Profiling the spatial-temporal expression pattern and characterizing the regulatory networks of brain tissues are vital for understanding the pathophysiology of Alzheimer's disease (AD).
We performed ...a systematic integrated analysis of expression profiles of AD-affected brain tissues (684 AD and 562 controls). A network-based convergent functional genomic approach was used to prioritize possible regulator genes during AD development, followed by functional characterization.
We generated a complete list of differentially expressed genes and hub genes of the transcriptomic network in AD brain and constructed a Web server (www.alzdata.org) for public access. Seventeen hub genes active at the early stages, especially YAP1, were recognized as upstream regulators of the AD network. Cellular assays proved that early alteration of YAP1 could promote AD by influencing the whole transcriptional network.
Early expression disturbance of hub genes is an important feature of AD development, and interfering with this process may reverse the disease progression.
According to the International Diabetes Federation (IDF),2 the prevalence of diabetes among adults aged 20–79 in 2017 was 8.8% from a total population of 425 million, which will reach 629 million by ...2045. SOD: superoxide dismutase; CAT: catalase; GSH-px: glutathione peroxidase; iNOS: inducible nitric oxide synthase; MDA: malondialdehyde. 34 Therefore, oxidative stress is most harmful to human pancreatic cells, causing diabetes. ...increasing studies35,36 have shown that oxidative stress can induce insulin resistance, which makes more evident that oxidative stress is an important factor in the onset or exacerbation of T2DM. ...anti-oxidative therapy is helpful for the treatment of T2DM.
Despite the marked success of applications of PD-1/PD-L1 checkpoint blockades in clinical, the efficacy and responsiveness of these agents varies greatly among different tumor types and across ...individual patients. Therefore, establishment of predictive biomarkers for checkpoint blockades is of the most importance to maximize the therapeutic benefits. In this review, we discuss the current progress and challenges of developing predictive biomarkers of immunotherapy responsiveness, aiming to provide some directions for future studies. PD-L1 expression is a logical biomarker for the prediction of response to anti-PD-(L)1 immunotherapies. However, the predictive values of PD-L1 expressions for immunotherapy are currently debating and challenging. Multiplex detecting methods and combined biomarkers may provide new strategies. For example, tumor mutation and neoantigens burden, some oncogene mutations, like EGFR, ALK, KRAS and STK11. In addition, with development of new probes and tracers, immuno-PET provide a new, non-invasive and quantitative strategy to monitor treatment response. As current evidence of those potential predictors, a consensus and standardization is needed to establish to widely applied in future studies. Multiplex detecting methods and combined biomarkers may provide new strategies.
•The predictive values of PD-L1 expressions for immunotherapy are currently debating and challenging.•Multiplex detecting methods and combined biomarkers, like tumor mutation burden, oncogene mutations, and immuno-PET, may provide new strategies.•This review discuss the current progress and challenges of predictive biomarkers, aiming to provide some directions for future studies.
Photosensitization associated with electron/energy transfer represents the central science of natural photosynthesis. Herein, we proposed a protocol to dramatically improve the sensitizing ability of ...metal–organic frameworks (MOFs) by switching their excited state distribution from 3MLCT (metal‐to‐ligand charge transfer) to 3IL (intraligand). The hierarchical organization of 3IL MOFs and Co/Cu catalysts facilitates electron transfer for efficient photocatalytic H2 evolution with a yield of 26 844.6 μmol g−1 and CO2 photoreduction with a record HCOOH yield of 4807.6 μmol g−1 among all the MOF photocatalysts. Systematic investigations demonstrate that strong visible‐light‐absorption, long‐lived excited state and ingenious multi‐component synergy in the 3IL MOFs can facilitate both interface and intra‐framework electron transfer to boost photocatalysis. This work opens up an avenue to boost solar‐energy conversion by engineering sensitizing centers at a molecular level.
A new protocol was proposed to switch the excited state from metal‐to‐ligand charge transfer to 3IL (intraligand) for dramatically improving the sensitizing ability of metal–organic frameworks (MOFs). Hierarchical integration of single‐site catalysts into 3IL MOFs can directionally and rapidly steer electron transfer, leading to an extremely high H2 evolution activity and a record HCOOH yield among all the MOF photocatalysts.
In ruminants, IFN-tau (IFNT) regulates the production of prostaglandins (PG) in the endometrium, which is crucial for conceptus adhesion. However, the related molecular regulatory mechanisms remain ...unclear. Forkhead box O1 (FOXO1), a member of the FOXO subfamily of transcription factors, is known to be important for mouse implantation and decidualization. In this study, we determined the spatiotemporal expression profile of FOXO1 in goat endometrium during early pregnancy. FOXO1 was highly expressed in the glandular epithelium since the onset of conceptus adhesion (d 16 of pregnancy). Then, we validated that FOXO1 could bind to the promoter of prostaglandin-endoperoxide synthase 2 (PTGS2) and increase its transcription. And the expression profile of PTGS2 was similar to that of FOXO1 in the peri-implantation uterus. Moreover, IFNT could upregulate the levels of FOXO1 and PTGS2 in goat uterus and primary endometrial epithelium cells (EEC). In EEC, the intracellular content of PGF2α was positively correlated with the levels of IFNT and FOXO1. Altogether, we found an IFNT/FOXO1/PTGS2 axis that controls the synthesis of PGF2α but not prostaglandin E2 in goat uterine glands. These findings contribute to better understanding the function of FOXO1 in the reproductive physiology of goats and provide more insights into the implantation of small ruminants.
Photosensitization associated with light absorption and energy/electron‐transfer represents the central processes for photosynthesis. However, it's still a challenge to develop a heavy‐atom‐free ...(HAF) strategy to improve the sensitizing ability of polymeric photosensitizers. Herein, we propose a new protocol to significantly improve the photosensitization by decorating mother conjugated microporous polymer (CMP‐1) with polycyclic aromatic hydrocarbons (PAHs), resulting in a series of CMPs (CMP‐2–4). Systematic study reveals that covalent modification with PAHs can transfer charge to Bodipy in CMP to further facilitate both intersystem crossing and electron‐hole separation, which can dramatically boost energy‐/electron‐transfer reactions. Remarkably, CMP‐2 as a representative CMP can efficiently drive the photosynthesis of methyl phenyl sulfoxide with 92 % yield, substantially higher than that of CMP‐1 (32 %). Experiments and theory calculations demonstrate the structure‐property‐activity relationship of these CMPs, opening a new horizon for developing HAF heterogeneous photosensitizers with highly efficient sensitizing activity by rational structure regulation at a molecular level.
A proof‐of‐concept strategy to trigger charge transfer for improving photosensitization is the covalent modification of conjugated microporous polymers (CMPs) with polycyclic aromatic hydrocarbons (PAHs). Charge transfer from the PAH donor to the Bodipy acceptor in CMPs can facilitate both intersystem crossing and electron–hole separation, leading to excellent performance for both energy‐ and electron‐transfer reactions.
Alzheimer’s disease (AD) is the most common form of dementia. The deposition of β-amyloid (Aβ) plaques in the brain was considered one of the main neuropathological hallmarks of AD. As the loss of ...synapses always occurs during AD progression, AD has been gradually regarded as a “synaptopathy.” The activity-regulated cytoskeleton-associated protein (Arc) was recently identified as a key factor for AD due to its active roles in synaptic plasticity, learning, memory, and Aβ generation. However, there is little evidence to support the association of the
Arc
gene with AD. In this study, a two-stage case-control study of 1471 Han Chinese was conducted to investigate the genetic association between the
Arc
gene and AD. Variant rs10097505 in the 3′UTR region was significantly associated with AD. The whole exons of the
Arc
gene were also screened in 99 AD patients with a high heritability (familial and/or onset age <55 years old). One missense variant (c.20G>A, p.T7I) was identified in two AD patients but was absent in the controls from the general populations. Both rs10097505 and c.20G>A were predicted to be potentially pathogenic. Further luciferase assay, data mining, and integrative analyses revealed that the AD-risk genotype AA of rs10097505 was associated with an increased
Arc
mRNA expression and an elevated Aβ level. Our results indicated that the
Arc
gene would confer susceptibility to AD in Han Chinese, probably through changing the protein structure or affecting the
Arc
expression in brain tissues, which would finally contribute to the pathogenesis and development of AD.
Recent analysis of the cannabinoid content of cannabis plants suggests a shift towards use of high potency plant material with high levels of Δ(9)-tetrahydrocannabinol (THC) and low levels of other ...phytocannabinoids, particularly cannabidiol (CBD). Use of this type of cannabis is thought by some to predispose to greater adverse outcomes on mental health and fewer therapeutic benefits. Australia has one of the highest per capita rates of cannabis use in the world yet there has been no previous systematic analysis of the cannabis being used. In the present study we examined the cannabinoid content of 206 cannabis samples that had been confiscated by police from recreational users holding 15 g of cannabis or less, under the New South Wales "Cannabis Cautioning" scheme. A further 26 "Known Provenance" samples were analysed that had been seized by police from larger indoor or outdoor cultivation sites rather than from street level users. An HPLC method was used to determine the content of 9 cannabinoids: THC, CBD, cannabigerol (CBG), and their plant-based carboxylic acid precursors THC-A, CBD-A and CBG-A, as well as cannabichromene (CBC), cannabinol (CBN) and tetrahydrocannabivarin (THC-V). The "Cannabis Cautioning" samples showed high mean THC content (THC+THC-A = 14.88%) and low mean CBD content (CBD+CBD-A = 0.14%). A modest level of CBG was detected (CBG+CBG-A = 1.18%) and very low levels of CBC, CBN and THC-V (<0.1%). "Known Provenance" samples showed no significant differences in THC content between those seized from indoor versus outdoor cultivation sites. The present analysis echoes trends reported in other countries towards the use of high potency cannabis with very low CBD content. The implications for public health outcomes and harm reduction strategies are discussed.
The polycomb group protein B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) is dysregulated in various cancers, and its upregulation strongly correlates with an invasive phenotype and poor ...prognosis in patients with nasopharyngeal carcinomas. However, the underlying mechanism of Bmi-1-mediated invasiveness remains unknown. In the current study, we found that upregulation of Bmi-1 induced epithelial-mesenchymal transition (EMT) and enhanced the motility and invasiveness of human nasopharyngeal epithelial cells, whereas silencing endogenous Bmi-1 expression reversed EMT and reduced motility. Furthermore, upregulation of Bmi-1 led to the stabilization of Snail, a transcriptional repressor associated with EMT, via modulation of PI3K/Akt/GSK-3beta signaling. Chromatin immunoprecipitation assays revealed that Bmi-1 transcriptionally downregulated expression of the tumor suppressor PTEN in tumor cells through direct association with the PTEN locus. This in vitro analysis was consistent with the statistical inverse correlation detected between Bmi-1 and PTEN expression in a cohort of human nasopharyngeal carcinoma biopsies. Moreover, ablation of PTEN expression partially rescued the migratory/invasive phenotype of Bmi-1-silenced cells, indicating that PTEN might be a major mediator of Bmi-1-induced EMT. Our results provide functional and mechanistic links between the oncoprotein Bmi-1 and the tumor suppressor PTEN in the development and progression of cancer.
Kudzu root (Gegen in Chinese) is the dried root of Puerarialobata (Willd.) Ohwi, a leguminous vine native to South East Asia, which has been used as a traditional Chinese medicine for the treatment ...of fever, acute dysentery, diarrhoea, thirst, diabetes and cardiovascular diseases for thousands of years. The present review summarises the traditional applications, phytochemistry, pharmacological activities, toxicology, quality control and potential interactions with conventional drugs from both English and Chinese literatures.
Kudzu root (Gegen in Chinese) is the dried root of Pueraria lobata (Willd.) Ohwi, a semi-woody, perennial and leguminous vine native to South East Asia. It is often used interchangeably in traditional Chinese medicine with thomson kudzu root (Fengen in Chinese), the dried root of P. thomsonii, although the Chinese Pharmacopoeia has separated them into two monographs since the 2005 edition. For more than 2000 years, kudzu root has been used as a herbal medicine for the treatment of fever, acute dysentery, diarrhoea, diabetes and cardiovascular diseases. Both English and Chinese literatures on the traditional applications, phytochemistry, pharmacological activities, toxicology, quality control and potential interactions with conventional drugs of both species have been included in the present review. Over seventy phytochemicals have been identified in kudzu root, with isoflavonoids and triterpenoids as the major constituents. Isoflavonoids, in particular puerarin, have been used in most of the pharmacological studies. Animal and cellular studies have provided support for the traditional uses of kudzu root on cardiovascular, cerebrovascular and endocrine systems, including diabetes and its complications. Further studies to define the active phytochemical compositions, quality standards and clinical efficacy are warranted. Strong interdisciplinary collaboration to bridge the gap between traditional medicine and modern biomedical medicine is therefore needed for the development of kudzu root as an effective medicine for the management of diabetes and cardiovascular diseases.
PDF
