Intranasal administration of phospholipid-based gelatin nanoparticles (GNP) was prepared to investigate the neuro-recovery effects of neuropeptide Substance P (SP) on hemiparkinsonian rats.
The ...SP-loaded gelatin nanoparticles (SP-GNP) were prepared by a water-in-water emulsion method and possessed high stability, encapsulating efficiency and loading capacity. PC-12 cells were used to examine the growth enhancement of SP-GNP in vitro by MTT assays and flow cytometry (FCM). The therapeutic effects of SP-GNP on 6-hydroxydopamine (6-OHDA) induced hemiparkinsonian rats were assessed by quantifying rotational behavior and the levels of tyrosine hydroxylase (TH), phosphorylated c-Jun protein (p-c-Jun) and Caspase-3 (Cas-3) expressed in substantia nigra (SN) region of hemiparkinsonian rats.
PC-12 cells under SP-GNP treatment showed better cell viability and lower degree of apoptosis than those under SP solution treatment. Hemiparkinsonian rats under intranasal SP-GNP administration demonstrated better behavioral improvement, higher level of TH in SN along with much lower extent of p-c-Jun and Cas-3 than those under intranasal SP solution administration and intravenous SP-GNP administration.
With the advantages of GNP and nose-to-brain pathway, SP can be effectively delivered into the damaged SN region and exhibit its neuro-recovery function through the inhibition on JNK pathway and dopaminergic neuron apoptosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to the accumulation of 15-hydroperoxy (Hp)-arachidonoyl-phosphatidylethanolamine (15-HpETE-PE), generated by complexes of ...15-lipoxygenase (15-LOX) and a scaffold protein, phosphatidylethanolamine (PE)-binding protein (PEBP)1. As the Ca2+-independent phospholipase A2β (iPLA2β, PLA2G6 or PNPLA9 gene) can preferentially hydrolyze peroxidized phospholipids, it may eliminate the ferroptotic 15-HpETE-PE death signal. Here, we demonstrate that by hydrolyzing 15-HpETE-PE, iPLA2β averts ferroptosis, whereas its genetic or pharmacological inactivation sensitizes cells to ferroptosis. Given that PLA2G6 mutations relate to neurodegeneration, we examined fibroblasts from a patient with a Parkinson’s disease (PD)-associated mutation (fPDR747W) and found selectively decreased 15-HpETE-PE-hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis. CRISPR-Cas9-engineered Pnpla9R748W/R748W mice exhibited progressive parkinsonian motor deficits and 15-HpETE-PE accumulation. Elevated 15-HpETE-PE levels were also detected in midbrains of rotenone-infused parkinsonian rats and α-synuclein-mutant SncaA53T mice, with decreased iPLA2β expression and a PD-relevant phenotype. Thus, iPLA2β is a new ferroptosis regulator, and its mutations may be implicated in PD pathogenesis.Ca2+-independent phospholipase A2β cleaves an oxidized form of phosphatidylethanolamine (PE) involved in ferroptosis such that increases in PE sensitize cells to ferroptosis. A mutant allele of the enzyme links neurodegeneration and ferroptosis.
Arterial calcification is a key pathologic component of vascular diseases such as atherosclerosis, coronary artery disease, and peripheral vascular disease. A hallmark of this pathological process is ...the phenotypic transition of vascular smooth muscle cells (VSMCs) to osteoblast-like cells. Several studies have demonstrated that microRNAs (miRNAs) regulate osteoblast differentiation, but it is unclear whether miRNAs also regulate VSMC-mediated arterial calcification. In the present study, we sought to characterize the role of miR-133a in regulating VSMC-mediated arterial calcification. Northern blotting analysis of VSMCs treated with β-glycerophosphate demonstrated that miR-133a was significantly decreased during osteogenic differentiation. Overexpression of miR-133a inhibited VSMC transdifferentiation into osteoblast-like cells as evidenced by a decrease in alkaline phosphatase activity, osteocalcin secretion, Runx2 expression, and mineralized nodule formation. Conversely, the knockdown of miR-133a using an miR-133a inhibitor promoted osteogenic differentiation of VSMCs by increasing alkaline phosphatase activity, osteocalcin secretion, and Runx2 expression. Runx2 was identified as a direct target of miR-133a by a cotransfection experiment in VSMCs with luciferase reporter plasmids containing wild-type or mutant 3′-untranslated region sequences of Runx2. Furthermore, the pro-osteogenic effects of miR-133a inhibitor were abrogated in Runx2-knockdown cells, and the inhibition of osteogenic differentiation by pre–miR-133a was reversed by overexpression of Runx2, providing functional evidence that the effects of miR-133a in osteogenic differentiation were mediated by targeting Runx2. These results demonstrate that miR-133a is a key negative regulator of the osteogenic differentiation of VSMCs.
Conjugated microporous polymers (CMPs) have been heralded as promising energy‐storage materials with advantages such as chemical flexibility, porous structure, and environmentally friendliness. ...Herein, a novel conjugated microporous polymer was synthesized by integrating triazine, thiophene, and benzothiadiazole into a polymer skeleton, and the Li+‐storage performance for the as‐synthesized polymer anode in Li‐ion batteries (LIBs) was investigated. Benefiting from the inherent large surface area, plentiful redox‐active units, and hierarchical porous structure, the polymer anode delivered a high Li+ storage capacity up to 1599 mAh g−1 at a current rate of 50 mA g−1 with an excellent rate behavior (363 mAh g−1 at 5 A g−1) and a long‐term cyclability of 326 mAh g−1 over 1500 cycles at 5 A g−1, implying that the newly developed polymer anode offers a great prospect for next‐generation LIBs.
Three for one: A conjugated microporous polymer consisting of triazine, thiophene, and benzothiadiazole, as anode for lithium‐ion batteries shows a high Li+ storage capacity of 1599 mAh g−1 and excellent rate performance as well as long‐term cyclability.
Brain capillaries are crucial for cognitive functions by supplying oxygen and other nutrients to and removing metabolic wastes from the brain. Recent studies have demonstrated that constriction of ...brain capillaries is triggered by beta-amyloid (Aβ) oligomers via endothelin-1 (ET1)-mediated action on the ET1 receptor A (ETRA), potentially exacerbating Aβ plaque deposition, the primary pathophysiology of Alzheimer’s disease (AD). However, direct evidence is still lacking whether changes in brain capillaries are causally involved in the pathophysiology of AD. Using APP/PS1 mouse model of AD (AD mice) relative to age-matched negative littermates, we identified that reductions of density and diameter of hippocampal capillaries occurred from 4 to 7 months old while Aβ plaque deposition and spatial memory deficit developed at 7 months old. Notably, the injection of ET1 into the hippocampus induced early Aβ plaque deposition at 5 months old in AD mice. Conversely, treatment of ferulic acid against the ETRA to counteract the ET1-mediated vasoconstriction for 30 days prevented reductions of density and diameter of hippocampal capillaries as well as ameliorated Aβ plaque deposition and spatial memory deficit at 7 months old in AD mice. Thus, these data suggest that reductions of density and diameter of hippocampal capillaries are crucial for initiating Aβ plaque deposition and spatial memory deficit at the early stages, implicating the development of new therapies for halting or curing memory decline in AD.
The blood brain barrier (BBB) limits the application of most therapeutic drugs for neurological diseases (NDs). Hybrid cell membrane‐coated nanoparticles derived from different cell types can mimic ...the surface properties and functionalities of the source cells, further enhancing their targeting precision and therapeutic efficacy. Neuroinflammation has been increasingly recognized as a critical factor in the pathogenesis of various NDs, especially Alzheimer's disease (AD). In this study, a novel cell membrane coating is designed by hybridizing the membrane from platelets and chemokine (C–C motif) receptor 2 (CCR2) cells are overexpressed to cross the BBB and target neuroinflammatory lesions. Past unsuccessful endeavors in AD drug development underscore the challenge of achieving favorable outcomes when utilizing single‐mechanism drugs.Two drugs with different mechanisms of actions into liposomes are successfully loaded to realize multitargeting treatment. In a transgenic mouse model for familial AD (5xFAD), the administration of these drug‐loaded hybrid cell membrane liposomes results in a significant reduction in amyloid plaque deposition, neuroinflammation, and cognitive impairments. Collectively, the hybrid cell membrane‐coated nanomaterials offer new opportunities for precise drug delivery and disease‐specific targeting, which represent a versatile platform for targeted therapy in AD.
A novel cell membrane coating is designed by hybridizing the membranes from platelets and chemokine receptor 2 overexpressing cells to cross the blood brain barrier (BBB) and target neuroinflammatory lesions. Rapamycin and 1‐trifluoromethoxyphenyl‐3‐(1‐propionylpiperidin‐4‐yl) urea (TPPU) are loaded into the liposomes to achieve a synergistic therapy. These drug‐loaded hybrid cell membrane‐coated liposomes precisely target specific lesions and ameliorate cognitive deficiency in Alzheimer's disease.
Molecular dynamics and Monte Carlo methods are common measurements to study the diffusion coefficients of the fluid particles under restricted conditions. Here, the collective diffusion coefficient ...will be obtained through two methods: the one is Fick’s first law (direct mode), and the other is the relationship between collective diffusion coefficient and self-diffusion coefficient (indirect mode). A comparison between two methods is also discussed. The ways of calculation, which are applied for the self-diffusion coefficient and collective diffusion coefficient, are helpful for studying transport characteristics of various molecules in defined space.
Graphical abstract
In this manuscript, we have reported the collective diffusion coefficient obtained through two methods: Fick’s first law (direct mode, as shown in Fig. 1) and the relationship between collective diffusion coefficient and self-diffusion coefficient (indirect mode, as shown in Fig. 2). It is shown that the two methods are accessible and each has their advantages and disadvantages.
Arterial calcification is a common cardiovascular disease that initiates from a process of osteoblastic differentiation of vascular smooth muscle cells (VSMCs). Accumulating evidence has demonstrated ...that microRNAs play an important role in regulating arterial calcification. miR-204 was significantly downregulated in calcified human renal arteries from patients with uremia; calcified arteries of mice, due to 5/6 nephrectomy with a high-phosphate diet (5/6 NTP); and in VSMCs induced by high phosphate concentration. The overexpression of miR-204 alleviated the osteoblastic differentiation of VSMCs. Bisulphite sequencing PCR revealed that CpG sites upstream of miR-204 DNA were hypermethylated in calcified VSMCs; in calcified arteries of mice, due to 5/6 NTP; and in calcified renal artery tissues from patients with uremia. Moreover, increased DNMT3a resulted in the hypermethylation of miR-204 in high phosphate concentration-induced VSMCs, whereas 5-aza-2'-deoxycytidine could restore the expression of miR-204 in high phosphate concentration-induced VSMCs. Moreover, we found that DNMT3a was the target of miR-204, and the methylation ratio of miR-204 was decreased significantly, meaning that the expression of miR-204 was restored when DNMT3a was knocked down by using DNMT3a small interfering RNA, resulting in abrogation of the effect of high phosphate concentration on VSMC calcification. The progress of arterial calcification is regulated by the miR-204/DNMT3a regulatory circuit.
Arterial calcification is a major complication of cardiovascular disease. Oestrogen replacement therapy in postmenopausal women is associated with lower levels of coronary artery calcification, but ...its mechanism of action remains unclear. Here, we show that oestrogen inhibits the osteoblastic differentiation of vascular smooth muscle cells (VSMCs) in vitro and arterial calcification in vivo by promoting autophagy. Through electron microscopy, GFP-LC3 redistribution, and immunofluorescence analyses as well as measurement of the expression of the autophagosome marker light-chain I/II (LC3I/II) and autophagy protein 5 (Atg5), we show that autophagy is increased in VSMCs by oestrogen in vitro and in vivo. The inhibitory effect of oestrogen on arterial calcification was counteracted by 3-methyladenine (3MA) or knockdown of Atg5 and was increased by rapamycin. Furthermore, the inhibitory effect of oestrogen on arterial calcification and the degree of autophagy induced by oestrogen were blocked by a nonselective oestrogen receptor (ER) antagonist (ICI 182780), a selective oestrogen receptor alpha (ERα) antagonist (MPP), and ERα-specific siRNA. Our data indicate that oestrogen inhibits the osteoblastic differentiation of VSMCs by promoting autophagy through the ERα signalling pathway in vitro and arterial calcification in vivo by increasing autophagy. Our findings provide new insights into the mechanism by which oestrogen contributes to vascular calcification in vitro and in vivo.
The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who ...had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAFV600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety‐three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAFV600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAFV600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population.
What's new?
The prevalence of Lynch syndrome (LS) varies significantly in different ethnic populations. In this study, the authors screened more than 3000 Chinese colorectal cancer patients for mutations associated with LS, including mismatch repair (MMR) and BRAFV600E mutations. They found that, while the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of mutations is different, including many not previously reported. Older patients had a decreased risk of LS, suggesting that germline sequencing may not be necessary in this population.
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