Lung cancer is the leading cause of cancer-related death. About 80% of lung cancers are non-small cell lung cancers (NSCLC). Radiotherapy is widely used in treatment of NSCLC. However, the outcome of NSCLC remains unsatisfactory. In this study, a vascular disrupting agent (VDA) combretastatin-A4-phosphate (CA4P) was used to provide massive necrosis targets. (131)I labeled necrosis-avid agent protohypericin ((131)I-prohy) was explored for therapy of NSCLC using tumor necrosis targeted radiotherapy (TNTR). Gamma counting, autoradiography, fluorescence microscopy and histopathology were used for biodistribution analysis. Magnetic resonance imaging (MRI) was used to monitor tumor volume, ratios of necrosis and tumor doubling time (DT). The biodistribution data revealed 131I-prohy was delivered efficiently to tumors. Tracer uptake peaked at 24 h in necrotic tumor of (131)I-prohy with and without combined CA4P (3.87 ± 0.38 and 2.96 ± 0.34%ID/g). (131)I-prohy + CA4P enhanced the uptake of (131)I-prohy in necrotic tumor compared to (131)I-prohy alone. The TNTR combined with CA4P prolonged survival of tumor bearing mice relative to vehicle control group, CA4P control group and (131)I-prohy control group with median survival of 35, 20, 22 and 27 days respectively. In conclusion, TNTR appeared to be effective for the treatment of NSCLC.

Liver cancer is one of the major diseases affecting human health. Modified drug delivery systems through the asialoglycoprotein receptor, which is highly expressed on the surface of hepatocytes, have become a research focus for the treatment of liver cancer. Resibufogenin (RBG) is a popular traditional Chinese medicine and natural anti-cancer drug that was isolated from Chansu, but its cardiotoxicity and hydrophobicity have limited its clinical applications. Galactosyl-succinyl-poloxamer 188 and galactosyl-succinyl-poloxamer 188-polylactide-co-glycolide (Gal-SP188-PLGA) were synthesized using galactose, P188, and PLGA to achieve active liver-targeting properties. RBG-loaded Gal-SP188-PLGA nanoparticles (RGPPNs) and coumarin-6-loaded Gal-SP188-PLGA nanoparticles (CGPPNs) were prepared. The in vitro cellular uptake, cytotoxicity, and apoptosis of nanoparticles in HepG2 cells were analyzed. The in vivo therapeutic effects of nanoparticles were assessed in a hepatocarcinogenic mouse model. The results showed that Gal-SP188-PLGA was successfully synthesized. The cellular uptake assay demonstrated that CGPPNs had superior active liver-targeting properties. The ratio of apoptotic cells was increased in the RGPPN group. In comparison to the other groups, RGPPNs showed superior in vivo therapeutic effects and anticancer efficacy. Thus, the active liver-targeting RGPPNs, which can enhance the pharmacological effects and decrease the toxicity of RBG, are expected to become a promising and effective treatment for liver cancer.

The major causes for cataract formation are free radicals, which are neutralized by the endogenous antioxidants. However, how the human lens clean these harmful free radicals is still unclear. Transcriptional factor heat shock factor 4 (HSF4) is a cataract-causing gene and plays important roles during lens development. Here we show that HMOX-1, an anti-oxidase, is a bona fide transcriptional target gene of HSF4 in HLECs (human lens epithelial cells). HSF4 directly binds to the HSE element in HMOX-1 promoter to mediate its mRNA transcription and protein accumulation. The HSE element located at the region of -389 bp to -362 bp upstream from the TSS (transcription start site), which is critical for HMOX-1 transcriptional activation. Furthermore, knockdown of HSF4 by siRNA inhibited HMOX-1 expression. Thus, these data revealed a novel transcription target of HSF4 and provided new insights into anti-oxidation regulation in lens and age-related cataract.

This study aimed to assess the effects of triterpene extract of Cyclocarya paliurus (Batal.) Iljinskaja (CPT) on diabetes-induced hepatic inflammation and to unveil the underlying mechanisms. Diabetes in db/db mice was alleviated after CPT administration, as assessed by the oral glucose tolerance test. In addition, treatment with CPT dramatically reduced serum insulin, aspartate amino-transaminase, alanine aminotransferase, triglyceride, and total cholesterol amounts. Besides, serum levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α were also reduced after CPT administration. Western blot analysis revealed that CPT treatment significantly reversed the protein expression levels of Rho, ROCK1, ROCK2, p-P65, p-IκBα, p-IKKα, and p-IKKβ in liver samples obtained from db/db mice. Upon palmitic acid stimulation, the protective effects of CPT on the liver were further assessed in HepG2 and LO2 cells, and no appreciable cytotoxic effects were found. Therefore, these findings indicate that CPT alleviates liver inflammation via Rho-kinase signaling. Chemical compounds evaluated in this report: Metformin (PubChem CID: 4091); Fasudil (PubChem CID: 3547); Palmitic acid (PubChem CID: 985).

Vitreomacular adhesion (VMA) has been reported to associated with age-related macular degeneration (AMD). Understanding the mechanisms underlying cyclic stretch induced in retinal pigment epithelial cells (RPE) may be important for the treatment of VMA-related AMD.

Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and a leading cause of cancer-related deaths worldwide. Emerging studies have shown that circular RNAs (circRNAs) are differentially expressed in HCC and play an important role in HCC pathogenesis and metastasis. However, the mechanism of circRNA in the chemoresistance of HCC remains unclear. In this study, we aimed to investigate the role of circRNA in cisplatin resistance of HCC. We identified a novel circRNA circRNA_101505 that was decreased in cisplatin-resistant HCC tissues and cell lines, and associated with a poor survival outcome. Gain-of-function investigations showed that overexpression of circRNA_101505 suppressed cancer cell growth in vivo and in vitro, and enhanced cisplatin toxicity in HCC cells. Mechanistic studies found that circRNA_101505 could sensitize HCC cells to cisplatin by sponging miR-103, and thereby promoting oxidored-nitro domain-containing protein 1 (NOR1) expression. In conclusion, the significant inhibitory effects indicate circRNA_101505 to be a potential therapeutic target for HCC treatment. Our findings provide significant evidence to further elucidate the therapeutic use of circRNA in HCC.

Cataract refers to opacities of the lens that impede the passage of light. Mutations in heat shock transcription factor 4 (HSF4) have been associated with cataract; however, the mechanisms regarding how mutations in HSF4 cause cataract are still obscure. In this study, we generated an hsf4 knockout zebrafish model using TALEN technology. The mutant zebrafish developed an early-onset cataract with multiple developmental defects in lens. The epithelial cells of the lens were overproliferated, resulting in the overabundance of lens fiber cells in hsf4null zebrafish lens. Consequently, the arrangement of the lens fiber cells became more disordered and irregular with age. More importantly, the terminal differentiation of the lens fiber cell was interrupted as the organelles cannot be cleaved in due time. In the cultured human lens epithelial cells, HSF4 could stabilize and retain p53 in the nucleus to activate its target genes such as fas cell surface death receptor (Fas) and Bcl-2-associated X apoptosis regulator (Bax). In the hsf4null fish, both p53 and activated-caspase3 were significantly decreased. Combined with the finding that the denucleation defect could be partially rescued through microinjection of p53, fas and bax mRNA into the mutant embryos, we directly proved that HSF4 promotes lens fiber cell differentiation by activating p53 and its downstream regulators. The data we presented suggest that apoptosis-related genes are involved in the lens fiber cell differentiation. Our finding that HSF4 functions in the upstream to activate these genes highlighted the new regulatory modes of HSF4 in the terminal differentiation of lens fiber cell.

Neuroinflammation and blood-brain barrier (BBB) disruption are two vital mechanisms of secondary brain injury following intracerebral hemorrhage (ICH). Recently, melanocortin-1 receptor (Mc1r) activation by Nle4-D-Phe7-α-MSH (NDP-MSH) was shown to play a neuroprotective role in an experimental autoimmune encephalomyelitis (EAE) mouse model. This study aimed to investigate whether NDP-MSH could alleviate neuroinflammation and BBB disruption after experimental ICH, as well as the potential mechanisms of its neuroprotective roles.

Specific highly polarized aquaporin-4 (AQP4) expression is reported to play a crucial role in blood-brain barrier (BBB) integrity and brain water transport balance. The upregulation of polymerase δ-interacting protein 2 (Poldip2) was involved in aggravating BBB disruption following ischemic stroke. This study aimed to investigate whether Poldip2-mediated BBB disruption and cerebral edema formation in mouse bacterial meningitis (BM) model occur via induction of AQP4 polarity loss.

Electrical remodelling as a result of homeodomain transcription factor 2 (Pitx2)-dependent gene regulation was linked to atrial fibrillation (AF) and AF patients with single nucleotide polymorphisms at chromosome 4q25 responded favorably to class I antiarrhythmic drugs (AADs). The possible reasons behind this remain elusive. The purpose of this study was to assess the efficacy of the AADs disopyramide, quinidine, and propafenone on human atrial arrhythmias mediated by Pitx2-induced remodelling, from a single cell to the tissue level, using drug binding models with multi-channel pharmacology. Experimentally calibrated populations of human atrial action po-tential (AP) models in both sinus rhythm (SR) and Pitx2-induced AF conditions were constructed by using two distinct models to represent morphological subtypes of AP. Multi-channel pharmaco-logical effects of disopyramide, quinidine, and propafenone on ionic currents were considered. Simulated results showed that Pitx2-induced remodelling increased maximum upstroke velocity (dVdtmax), and decreased AP duration (APD), conduction velocity (CV), and wavelength (WL). At the concentrations tested in this study, these AADs decreased dVdtmax and CV and prolonged APD in the setting of Pitx2-induced AF. Our findings of alterations in WL indicated that disopyramide may be more effective against Pitx2-induced AF than propafenone and quinidine by prolonging WL.

Living in areas with more vegetation (referred to as residential greenness) may be associated with cardiovascular disease (CVD), but little data are available from low- and middle-income countries. In addition, it remains unclear whether the presence of cardiometabolic disorders modifies or mediates the association between residential greenness and CVD.

Tiantian capsule (TTC), as a functional food, which consists of four herb medicines, including Aloe vera Burm.f. (25%), leaf juices, dried; Cucurbita moschata Duch. (25%), fructus, dried; Poria cocos (Schw.) Wolf. (12.5%), sclerotium, dried; Tremella fuciformis Berk. (12.5%), fruiting bodies, dried, and one extract xylooligosaccharides (25%) from Maize Cob by enzymolysis, has been commonly used in China to ameliorate constipation.

Purpose: Circular RNA (circRNA) is a key regulatory factor in the development and progression of human tumors. However, the working mechanism and clinical significance of most circRNAs remain unknown in human cancers, including multiple myeloma (MM). Patients and Methods: This study employs high-throughput circRNA microarray with bioinformatics to identify differentially expressed circRNAs in patients with MM. The hsa_circ_0007841 expressions were observed in the MM tissues of 86 patients. Drug-resistant cell lines and pathological features were also detected. In addition, the relationship between hsa_circ_0007841 expressions in the MM tissues and the pathological features of patients with MM were evaluated and role of hsa_circ_0007841 as a potential biomarker and therapeutic target was assessed. Results: The results show that in the MM cell lines and drug-resistant cell lines, hsa_circ_0007841 expression was significantly upregulated, which was closely associated with disease prognosis. Specifically, hsa_circ_0007841 upregulation was correlated with chromosomal aberrations such as gain 1q21, t (4:14) and mutations in ATR and IRF4 genes. This finding was corroborated in large samples. Finally, bioinformatics analysis showed that eight differentially expressed miRNAs and 10 candidate mRNAs interacted with hsa_circ_0007841, shedding some new light on the basic functional research. Conclusion: This study may be the first to report that hsa_circ_0007841 is significantly upregulated in MM. It also suggests that hsa_circ_0007841 may be a novel biomarker for MM and its involvement in the progression of MM.

Pleurotus eryngii (King Oyster) is one of the most highly prized edible mushrooms. Among the diverse varieties within P. eryngii, P. eryngii var. eryngii is the commonest one, with a worldwide distribution, while P. eryngii var. ferulae is only distributed in Europe and China, and is especially adapted to the Gobi Desert in Xinjiang Autonomous Region of China. However, little is known about the genome-wide pattern of evolution and adaptation to the divergent environments of P. eryngii. Here, we present the high-quality genome sequences of P. eryngii var. eryngii strain PEE81 originating from Europe and P. eryngii var. ferulae strain PEF12 originating from the Gobi Desert of China. The assembled genome sizes of PEE81 and PEF12 were 53.6 and 48.0 Mbp, respectively, which are larger than other reported genomes in the genus Pleurotus. We propose that the selective amplification of long terminal repeat (LTR) retrotransposons increases the genome size of the genus Pleurotus, and may play a key role in driving their rapid species diversification. Molecular clock analyses of five Pleurotus species, namely PEE81, PEF12, P. tuoliensis, P. ostreatus and P. cf. floridanus suggest that the divergence estimates of the genus Pleurotus over time scales ranged from ∼4 to ∼38 million years ago (Mya), and PEE81 and PEF12 diverged at ∼13 Mya. The whole genome resequencing of 33 geographically diverse strains of P. eryngii var. eryngii and var. ferulae was then performed and the genome variation among and within these two populations were investigated. Comparative analyses of these two populations detected several candidate genes related to stress responses and DNA repair that are putatively involved in adaptation to the Gobi Desert environment. These findings offer insights into genome evolution of the genus Pleurotus and provide valuable genomic resources for King Oyster mushroom breeding.

Ambient air pollution exposure and influenza virus infection have been documented to be independently associated with reduced lung function previously. Influenza vaccination plays an important role in protecting against influenza-induced severe diseases. However, no study to date has focused on whether influenza vaccination may modify the associations between ambient air pollution exposure and lung function.

Malignant ventricular arrhythmia (VA) is the most common cause of death associated with acute myocardial infarction (MI). Recent studies have revealed direct involvement of the paraventricular nucleus (PVN) in the occurrence of VA. However, the underlying mechanisms remain incompletely understood. In this study, we investigated changes in the interleukin-6 (IL-6)-glycoprotein 130-signal transducer and activator of transcription 3 (STAT3) pathway in the PVN during acute MI and the effects of this pathway on ventricular stability.

The general transcription factor, CREB has been shown to play an essential role in promoting cell proliferation, neuronal survival and synaptic plasticity in the nervous system. However, its function in stress response remains to be elusive. In the present study, we demonstrated that CREB plays a major role in mediating stress response. In both rat lens organ culture and mouse lens epithelial cells (MLECs), CREB promotes oxidative stress-induced apoptosis. To confirm that CREB is a major player mediating the above stress response, we established stable lines of MLECs stably expressing CREB and found that they are also very sensitive to oxidative stress-induced apoptosis. To define the underlying mechanism, RNAseq analysis was conducted. It was found that CREB significantly suppressed expression of the αB-crystallin gene to sensitize CREB-expressing cells undergoing oxidative stress-induced apoptosis. CREB knockdown via CRISPR/CAS9 technology led to upregulation of αB-crystallin and enhanced resistance against oxidative stress-induced apoptosis. Moreover, overexpression of exogenous human αB-crystallin can restore the resistance against oxidative stress-induced apoptosis. Finally, we provided first evidence that CREB directly regulates αB-crystallin gene. Together, our results demonstrate that CREB is an important transcription factor mediating stress response, and it promotes oxidative stress-induced apoptosis by suppressing αB-crystallin expression.

Although antimicrobial titanium implants can prevent biomaterial-associated infection (BAI) in orthopedics, they display cytotoxicity and delayed osseointegration. Therefore, versatile implants are desirable for simultaneously inhibiting BAI and promoting osseointegration, especially "statically-versatile" ones with nonessential external stimulations for facilitating applications. Herein, we develop a "statically-versatile" titanium implant by immobilizing an innovative fusion peptide (FP) containing HHC36 antimicrobial sequence and QK angiogenic sequence via sodium borohydride reduction promoted Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC-SB), which shows higher immobilization efficiency than traditional CuAAC with sodium ascorbate reduction (CuAAC-SA). The FP-engineered implant exhibits over 96.8% antimicrobial activity against four types of clinical bacteria (S. aureus, E. coli, P. aeruginosa and methicillin-resistant S. aureus), being stronger than that modified with mixed peptides. This can be mechanistically attributed to the larger bacterial accessible surface area of HHC36 sequence. Notably, the implant can simultaneously enhance cellular proliferation, up-regulate expressions of angiogenesis-related genes/proteins (VEGF and VEGFR-2) of HUVECs and osteogenesis-related genes/proteins (ALP, COL-1, RUNX-2, OPN and OCN) of hBMSCs. In vivo assay with infection and non-infection bone-defect model reveals that the FP-engineered implant can kill 99.63% of S. aureus, and simultaneously promote vascularization and osseointegration. It is believed that this study presents an excellent strategy for developing "statically-versatile" orthopedic implants.

Disruption of microbiota balance may result in severe diseases in animals and phytotoxicity in plants. While substantial concerns have been raised on engineered nanomaterial (ENM) induced hazard effects (e.g., lung inflammation), exploration of the impacts of ENMs on microbiota balance holds great implications.