Acute renal injury (AKI) causes a long-term risk for progressing into chronic kidney disease (CKD) and interstitial fibrosis. Yes-associated protein (YAP), a key transcriptional cofactor in Hippo ...signaling pathway, shuttles between the cytoplasm and nucleus, which is required for the renal tubular epithelial cells repair in the acute phase of AKI. In this study we investigated the role of YAP during ischemia-reperfusion (IR)-induced AKI to CKD. Mice were subjected to left kidney IR followed by removal of the right kidney on the day before tissue harvests. Mouse shRNA expression adenovirus (Ad-shYAP or Ad-shKLF4) and mouse KLF4 expression adenovirus (Ad-KLF4) were delivered to mice by intrarenal injection on D7 after IR. We showed that the expression and nucleus distribution of YAP were persistently increased until the end of experiment (D21 after IR). The sustained activation of YAP in post-acute phase of AKI was accompanied by renal dysfunction and interstitial fibrosis. Knockdown of YAP significantly attenuated IR-induced renal dysfunction and decreased the expression of fibrogenic factors TGF-β and CTGF in the kidney. We showed that the expression of the transcription factor KLF4, lined on the upstream of YAP, was also persistently increased. Knockdown on KLF4 attenuated YAP increase and nuclear translocation as well as renal functional deterioration and interstitial fibrosis in IR mice, whereas KLF4 overexpression caused opposite effects. KLF4 increased the expression of ITCH, and ITCH facilitated YAP nuclear translocation via degrading LATS1. Furthermore, we demonstrated in primary cultured renal tubular cells that KLF4 bound to the promoter region of YAP and positively regulates YAP expression. In biopsy sample from CKD patients, we also observed increased expression and nuclear distribution of YAP. In conclusion, the activation of YAP in the post-acute phase of AKI is implicated in renal functional deterioration and fibrosis although it exhibits beneficial effect in acute phase. Reprogramming factor KLF4 is responsible for the persistent activation of YAP. Blocking the activation of KLF4-YAP pathway might be a way to prevent the transition of AKI into CKD.
A method which enables the investigation of the buried interfaces without altering the properties of the polymer films is used to study vertical phase separation of spin‐coated poly(3‐hexylthiophene) ...(P3HT):fullerene derivative blends. X‐ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM) analysis reveals the P3HT enrichment at the free (air) surfaces and abundance of fullerene derivatives at the organic/substrate interfaces. The vertical phase separation is attributed to the surface energy difference of the components and their interactions with the substrates. This inhomogeneous distribution of the donor and acceptor components significantly affects photovoltaic device performance and makes the inverted device structure a promising choice.
A method which enables the investigation of the buried interfaces without altering the properties of the polymer films is used to study vertical phase separation of spin‐coated poly(3‐hexylthiophene) (P3HT):fullerene derivative blends.
Cancer has become a major health issue worldwide, contributing to a high mortality rate. Tumor metastasis is attributed to the death of most patients. Epithelial-to-mesenchymal transition (EMT) plays ...a vital role in inducing metastasis. During EMT, epithelial cells lose their characteristics, such as cell-to-cell adhesion and cell polarity, and cells gain motility, migratory potential, and invasive properties to become mesenchymal stem cells. Circular RNAs (circRNAs) are closely associated with tumor metastasis and patient prognosis, as revealed by increasing lines of evidence. CircRNA is a type of single-stranded RNA that forms a covalently closed continuous loop. CircRNAs are insensitive to ribonucleases and are widespread in body fluids. This work is the first review on EMT-related circRNAs. In this review, we briefly discuss the characteristics and functions of circRNAs. The correlation of circRNAs with EMT has been reported, and we discuss the ways circRNAs can regulate EMT progression through EMT transcription factors, EMT-related signaling pathways, and other mechanisms. This work summarizes current studies on EMT-related circRNAs in various cancers and provides a theoretical basis for the use of EMT-related circRNAs in targeted management and therapy.
Over the past few years, three photorespiratory bypasses have been introduced into plants, two of which led to observable increases in photosynthesis and biomass yield. However, most of the ...experiments were carried out using Arabidopsis under controlled environmental conditions, and the increases were only observed under low-light and short-day conditions. In this study, we designed a new photorespiratory bypass (called GOC bypass), characterized by no reducing equivalents being produced during a complete oxidation of glycolate into CO2 catalyzed by three rice-self-originating enzymes, i.e., glycolate oxidase, oxalate oxidase, and catalase. We successfully established this bypass in rice chloroplasts using a multi-gene assembly and transformation system. Transgenic rice plants carrying GOC bypass (GOC plants) showed significant increases in photosynthesis efficiency, biomass yield, and nitrogen content, as well as several other CO2-enriched phenotypes under both greenhouse and field conditions. Grain yield of GOC plants varied depending on seeding season and was increased significantly in the spring. We further demonstrated that GOC plants had significant advantages under high-light conditions and that the improvements in GOC plants resulted primarily from a photosynthetic CO2-concentrating effect rather than from improved energy balance. Taken together, our results reveal that engineering a newly designed chloroplastic photorespiratory bypass could increase photosynthetic efficiency and yield of rice plants grown in field conditions, particularly under high light.
A new photorespiratory bypass (GOC bypass), catalyzed by three rice-self-originating enzymes, i.e., glycolate oxidase, oxalate oxidase, and catalase, was designed and successfully established in rice chloroplasts. Transgenic plants carrying GOC bypass showed increased photosynthetic efficiency and productivity in rice under field conditions, with particular advantages under high light, which were found to be resulted from a photosynthetic CO2-concentrating effect.
Ischemia/reperfusion (I/R) injury is a major cause of acute kidney injury (AKI) in clinic. The activation of NLRP3 inflammasome is associated with inflammation and renal injury in I/R-induced AKI. In ...the current study we explored the molecular and cellular mechanisms for NLRP3 inflammasome activation following renal I/R. Mice were subjected to I/R renal injury by clamping bilateral renal pedicles. We showed that I/R injury markedly increased caspase-11 expression and the cleavage of pannexin 1 (panx1) in the kidneys accompanied by NLRP3 inflammasome activation evidenced by the activation of caspase-1 and interlukin-1β (IL-1β) maturation. In Casp-11
mice, I/R-induced panx1 cleavage, NLRP3 inflammasome activation as well as renal functional deterioration and tubular morphological changes were significantly attenuated. In cultured primary tubular cells (PTCs) and NRK-52E cells, hypoxia/reoxygenation (H/R) markedly increased caspase-11 expression, NLRP3 inflammasome activation, IL-1β maturation and panx1 cleavage. Knockdown of caspase-11 attenuated all those changes; similar effects were observed in PTCs isolated from Casp-11
mice. In NRK-52E cells, overexpression of caspase-11 promoted panx1 cleavage; pretreatment with panx1 inhibitor carbenoxolone or knockdown of panx1 significantly attenuated H/R-induced intracellular ATP reduction, extracellular ATP elevation and NLRP3 inflammasome activation without apparent influence on H/R-induced caspase-11 increase; pretreatment with P2X7 receptor inhibitor AZD9056 also attenuated NLRP3 inflammasome activation. The above results demonstrate that the cleavage of panx1 by upregulated caspase-11 is involved in facilitating ATP release and then NLRP3 inflammasome activation in I/R-induced AKI. This study provides new insight into the molecular mechanism of NLRP3 inflammasome activation in AKI.
Long‐term neurological deficits after severe traumatic brain injury (TBI), including cognitive dysfunction and emotional impairments, can significantly impair rehabilitation. Glial activation induced ...by inflammatory response is involved in the neurological deficits post‐TBI. This study aimed to investigate the role of the stimulator of interferon genes (STING)–nucleotide‐binding oligomerization domain‐like receptor pyrin domain‐containing‐3 (NLRP3) signaling in a rodent model of severe TBI. Severe TBI models were established using weight‐drop plus blood loss reinfusion model. Selective STING agonist ADU‐S100 or antagonist C‐176 was given as a single dose after modeling. Further, NLRP3 inhibitor MCC950 or activator nigericin, or caspase‐1 inhibitor VX765, was given as an intracerebroventricular injection 30 min before modeling. After that, a novel object recognition test, open field test, force swimming test, western blot, and immunofluorescence assays were used to assess behavioral and pathological changes in severe TBI. Administration of C‐176 alleviated TBI‐induced cognitive dysfunction and emotional impairments, neuronal loss, and inflammatory activation of glia cells. However, the administration of STING agonist ADU‐S100 exacerbated TBI‐induced behavioral and pathological changes. In addition, STING activation exacerbated pyroptosis‐associated neuroinflammation via promoting glial activation, as evidenced by increased cleaved caspase‐1 and GSDMD N‐terminal expression. In contrast, the administration of C‐176 showed anti‐pyroptotic effects. The neuroprotective effects of C‐176 were partially reversed by the NLRP3 activator, nigericin. Collectively, glial STING is responsible for neuroinflammation post‐TBI. However, pharmacologic inhibition of STING led to a remarkable improvement of neuroinflammation partly through suppressing NLRP3 signaling. The STING–NLRP3 signaling is a potential therapeutic target in TBI‐induced neurological dysfunction.
Glial activation induced by inflammatory responses is involved in neurological deficits post‐traumatic brain injury (TBI). In this study, we demonstrated that severe TBI activated glial stimulator of interferon genes (STING), which subsequently activated nucleotide‐binding oligomerization domain‐like receptor pyrin domain‐containing‐3 (NLRP3)‐associated pyroptosis, resulting in astrocytic and microglial activation, as well as neuronal degeneration. Pharmacological inhibition of STING with C‐176 attenuated TBI‐induced inflammatory response. Our findings suggest that glial STING is responsible for neuroinflammation post‐TBI and highlight STING–NLRP3 signaling as a potential therapeutic target in TBI‐induced neurological dysfunction.
A combination of humidity-dependent single crystal to single crystal (SC–SC) structural transformation and single crystal proton conductivity measurements is essential to elucidate the underlying ...proton transport mechanism in metal–organic framework materials. Herein, we report a new layered Co–Ca phosphonate CoIIICaII(notpH2)(H2O)2ClO4·nH2O abbreviated as CoCa·nH 2 O, where notpH6 = 1,4,7-triazacyclononane-1,4,7-triyl-tris(methylenephosphonic acid), C9H18N3(PO3H2)3. CoCa·nH 2 O undergoes a reversible relative humidity (RH) dependent SC–SC structural transformation between CoCa·2H 2 O and CoCa·4H 2 O at room temperature. Accordingly the continuous hydrogen bond network observed in CoCa·4H 2 O (95% RH) is interrupted in CoCa·2H 2 O (40% RH), leading to a drastic decrease in proton conductivity by ∼5 orders of magnitude. The process is reversible; hence, the proton conductivity is tunable simply through humidity control. The AC impedance measurements using single crystals of CoCa·nH 2 O reveal that the 010 direction of H-bond extension is the preferred proton conduction pathway showing the greatest conductivity of 1.00 × 10–3 S cm–1 at 25 °C and 95% RH. Although the 20–1 direction, which involves the phosphonate oxygen atoms in the H-bond network shows the lowest conductivity of 4.35 × 10–8 S cm–1 at 25 °C and 95% RH, the ClO4 – anions play a key role in not only connecting the lattice water molecules into a continuous hydrogen bond network but also assisting the proton diffusion between the lattice water molecules. This work provides a rare example of a proton conductive MOF with a well-illustrated proton conduction mechanism and is a promising humidity sensor for future applications.
The COVID-19 pandemic is one of those global challenges that transcends territorial, political, ideological, religious, cultural, and certainly academic boundaries. Public health and healthcare ...workers are at the frontline, working to contain and to mitigate the spread of this disease. Although intervening biological and immunological responses against viral infection may seem far from the physical sciences and engineering that typically work with inanimate objects, there actually is much that canand shouldbe done to help in this global crisis. In this Perspective, we convert the basics of infectious respiratory diseases and viruses into physical sciences and engineering intuitions, and through this exercise, we present examples of questions, hypotheses, and research needs identified based on clinicians’ experiences. We hope researchers in the physical sciences and engineering will proactively study these challenges, develop new hypotheses, define new research areas, and work with biological researchers, healthcare, and public health professionals to create user-centered solutions and to inform the general public, so that we can better address the many challenges associated with the transmission and spread of infectious respiratory diseases.
Resina Draconis is a traditional Chinese medicine, with the in-depth research, its medicinal value in anti-tumor has been revealed. Loureirin A is extracted from Resina Draconis, however, research on ...the anti-tumor efficacy of Loureirin A is rare. Herein, we investigated the function of Loureirin A in melanoma. Our research demonstrated that Loureirin A inhibited the proliferation of and caused G0/G1 cell cycle arrest in melanoma cells in a concentration-dependent manner. Further study showed that the melanin content and tyrosinase activity was enhanced after Loureirin A treatment, demonstrated that Loureirin A promoted melanoma cell differentiation, which was accompanied with the reduce of WNT signaling pathway. Meanwhile, we found that Loureirin A suppressed the migration and invasion of melanoma cells through the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. Taken together, this study demonstrated for the first time the anti-tumor effects of Loureirin A in melanoma cells, which provided a novel therapeutic strategy against melanoma.
The clinical application of antitumor immunotherapy still faces severe challenges related to efficacy. Here, a light‐triggered core–shell nanosystem is designed to boost antitumor immune response via ...controlled release of anti‐PD‐L1 (αPD‐L1) antibodies and enhanced antigen presentation. The nanosystem (AZ‐P@P) is constructed via integrating gold nanorods (AuNRs) as a photothermal core and zeolitic imidazolate framework‐8 (ZIF‐8) as a shell for aPD‐L1 delivery, and further PEGylating. In the nanosystem, the ZIF‐8 shell protects αPD‐L1 antibody from the complex physiological environment and hyperthermia. Once accumulated at the tumor site, AZ‐P@P under near‐infrared (NIR) light‐triggered heating induces tumor cell deaths releasing tumor‐derived protein antigens (TDPAs) and adenosine triphosphate (ATP). Thereafter, the released ATP degrades the ZIF‐8 shell to expose the AuNRs, which can promote intratumoral T cell infiltration by capturing TDPAs and transporting them to dendritic cells (DCs). Concurrently, a large amount of αPD‐L1 is released in situ to reinvigorate T cell activity. Mechanistic studies reveal that AZ‐P@P promotes the maturation of DCs and the infiltration of activated T cells, thus eliciting a robust antitumor immunity. It is demonstrated that AZ‐P@P triggered by NIR light can significantly destroy primary tumors and suppress metastasis. This multiple immunoregulatory system provides a promising tool for tumor treatment.
An integrated core–shell nanosystem is designed to achieve the near‐infrared light‐triggered immune response by controlling the release of αPD‐L1 antibodies and enhancing the release and presentation of antigens. After local photothermal treatment, this nanosystem can induce a robust antitumor immune response to effectively inhibit tumor metastasis.
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