Zika virus (ZIKV) has become a global public health emergency due to its rapidly expanding range and its ability to cause severe congenital defects such as microcephaly. However, there are no ...FDA-approved therapies or vaccines against ZIKV infection. Through our screening of viral entry inhibitors, we found that chloroquine (CQ), a commonly used antimalarial and a FDA-approved drug that has also been repurposed against other pathogens, could significantly inhibit ZIKV infection in vitro, by blocking virus internalization. We also demonstrated that CQ attenuates ZIKV-associated morbidity and mortality in mice. Finally, we proved that CQ protects fetal mice from microcephaly caused by ZIKV infection. Our methodology of focusing on previously identified antivirals in screens for effectiveness against ZIKV proved to be a rapid and efficient means of discovering new ZIKV therapeutics. Selecting drugs that were previously FDA-approved, such as CQ, also improves the likelihood that they may more quickly reach stages of clinical testing and use by the public.
•5 out 16 tested Ebola virus entry inhibitors can inhibit ZIKV entry efficiently•Chloroquine can inhibit ZIKV internalization in vitro and reduce ZIKV-associated morbidity and mortality in mice•Chloroquine prevents ZIKV-associated congenital microcephaly in mice
Zika virus (ZIKV) is an emerging virus which can cause birth defects, however there are currently no effective treatments or vaccines. We tested the effects of 16 verified Ebola virus cell entry inhibitors on ZIKV infection, and found that chloroquine (CQ) could prevent ZIKV infection in cell cultures, consistent with results from a previous study. We then demonstrated that CQ can reduce ZIKV-associated morbidity and mortality in mice. Most importantly, it protects fetal mice from microcephaly caused by ZIKV infection. Therefore, CQ is a potential drug which would be used to treat ZIKV infection after clinical test.
Transient receptor potential (TRP) melastatin 2 (TRPM2) is a cation channel associated with numerous diseases. It has a C-terminal NUDT9 homology (NUDT9H) domain responsible for binding adenosine ...diphosphate (ADP)-ribose (ADPR), and both ADPR and calcium (Ca
) are required for TRPM2 activation. Here we report cryo-electron microscopy structures of human TRPM2 alone, with ADPR, and with ADPR and Ca
NUDT9H forms both intra- and intersubunit interactions with the N-terminal TRPM homology region (MHR1/2/3) in the apo state but undergoes conformational changes upon ADPR binding, resulting in rotation of MHR1/2 and disruption of the intersubunit interaction. The binding of Ca
further engages transmembrane helices and the conserved TRP helix to cause conformational changes at the MHR arm and the lower gating pore to potentiate channel opening. These findings explain the molecular mechanism of concerted TRPM2 gating by ADPR and Ca
and provide insights into the gating mechanism of other TRP channels.
Chemotherapy has been widely applied in clinics. However, the therapeutic potential of chemotherapy against cancer is seriously dissatisfactory due to the nonspecific drug distribution, multidrug ...resistance (MDR) and the heterogeneity of cancer. Therefore, combinational therapy based on chemotherapy mediated by nanotechnology, has been the trend in clinical research at present, which can result in a remarkably increased therapeutic efficiency with few side effects to normal tissues. Moreover, to achieve the accurate pre-diagnosis and real-time monitoring for tumor, the research of nano-theranostics, which integrates diagnosis with treatment process, is a promising field in cancer treatment. In this review, the recent studies on combinational therapy based on chemotherapy will be systematically discussed. Furthermore, as a current trend in cancer treatment, advance in theranostic nanoparticles based on chemotherapy will be exemplified briefly. Finally, the present challenges and improvement tips will be presented in combination therapy and nano-theranostics.
Cold stress limits plant geographical distribution and influences plant growth, development, and yields. Plants as sessile organisms have evolved complex biochemical and physiological mechanisms to ...adapt to cold stress. These mechanisms are regulated by a series of transcription factors and proteins for efficient cold stress acclimation. It has been established that the
signaling pathway in plants regulates how plants acclimatize to cold stress. Cold stress is perceived by receptor proteins, triggering signal transduction, and
(
) genes are activated and regulated, consequently upregulating the transcription and expression of the
(
) genes. The
protein binds to the
(
), a homeopathic element of the
genes (
gene) promoter, activating their transcription. Transcriptional regulations and post-translational modifications regulate and modify these entities at different response levels by altering their expression or activities in the signaling cascade. These activities then lead to efficient cold stress tolerance. This paper contains a concise summary of the
pathway elucidating on the cross interconnections with other repressors, inhibitors, and activators to induce cold stress acclimation in plants.
Activation of tumor suppressors for the treatment of human cancer has been a long sought, yet elusive, strategy. PTEN is a critical tumor suppressive phosphatase that is active in its dimer ...configuration at the plasma membrane. Polyubiquitination by the ubiquitin E3 ligase WWP1 (WW domain-containing ubiquitin E3 ligase 1) suppressed the dimerization, membrane recruitment, and function of PTEN. Either genetic ablation or pharmacological inhibition of WWP1 triggered PTEN reactivation and unleashed tumor suppressive activity.
appears to be a direct MYC (MYC proto-oncogene) target gene and was critical for MYC-driven tumorigenesis. We identified indole-3-carbinol, a compound found in cruciferous vegetables, as a natural and potent WWP1 inhibitor. Thus, our findings unravel a potential therapeutic strategy for cancer prevention and treatment through PTEN reactivation.
Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton ...transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. Here, we report cryoelectron microscopy structures of human V-ATPase in three rotational states at up to 2.9-Å resolution. Aided by mass spectrometry, we build all known protein subunits with associated N-linked glycans and identify glycolipids and phospholipids in the Vo complex. We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits and phospholipids in the c-ring. The glycolipids and the glycosylated Vo subunits form a luminal glycan coat critical for V-ATPase folding, localization, and stability. This study identifies mechanisms of V-ATPase assembly and biogenesis that rely on the integrated roles of ATP6AP1, glycans, and lipids.
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•Cryo-EM structures of the human V-ATPase reveal the mechanism of its assembly•The luminal domain of ATP6AP1 adopts a β-prism fold and belongs to the LAMP family•Dol-pp-glycan and lipids are bona fide components of the human V-ATPase•Biogenesis of V-ATPases rely on the synergy among proteins, glycans, and lipids
Wang et al. report the mechanisms of human V-ATPase assembly. Cryo-EM structures of human V-ATPase combined with mass spectrometry analysis reveal that the protein subunits, glycans, glycolipids, and phospholipids are essential components of V-ATPase. The subunit ATP6AP1, glycans, and lipids have important roles in V-ATPase assembly and biogenesis.
Transient receptor potential melastatin 2 (TRPM2) is a non‐selective cation channel that allows Ca2+ influx across the plasma membrane and efflux from lysosomes upon opening. TRPM2 is best known as a ...biosensor of reactive oxygen species (ROS), which mediates some of the body's responses to oxidative stress. As such, TRPM2 is involved in a plethora of biological processes including immune response, insulin secretion, body temperature control and neuronal cell death, and represents an emerging therapeutic target for many human diseases, from diabetes to inflammatory and neurodegenerative diseases. A direct ligand of TRPM2 is ADP‐ribose (ADPR), which accumulates in cells at high levels of ROS, and activates TRPM2 synergistically with intracellular calcium (Ca2+). Here, we describe recent cryo‐electron microscopy (cryo‐EM) structures of TRPM2 and summarize the insights they provided into the gating mechanism of the channel.
Transient receptor potential melastatin 2 (TRPM2) is a non‐selective cation channel gated by ADP‐ribose (ADPR) and calcium (Ca2+). A recent structural study revealed the gating mechanism of human TRPM2, with priming by ADPR as the first step followed by Ca2+‐induced channel opening. The human TRPM2 structures, together with the structures of its zebrafish and sea anemone homologs, provided an in‐depth mechanistic picture of TRPM2 channel gating across species.
As organelles of the innate immune system, inflammasomes activate caspase-1 and other inflammatory caspases that cleave gasdermin D (GSDMD). Caspase-1 also cleaves inactive precursors of the ...interleukin (IL)-1 family to generate mature cytokines such as IL-1β and IL-18. Cleaved GSDMD forms transmembrane pores to enable the release of IL-1 and to drive cell lysis through pyroptosis
. Here we report cryo-electron microscopy structures of the pore and the prepore of GSDMD. These structures reveal the different conformations of the two states, as well as extensive membrane-binding elements including a hydrophobic anchor and three positively charged patches. The GSDMD pore conduit is predominantly negatively charged. By contrast, IL-1 precursors have an acidic domain that is proteolytically removed by caspase-1
. When permeabilized by GSDMD pores, unlysed liposomes release positively charged and neutral cargoes faster than negatively charged cargoes of similar sizes, and the pores favour the passage of IL-1β and IL-18 over that of their precursors. Consistent with these findings, living-but not pyroptotic-macrophages preferentially release mature IL-1β upon perforation by GSDMD. Mutation of the acidic residues of GSDMD compromises this preference, hindering intracellular retention of the precursor and secretion of the mature cytokine. The GSDMD pore therefore mediates IL-1 release by electrostatic filtering, which suggests the importance of charge in addition to size in the transport of cargoes across this large channel.
To compare achieved and predicted tooth movements of maxillary first molars and central incisors in first premolar extraction cases treated with Invisalign.
The present study included 30 patients who ...received maxillary first premolar extraction treatment with Invisalign. The actual posttreatment model was registered with the pretreatment model on the palatal stable region and superimposed with the virtual posttreatment model. Achieved and predicted tooth movements of maxillary first molars and central incisors were compared using paired
-test. Linear mixed-effect model analyses were used to explore the influence of age (adolescents vs adults), attachment (G6-optimized vs 3-mm vertical, 3-mm horizontal, and 5-mm horizontal), and initial crowding on the differences between predicted and achieved tooth movement (DPATM).
First molars achieved greater mesial tipping, mesial translation, and intrusion than predicted. Central incisors achieved less retraction and greater lingual crown torque and extrusion than predicted. Adolescents showed greater DPATM in the mesiodistal translation of first molars and labiolingual translation of central incisors and smaller DPATM in the occlusogingival translation of the first molars and crown torque of the central incisors than adults. The 3-mm vertical attachment group showed greater DPATM in the mesiodistal translation of the first molars vs the G6-optimized attachment group. Initial crowding had an inverse correlation with DPATM in angulation and mesiodistal translation of the first molars.
First molar anchorage control and central incisor retraction were not fully achieved as predicted in first premolar extraction treatment with Invisalign. Age, attachment, and initial crowding affected the differences between predicted and achieved tooth movement.
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