centipede (Scolopendra subspinipes) venom. On the basis of this mechanism, a major toxin component [Ssm Spooky Toxin (SsTx)] in centipede venom inhibits the Shal channel in conspecifics but not in heterospecifics to cause short-term, recoverable, and nonlethal envenomation. This same toxin causes fatal heterospecific envenomation, for example, by switching its target to the Shaker channels in heterospecifics without inhibiting the Shaker channel of conspecific S. subspinipes individuals. These findings suggest that venom components exhibit intricate coevolution with their targets in both heterospecifics and conspecifics, which enables a single toxin to develop graded intraspecific and interspecific antagonistic interactions.
Shilong Yang; Yunfei Wang; Lu Wang; Peter Kamau; Hao Zhang; Anna Luo; Xiancui Lu; Ren Lai. Target switch of centipede toxins for antagonistic switch. Science Advances 2020, 6, eabb5734 .
AMA StyleShilong Yang, Yunfei Wang, Lu Wang, Peter Kamau, Hao Zhang, Anna Luo, Xiancui Lu, Ren Lai. Target switch of centipede toxins for antagonistic switch. Science Advances. 2020; 6 (32):eabb5734.
Chicago/Turabian StyleShilong Yang; Yunfei Wang; Lu Wang; Peter Kamau; Hao Zhang; Anna Luo; Xiancui Lu; Ren Lai. 2020. "Target switch of centipede toxins for antagonistic switch." Science Advances 6, no. 32: eabb5734.
Zika virus (ZIKV) is a mosquito-borne virus belonging to the genus Flavivirus and has reemerged in recent years with epidemic potential. ZIKV infection may result in severe syndromes such as neurological complications and microcephaly in newborns. Therefore, ZIKV has become a global public health threat and currently there is no approved specific drug for its treatment. Animal venoms are important resources of novel drugs. Cathelicidin-BF (BF-30) is a defensive peptide identified from Bungarus fasciatus snake venom and has been shown to be an excellent template for applicable peptide design. In this study, we found that ZY13, one of the peptidic analogs of BF-30, inhibits ZIKV infection in vitro and in vivo. Mechanistic studies revealed that ZY13 can directly inactivate ZIKV and reduce the production of infectious virions. Further studies also indicated that administration of ZY13 strengthen the host antiviral immunity via AXL-SOCS (suppressor of cytokine signaling protein) pathway. Additionally, the results of mouse experiment suggest that ZY13 efficiently restrict ZIKV infection and improve the growth defects of ZIKV-infected mouse pups. Together, our findings not only demonstrate that ZY13 might be a candidate for anti-ZIKV drug, but also indicated the importance of animal venom peptides as templates for antivirals development.
Meichen Xing; Mengyao Ji; Jingmei Hu; Tengyu Zhu; Yaoyao Chen; Xuewei Bai; James Mwangi; Guoxiang Mo; Ren Lai; Lin Jin. Snake Cathelicidin Derived Peptide Inhibits Zika Virus Infection. Frontiers in Microbiology 2020, 11, 1871 .
AMA StyleMeichen Xing, Mengyao Ji, Jingmei Hu, Tengyu Zhu, Yaoyao Chen, Xuewei Bai, James Mwangi, Guoxiang Mo, Ren Lai, Lin Jin. Snake Cathelicidin Derived Peptide Inhibits Zika Virus Infection. Frontiers in Microbiology. 2020; 11 ():1871.
Chicago/Turabian StyleMeichen Xing; Mengyao Ji; Jingmei Hu; Tengyu Zhu; Yaoyao Chen; Xuewei Bai; James Mwangi; Guoxiang Mo; Ren Lai; Lin Jin. 2020. "Snake Cathelicidin Derived Peptide Inhibits Zika Virus Infection." Frontiers in Microbiology 11, no. : 1871.
Bleeding and thrombocytopenia to readministration are the most serious side effects of clinical integrin αIIbβ3 antagonists such as RGD-containing peptides. Here we show that a non-RGD peptide ZDPI, identified from skin secretions of Amolops loloensis, inhibited platelet aggregation induced by agonists, such as adenosine diphosphate, collagen, arachidonic acid, PAR1AP, and integrin αIIbβ3 allosteric activator, and reduces soluble fibrinogen binding to activated platelets without perturbing adhesion numbers on immobilized fibrinogen. Further study showed that ZDPI preferred to bind to the active conformation of integrin αIIbβ3, and thus inhibited c-Src-mediated integrin signaling transduction. In contrast to currently used clinical blockers of integrin αIIbβ3, which are all conformation-unspecific blockers, ZDPI conformation specifically binds to activated integrin αIIbβ3, subsequently suppressing platelet spreading. In vivo study revealed that ZDPI inhibited carotid arterial thrombosis with limited bleeding and thrombocytopenia. A non-RGD peptide which targets the active conformation of integrin αIIbβ3, such as ZDPI, might be an excellent candidate or template to develop antithrombotics without significant bleeding and thrombocytopenia side effects.
Chuanbin Shen; Ming Liu; Huiwen Tian; Jiameng Li; Runjia Xu; James Mwangi; Qiumin Lu; Xue Hao; Ren Lai. Conformation-Specific Blockade of αIIbβ3 by a Non-RGD Peptide to Inhibit Platelet Activation without Causing Significant Bleeding and Thrombocytopenia. Thrombosis and Haemostasis 2020, 120, 1432 -1441.
AMA StyleChuanbin Shen, Ming Liu, Huiwen Tian, Jiameng Li, Runjia Xu, James Mwangi, Qiumin Lu, Xue Hao, Ren Lai. Conformation-Specific Blockade of αIIbβ3 by a Non-RGD Peptide to Inhibit Platelet Activation without Causing Significant Bleeding and Thrombocytopenia. Thrombosis and Haemostasis. 2020; 120 (10):1432-1441.
Chicago/Turabian StyleChuanbin Shen; Ming Liu; Huiwen Tian; Jiameng Li; Runjia Xu; James Mwangi; Qiumin Lu; Xue Hao; Ren Lai. 2020. "Conformation-Specific Blockade of αIIbβ3 by a Non-RGD Peptide to Inhibit Platelet Activation without Causing Significant Bleeding and Thrombocytopenia." Thrombosis and Haemostasis 120, no. 10: 1432-1441.
Hypercytokinemia is a critically fatal factor in COVID-19. However, underlying pathogenic mechanisms are unknown. Here we show that fibrinogen and leukotriene-A4 hydrolase (LTA4H), two of the most potent inflammatory contributors, are elevated by 67.7 and astonishing 227.7% in the plasma of patients infected by SARS-CoV-2 and admitted to intensive care unit in comparison with healthy control, respectively. Conversely, transferrin identified as a fibrinogen immobilizer in our recent work and Spink6 are down-regulated by 40.3 and 25.9%, respectively. Furthermore, we identify Spink6 as the first endogenous inhibitor of LTA4H, a pro-inflammatory enzyme catalyzing final and rating limited step in biosynthesis of leukotriene-B4 that is an extremely inflammatory mediator and a target to design superior anti-inflammatory drugs. Additionally, virus Spike protein is found to evoke LTA4H and fibrinogen expression in vivo. Collectively, these findings identify the imbalance between inflammatory drivers and antagonists, which likely contributes to hypercytokinemia in COVID-19. Spink6 may have superior anti-inflammatory function because it specifically targets epoxide hydrolase of LTA4H to inhibit leukotriene-B4 biosynthesis without effecting LTA4H’s aminopeptidase activity.
Xiaopeng Tang; Mingqian Fang; Juan Zhang; Zhiyi Liao; Ruomei Cheng; Kuanhong Xu; Hongwen Zhao; Jing Wang; Zhaoxia Tan; Gan Wang; Peter M Kamau; Zhiye Zhang; James Mwangi; Qiumin Lu; Guohong Deng; Ren Lai. Spike protein up-regulates inflammatory axis of both thromboinflammation and leukotriene in severe COVID-19. 2020, 1 .
AMA StyleXiaopeng Tang, Mingqian Fang, Juan Zhang, Zhiyi Liao, Ruomei Cheng, Kuanhong Xu, Hongwen Zhao, Jing Wang, Zhaoxia Tan, Gan Wang, Peter M Kamau, Zhiye Zhang, James Mwangi, Qiumin Lu, Guohong Deng, Ren Lai. Spike protein up-regulates inflammatory axis of both thromboinflammation and leukotriene in severe COVID-19. . 2020; ():1.
Chicago/Turabian StyleXiaopeng Tang; Mingqian Fang; Juan Zhang; Zhiyi Liao; Ruomei Cheng; Kuanhong Xu; Hongwen Zhao; Jing Wang; Zhaoxia Tan; Gan Wang; Peter M Kamau; Zhiye Zhang; James Mwangi; Qiumin Lu; Guohong Deng; Ren Lai. 2020. "Spike protein up-regulates inflammatory axis of both thromboinflammation and leukotriene in severe COVID-19." , no. : 1.
Predation and defense are the core contents of ecological adaptation and physiological ecology of species. Animal venom system is a typical “biochemical weapon system” for animals to implement predation and defense functions, which is of great significance for understanding the physiological mechanism of animal ecological adaptation. Toxin molecules from various venomous animals have high structural and functional diversity. A variety of biological activities have been identified from the venom of poisonous animals, including neurotoxic activity, enzyme activity, cytotoxic activity, antibacterial activity, agglutinin activity, hemolytic activity, antithrombotic activity, coagulation activity, immunomodulatory activity, enzyme inhibitor activity, bradykinin enhancing activity, and antiviral activity. Toxins with high affinity and high selectivity are used by venomous animals to act on cell membranes, ion channels, receptors or enzymes to affect the nervous system, skeletal system, cardiovascular and cerebrovascular system and immune system, thus implementing fast and efficient predation and defense. In order to prey on poisonous animals, predators have been undergoing coevolution with poisonous animals. In this review, we introduce the molecular basis of predation and defense of venomous animals, the diversity of pharmacological functions and the adaptive mechanisms related to predation and defense of several typical venomous animals.
Lei Luo; Lin Jin; Qiumin Lv; Ren Lai. Venom-dominated animal survival adaptation. SCIENTIA SINICA Vitae 2020, 50, 812 -826.
AMA StyleLei Luo, Lin Jin, Qiumin Lv, Ren Lai. Venom-dominated animal survival adaptation. SCIENTIA SINICA Vitae. 2020; 50 (8):812-826.
Chicago/Turabian StyleLei Luo; Lin Jin; Qiumin Lv; Ren Lai. 2020. "Venom-dominated animal survival adaptation." SCIENTIA SINICA Vitae 50, no. 8: 812-826.
Coumarins, naturally occurring phytochemicals, display a wide spectrum of biological activities by acting on multiple targets. Herein, nine coumarins from the root of Toddalia asiatica were evaluated for activities related to pathogenesis of Alzheimer’s disease (AD). They were examined for acetylcholinesterase (AChE) and AChE- or self-induced amyloid beta (Aβ) aggregation inhibitory activities, as well as neuroprotection against H2O2- and Aβ1–42-induced human neuroblastoma SH-SY5Y cell damage. Moreover, in order to understand the mechanism, the binding interactions between coumarins and their targets: (i) AChE and (ii) Aβ1–42 peptide were investigated in silico. All coumarins exhibited mild to moderate AChE and self-induced Aβ aggregation inhibitory actions. In addition, the coumarins substituted with the long alkyl chain at position 6 or 8 illustrated ability to inhibit AChE-induced Aβ aggregation, resulting from their dual binding site at catalytic anionic site and peripheral active site in AChE. Moreover, the most potent multifunctional coumarin, phellopterin, could attenuate neuronal cell damage induced by H2O2 and Aβ1–42 toxicity. Conclusively, seven out of nine coumarins were identified as multifunctional agents inhibiting the pathogenesis of AD. The structure–activity relationship information obtained might be applied for further optimization of coumarins into a useful drug which may combat AD.
Pitchayakarn Takomthong; Pornthip Waiwut; Chavi Yenjai; Bungon Sripanidkulchai; Prasert Reubroycharoen; Ren Lai; Peter Kamau; Chantana Boonyarat. Structure–Activity Analysis and Molecular Docking Studies of Coumarins from Toddalia asiatica as Multifunctional Agents for Alzheimer’s Disease. Biomedicines 2020, 8, 107 .
AMA StylePitchayakarn Takomthong, Pornthip Waiwut, Chavi Yenjai, Bungon Sripanidkulchai, Prasert Reubroycharoen, Ren Lai, Peter Kamau, Chantana Boonyarat. Structure–Activity Analysis and Molecular Docking Studies of Coumarins from Toddalia asiatica as Multifunctional Agents for Alzheimer’s Disease. Biomedicines. 2020; 8 (5):107.
Chicago/Turabian StylePitchayakarn Takomthong; Pornthip Waiwut; Chavi Yenjai; Bungon Sripanidkulchai; Prasert Reubroycharoen; Ren Lai; Peter Kamau; Chantana Boonyarat. 2020. "Structure–Activity Analysis and Molecular Docking Studies of Coumarins from Toddalia asiatica as Multifunctional Agents for Alzheimer’s Disease." Biomedicines 8, no. 5: 107.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Lei Luo; Yunfei Wang; Bowen Li; Lizhen Xu; Peter Muiruri Kamau; Jie Zheng; Fan Yang; Shilong Yang; Ren Lai. Author Correction: Molecular basis for heat desensitization of TRPV1 ion channels. Nature Communications 2020, 11, 1798 -1.
AMA StyleLei Luo, Yunfei Wang, Bowen Li, Lizhen Xu, Peter Muiruri Kamau, Jie Zheng, Fan Yang, Shilong Yang, Ren Lai. Author Correction: Molecular basis for heat desensitization of TRPV1 ion channels. Nature Communications. 2020; 11 (1):1798-1.
Chicago/Turabian StyleLei Luo; Yunfei Wang; Bowen Li; Lizhen Xu; Peter Muiruri Kamau; Jie Zheng; Fan Yang; Shilong Yang; Ren Lai. 2020. "Author Correction: Molecular basis for heat desensitization of TRPV1 ion channels." Nature Communications 11, no. 1: 1798-1.
To adapt to habitat temperature, vertebrates have developed sophisticated physiological and ecological mechanisms through evolution. Transient receptor potential melastatin 8 (TRPM8) serves as the primary sensor for cold. However, how cold activates TRPM8 and how this sensor is tuned for thermal adaptation remain largely unknown. Here we established a molecular framework of how cold is sensed in TRPM8 with a combination of patch-clamp recording, unnatural amino acid imaging, and structural modeling. We first observed that the maximum cold activation of TRPM8 in eight different vertebrates (i.e., African elephant and emperor penguin) with distinct side-chain hydrophobicity (SCH) in the pore domain (PD) is tuned to match their habitat temperature. We further showed that altering SCH for residues in the PD with solvent-accessibility changes leads to specific tuning of the cold response in TRPM8. We also observed that knockin mice expressing the penguin’s TRPM8 exhibited remarkable tolerance to cold. Together, our findings suggest a paradigm of thermal adaptation in vertebrates, where the evolutionary tuning of the cold activation in the TRPM8 ion channel through altering SCH and solvent accessibility in its PD largely contributes to the setting of the cold-sensitive/tolerant phenotype.
Shilong Yang; Xiancui Lu; Yunfei Wang; Lizhen Xu; Xiaoying Chen; Fan Yang; Ren Lai. A paradigm of thermal adaptation in penguins and elephants by tuning cold activation in TRPM8. Proceedings of the National Academy of Sciences 2020, 117, 8633 -8638.
AMA StyleShilong Yang, Xiancui Lu, Yunfei Wang, Lizhen Xu, Xiaoying Chen, Fan Yang, Ren Lai. A paradigm of thermal adaptation in penguins and elephants by tuning cold activation in TRPM8. Proceedings of the National Academy of Sciences. 2020; 117 (15):8633-8638.
Chicago/Turabian StyleShilong Yang; Xiancui Lu; Yunfei Wang; Lizhen Xu; Xiaoying Chen; Fan Yang; Ren Lai. 2020. "A paradigm of thermal adaptation in penguins and elephants by tuning cold activation in TRPM8." Proceedings of the National Academy of Sciences 117, no. 15: 8633-8638.