Human cerebral cortex size and complexity has increased greatly during evolution. While increased progenitor diversity and enhanced proliferative potential play important roles in human neurogenesis ...and gray matter expansion, the mechanisms of human oligodendrogenesis and white matter expansion remain largely unknown. Here, we identify EGFR-expressing “Pre-OPCs” that originate from outer radial glial cells (oRGs) and undergo mitotic somal translocation (MST) during division. oRG-derived Pre-OPCs provide an additional source of human cortical oligodendrocyte precursor cells (OPCs) and define a lineage trajectory. We further show that human OPCs undergo consecutive symmetric divisions to exponentially increase the progenitor pool size. Additionally, we find that the OPC-enriched gene, PCDH15, mediates daughter cell repulsion and facilitates proliferation. These findings indicate properties of OPC derivation, proliferation, and dispersion important for human white matter expansion and myelination.
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•Human oRGs are a source of EGFR+ Pre-OPCs•Pre-OPCs undergo diminutive MST during division•Human OPC proliferation exponentially increases the progenitor pool•OPC-enriched PCDH15 regulates daughter cell repulsion and proliferation
The properties of human oligodendrocyte precursor cell derivation, proliferation, and dispersion are explored and provide insight into white matter expansion and myelination in the human brain.
Tetrahydropalmatine (THP), a tetrahydroproberine isoquinoline alkaloid, is widely present in some botanical drugs, such as
H.S. Lo (Menispermaceae; Radix stephaniae epigaeae),
(Y.H.Chou & Chun C.Hsu) ...W.T. Wang ex Z.Y. Su and C.Y. Wu (Papaveraceae; Corydalis rhizoma), and
C.K.Schneid (Berberidaceae; Phellodendri chinensis cortex). THP has attracted considerable attention because of its diverse pharmacological activities. In this review, the chemical properties, plant sources, pharmacological activities, pharmacokinetic and toxicological characteristics of THP were systematically summarized for the first time. The results indicated that THP mainly existed in
and
families. Its pharmacological activities include anti-addiction, anti-inflammatory, analgesic, neuroprotective, and antitumor effects. Pharmacokinetic studies showed that THP was inadequately absorbed in the intestine and had rapid clearance and low bioavailability
, as well as self-microemulsifying drug delivery systems, which could increase the absorption level and absorption rate of THP and improve its bioavailability. In addition, THP may have potential cardiac and neurological toxicity, but toxicity studies of THP are limited, especially its long-duration and acute toxicity tests. In summary, THP, as a natural alkaloid, has application prospects and potential development value, which is promising to be a novel drug for the treatment of pain, inflammation, and other related diseases. Further research on its potential target, molecular mechanism, toxicity, and oral utilization should need to be strengthened in the future.
HSV glycoprotein K (gK) is an essential herpes protein that contributes to enhancement of eye disease. We previously reported that gK binds to signal peptide peptidase (SPP) and that depletion of SPP ...reduces HSV-1 infectivity
in vivo
. To determine the therapeutic potential of blocking gK binding to SPP on virus infectivity and pathogenicity, we mapped the gK binding site for SPP to a 15mer peptide within the amino-terminus of gK. This 15mer peptide reduced infectivity of three different virus strains
in vitro
as determined by plaque assay, FACS, and RT-PCR. Similarly, the 15mer peptide reduced ocular virus replication in both BALB/c and C57BL/6 mice and also reduced levels of latency and exhaustion markers in infected mice when compared with control treated mice. Addition of the gK-15mer peptide also increased the survival of infected mice when compared with control mice. These results suggest that blocking gK binding to SPP using gK peptide may have therapeutic potential in treating HSV-1-associated infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We previously reported that knocking out signal peptide peptidase (SPP), a glycoprotein K (gK) binding partner, in mouse peripheral sensory neurons reduced latency-reactivation in infected mice ...without affecting primary virus replication or eye disease. Since virus replication in the eye plays an essential role in eye disease, we generated a conditional knockout mouse lacking SPP expression in the eye by crossing Pax6 (paired box 6)-Cre mice that have intact Pax6 expression with SPPflox/flox mice. Significantly less SPP protein expression was detected in the eyes of Pax6-SPP-/- mice than in WT control mice. HSV-1 replication in the eyes of Pax6-SPP-/- mice was significantly lower than in WT control mice. Levels of gB, gK, and ICP0 transcripts in corneas, but not trigeminal ganglia (TG), of Pax6-SPP-/- infected mice were also significantly lower than in WT mice. Corneal scarring and angiogenesis were significantly lower in Pax6-SPP-/- mice than in WT control mice, while corneal sensitivity was significantly higher in Pax6-SPP-/- mice compared with WT control mice. During acute viral infection, absence of SPP in the eye did not affect CD4 expression but did affect CD8α and IFNγ expression in the eye. However, in the absence of SPP, latency-reactivation was similar in Pax6-SPP-/- and WT control groups. Overall, our results showed that deleting SPP expression in the eyes reduced primary virus replication in the eyes, reduced CD8α and IFNγ mRNA expression, reduced eye disease and reduced angiogenesis but did not alter corneal sensitivity or latency reactivation to HSV-1 infection. Thus, blocking gK binding to SPP in the eye may have therapeutic potential by reducing both virus replication in the eye and eye disease associated with virus replication.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aconitine is a diterpenoid alkaloid, which mainly exists in the plants of Aconitum. In the last decade, a plethora of studies on the pharmacological activities of aconitine has been conducted and ...demonstrated that aconitine possessed an extensive range of pharmacological activities such as anti-tumor, anti-inflammatory, analgesic, local anesthesia, and immunomodulatory effects. Pharmacokinetic studies indicated that aconitine may have the characteristics of poor bioavailability, wide distribution, and slow elimination. However, studies have also found that aconitine has toxic effects on the heart, nerves, embryos, etc. Therefore, we believe that aconitine may not be suitable for heart patients and pregnant women to treat related diseases. It is important to note that all of these pharmacological effects require further high-quality studies to determine the clinical efficacy of aconitine. This review aims to summarize the advances in pharmacological, pharmacokinetics, toxicity, and detoxification of aconitine in the last decade with an emphasis on its anti-tumor and anti-inflammatory activities, to provide researchers with the latest information and point out the limitations of relevant research at the current stage and the aspects that should be strengthened in future research.
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•Delineated pharmacokinetics, pharmacology and toxicity of aconitine.•Summarized the advances in anti-tumor mechanism of aconitine.•Discussed detoxification and some promising direction for further research on aconitine.
Lung adenocarcinoma (LUAD) is the most ordinary histological subtype of lung cancer, and regulatory cell death is an attractive target for cancer therapy. Recent reports suggested that cuproptosis is ...a novel copper-dependent modulated form of cell death dependent on mitochondrial respiration. However, the role of cuproptosis-related genes (CRGs) in the LUAD process is unclear. In the current study, we found that DLD, LIAS, PDHB, DLAT and LIPA1 in 10 differentially expressed CRGs were central genes. GO and KEGG enrichment results showed that these 10 CRGs were mainly enriched in acetyl-CoA biosynthetic process, mitochondrial matrix, citrate cycle (TCA cycle) and pyruvate metabolism. Furthermore, we constructed a prognostic gene signature model based on the six prognostic CRGs, which demonstrated good predictive potential. Excitedly, we found that these six prognostic CRGs were significantly associated with most immune cell types, with DLD being the most significant (19 types). Significant correlations were noted between some prognostic CRGs and tumor mutation burden and microsatellite instability. Clinical correlation analysis showed that DLD was related to the pathological stage, T stage, and M stage of patients with LUAD. Lastly, we constructed the lncRNA UCA1/miR-1-3p/DLD axis that may play a key role in the progression of LUAD and screened nine active components of traditional Chinese medicine (TCM) that may regulate DLD. Further,
in vitro
cell experiments and molecular docking were used to verify this. In conclusion, we analyzed the potential value of CRGs in the progression of LUAD, constructed the potential regulatory axis of ceRNA, and obtained the targeted regulatory TCM active ingredients through comprehensive bioinformatics combined with experimental validation strategies. This work not only provides new insights into the treatment of LUAD but also includes a basis for the development of new immunotherapy drugs that target cuproptosis.
An important research gap in the field of switched systems is the design of fault tolerant control for Lipschitz non-linear delayed switched systems using a model predictive method. This study ...addresses this gap by taking into account the failure of the actuators and develops a fault-tolerant model predictive control technique for the non-linear delayed Lipschitz switched systems with arbitrary switching signal to asymptotically stabilize the closed-loop system. The non-convex optimization issue is phrased as a linear matrix inequality optimization problem and a set of novel stability criteria are derived by taking into account the cost function with infinite predictive horizon and input limitation and employing switched Lyapunov-Krasovskii functional. The success of the suggested scheme is then evaluated using a computer simulation of a system that causes water pollution. The results support the proposed scheme’s successful execution.
Introduction:
Apoptosis and autophagy impact cell death in multiple systems of the body. Development of new therapeutic strategies that target these processes must address their complex role during ...developmental cell growth as well as during the modulation of toxic cellular environments.
Areas covered:
Novel signaling pathways involving Wnt1-inducible signaling pathway protein 1 (WISP1), phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), β-catenin and mammalian target of rapamycin (mTOR) govern apoptotic and autophagic pathways during oxidant stress that affect the course of a broad spectrum of disease entities including Alzheimer's disease, Parkinson's disease, myocardial injury, skeletal system trauma, immune system dysfunction and cancer progression. Implications of potential biological and clinical outcome for these signaling pathways are presented.
Expert opinion:
The CCN family member WISP1 and its intimate relationship with canonical and non-canonical wingless signaling pathways of PI3K, Akt1, β-catenin and mTOR offer an exciting approach for governing the pathways of apoptosis and autophagy especially in clinical disorders that are currently without effective treatments. Future studies that can elucidate the intricate role of these cytoprotective pathways during apoptosis and autophagy can further the successful translation and development of these cellular targets into robust and safe clinical therapeutic strategies.
Gait recognition aims to identify a person based on his unique walking pattern. Compared with silhouettes and skeletons, skinned multi-person linear (SMPL) models can simultaneously provide human ...pose and shape information and are robust to viewpoint and clothing variances. However, previous approaches have only considered SMPL parameters as a whole and are yet to explore their potential for gait recognition thoroughly. To address this problem, we concentrate on SMPL representations and propose a novel SMPL-based method named GaitSG for gait recognition, which takes SMPL parameters in the graph structure as input. Specifically, we represent the SMPL model as graph nodes and employ graph convolution techniques to effectively model the human model topology and generate discriminative gait features. Further, we utilize prior knowledge of the human body and elaborately design a novel part graph pooling block, PGPB, to encode viewpoint information explicitly. The PGPB also alleviates the physical distance-unaware limitation of the graph structure. Comprehensive experiments on public gait recognition datasets, Gait3D and CASIA-B, demonstrate that GaitSG can achieve better performance and faster convergence than existing model-based approaches. Specifically, compared with the baseline SMPLGait (3D only), our model achieves approximately twice the Rank-1 accuracy and requires three times fewer training iterations on Gait3D.
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