Overexpression of estrogen receptor beta alleviates the toxic effects of beta-amyloid protein on PC12 cells via non-hormonal ligands

After binding to the estrogen receptor, estrogen can alleviate the toxic effects of beta-amyloid protein, and thereby exert a therapeutic effect on Alzheimer＇s disease patients. Estrogen can increase the incidence of breast carcinoma and endometrial cancer in post-menopausal women, so it is not suitable for clinical treatment of Alzheimer＇s disease. There is recent evidence that the estrogen receptor can exert its neuroprotective effects without estrogen dependence. Real-time quantitative PCR and flow cytometry results showed that, compared with non-transfected PC12 cells, adenovirus-mediated estrogen receptor β gene-transfected PC12 cells exhibited lower expression of tumor necrosis factor a and interleukin 1β under stimulation with beta-amyloid protein and stronger protection from apoptosis. The Akt-specific inhibitor Abi-2 decreased the anti-inflammatory and anti-apoptotic effects of estrogen receptor β gene-transfection. These findings suggest that overexpression of estrogen receptor β can alleviate the toxic effect of beta-amyloid protein on PC12 cells, without estrogen dependence. The Akt pathway is one of the potential means for the anti-inflammatory and anti-apoptotic effects of the estrogen receptor.

Telencephalin protects Paju cells from beta-amyloid protein-induced apoptosis

Previous studies have confirmed that telencephalin （TLN） is a neural glycoprotein that protects axonal disruption induced by the beta-amyloid protein （Aβ42/35） in the neural crest-derived tumor cell line Paju. The present study investigated the effects of TLN on neuronal degeneration induced by Aβ42 in the differentiated Paju cell line. Results demonstrated that after cultivating cells in Aβ42 medium, the survival rate of Paju-TLN cells was significantly higher than that of Paju-neo cells, and that apoptotic rate was noticeably reduced. These results indicate that TLN reduces Paju cell apoptosis induced by Aβ42.

High-frequency magnetic stimulation attenuates beta-amyloid protein 1-42 neurotoxicity in organotypic hippocampal slices

Repetitive transcranial magnetic stimulation （rTMS） has been utilized as a therapeutic tool for neurodegenerative disorders including Alzheimer＇s disease. However, the precise mechanisms of its clinical effects remain unknown. β-amyloid （Aβ） exhibits direct neurotoxic effects and is closely related to neuronal degeneration in Alzheimer＇s disease. Therefore, it has been hypothesized that the neuroprotective effects of rTMS are related to the mechanisms of protection against Aβ neurotoxicity. Organotypic hippocampal slices were prepared from 8-day old, Sprague Dawley rats. The tissue slices were exposed to 100 μmol/L Al3142 since day 12 in vitro with and without high-frequency （20 Hz） magnetic stimulation. Magnetic stimulation efficacy was evaluated by measuring neuronal nuclei （NeuN） protein expression and by observing cultures following propidium iodide fluorescence staining and bromodeoxyuridine （BrdU） immunohistochemistry. Lactate dehydrogenase activity was detected in the culture media to evaluate hippocampal neuronal damage. Our results demonstrated that high-frequency magnetic stimulation significantly reversed the reduction of NeuN protein expression because of Aβ1-42 exposure （P 〈 0.05） and significantly reduced the number of damaged cells in the hippocampal slices （P 〈 0.05）. However, lactate dehydrogenase levels and anti-BrdU staining results did not reveal any statistical differences These findings indicate that high-frequency magnetic stimulation might have protective effect on hippocampal neurons from Aβ1-42 neurotoxicity.

Effect of Panax notoginseng saponins on the expression of beta-amyloid protein in the cortex of the parietal lobe and hippocampus, and spatial learning and memory in a mouse model of senile dementia

BACKGROUND： The pharmacological actions of Panax notoginseng saponins （PNS） lie in removing free radicals, anti-inflammation and anti-oxygenation. It can also improve memory and behavior in rat models of Alzheimer＇s disease. OBJECTIVE： Using the Morris water maze, immunohistochemistry, real-time PCR and RT-PCR, this study aimed to measure improvement in spatial learning, memory, expression of amyloid precursor protein （App） and β -amyloid （A β ）, to investigate the mechanism of action of PNS in the treatment of AD in the senescence accelerated mouse-prone 8 （SAMP8） and compare the effects with huperzine A. DESIGN, TIME AND SETTING： A completely randomized grouping design, controlled animal experiment was performed in the Center for Research ＆ Development of New Drugs, Guangxi Traditional Chinese Medical University from July 2005 to April 2007. MATERIALS： Sixty male SAMP8 mice, aged 3 months, purchased from Tianjin Chinese Traditional Medical University of China, were divided into four groups： PNS high-dosage group, PNS low-dosage group, huperzine A group and control group. PNS was provided by Weihe Pharmaceutical Co., Ltd. （batch No.： Z53021485, Yuxi, Yunan Province, China）. Huperzine A was provided by Zhenyuan Pharmaceutical Co., Ltd. （batch No.： 20040801, Zhejiang, China）. METHODS： The high-dosage group and low-dosage group were treated with 93.50 and 23.38 mg/kg PNS respectively per day and the huperzine A group was treated with 0.038 6 mg/kg huperzine A per day, all by intragastric administration, for 8 consecutive weeks. The same volume of double distilled water was given to the control group. MAIN OUTCOME MEASURES： After drug administration, learning and memory abilities were assessed by place navigation and spatial probe tests. The recording indices consisted of escape latency （time-to-platform）, and the percentage of swimming time spent in each quadrant. The number of A β 1-40, A β 1-42 and App immunopositive neurons in the brains of SAMP8 mice was analyzed by immunohistochemistry. The mRNA content ofApp, tau, acetylcholinesterase, and synaptophysin （Syp） was tested by real time PCR and RT-PCR. RESULTS： The PCR results show that PNS can downregulate the expression of the App gene and upregulate the expression of the Syp gene in the parietal cortex and hippocampus of SAMP8 mice. The therapeutic effects of the PNS high-dosage group were greater than those of the PNS low-dosage group and the huperzine A group （P 〈 0.05）. The results of the Morris water maze and immunohistochemistry indicated that PNS can improve the capacity for spatial learning and memory in SAMP8 mice, and reduce the content of A β 1-40, A β 1-42 and expression of App in the brains of SAMP8 mice. The therapeutic effects of the PNS high-dosage group were greater than that of the PNS low-dosage group and the huperzine A group （P 〈 0.05）. CONCLUSION： These results support the hypothesis that PNS plays a therapeutic and protective role on the pathological lesions and learning dysfunction of Alzheimer＇s disease. The therapeutic effects of PNS for Alzheimer＇s disease are possibly achieved through downregulating the expression of the App gene and upregulating the expression of the Syp gene. The therapeutic effects of PNS are dose-dependent and are greater than the effect of huperzine A.

Dynamic changes of beta-amyloid protein deposition in hippocampus of female ovariectomized rats

BACKGROUND： To evaluate and summarize the effects of cerebral perfusion and vascular reserve on the treatment of SICAS. Recently, research on β-amyloid protein has focused on the regulatory effects of estrogen or phytoestrogen on its deposition. However, there have been only a few reports on dynamic changes of β -amyloid protein deposition in hippocampus of ovariectomized rats. OBJECTIVE： To measure β -amyloid protein deposition in the hippocampal formation of ovariectomized rats by using immunohistochemistry; to observe time-dependent dynamic changes. DESIGN： Randomized controlled animal study. SETTING： Third Xiangya Hospital of Central South University. MATERIALS： The experiment was carried out in the Central Laboratory of the Third Xiangya Hospital of Central South University from November 2005 to December 2006. Fifty healthy female Sprague Dawley （SD） rats, weighing （293 ± 10） g, were provided by the Animal Laboratory of Xiangya Medical College, Central South University. All rats had neither a childbearing history nor hepatic or renal disease, or skeletal deformity. β-amyloid protein immunohistochemical kit was provided by Wuhan Boster Company. The experiment was in accordance with animal ethics standards. METHODS： All rats were randomly divided into five groups, including normal control group （n = 10）, sham operation group （n = 10）, and ovariectomized group （n = 30）. After anesthesia in the ovariectomized group, the bilateral ovaries were separated and resected. The same volume of fat was resected in the sham operation group. Rats from the normal control group, however, did not receive any surgical treatments. Rats in the normal control group and sham operation group were sacrificed by anesthesia 7 weeks after surgery. Every ten rats from the ovariectomized group was respectively sacrificed at 7, 15, and 30 weeks after surgery. lmmunohistochemistry was used to detect β-amyloid protein deposition in hippocampal sections. Cell counting and gray value measurements served to record the dynamic changes in β-amyloid protein deposition. MAIN OUTCOME MEASURES： （1） Morphological changes. （2） Positive cell counts from β -amyloid protein stainings and gray value measurements. RESULTS： All 50 rats were involved in the final analysis. （1） Morphological changes. β -amyloid-positive cells were detected in the hippocampus of all rats. Biebrich scarlet stained neurites with a swollen cytoplasm. A few β -amyloid-positive cells were observed in all groups 7 weeks after surgery, and plasma and neurites were slightly stained. By 15 weeks after surgery, a number of β -amyloid-positive cells were observed in the ovariectomized group, and plasma and neurites were also slightly stained. By 30 weeks after surgery, however, many β-amyloid-positive cells were observed in the ovariectomized group. These cells were partially aggregated and darkly stained. （2） Positive cell counts and gray value of β-amyloid protein in hippocampus. At 7 weeks after surgery, cell counts and gray value measurements were not significantly different in the ovariectomized group compared to the sham operation group and normal control group （P 〉 0.05）. Cell counts and gray value measurements were higher in the ovariectomized group by 15 weeks compared to those by 7 weeks in the normal control group, sham operation group and ovariectomized group （P 〈 0.05）. At 30 weeks after surgery, cell counts and gray value measurements were higher in the ovariectomized group compared to the normal control group. In addition, there were significant differences between sham operation group and ovariectomized group, at 7 and 15 weeks after operation （P 〈 0.05-0.01 ）. Cell counts and gray value measurements increased in all groups over time. CONCLUSION： Extended estrogen deficiency in rats can increase β-amyloid protein deposition in the hippocampus and the deposition increases over time.

Curcumin inhibits beta-amyloid protein 40/42 expression in the brain in a concentration-and time-dependent manner

Several studies have demonstrated that the amount of beta-amyloid （Aβ） protein in the brain can be lowered by down-regulating Aβ production, promoting Aβ degradation, reducing Aβ oligomerization or deposition, thereby alleviating symptoms of Alzheimer＇s disease. Curcumin has been known to be a peroxisome proliferator activated receptor gamma （PPARy） agonist and can obviously inhibit Aβ production and oligomerization. This study investigated the effects of curcumin on the G-site APP cleaving enzyme 1 （BACE1） activity and PPARy expression in human neuroblastoma SH-SY5Y cells, and validated the inhibitory effects of curcumin on Aβ40/42 expression in the brain. Results revealed that PPARy mRNA and protein expression in the human neuroblastoma SH-SY5Y cells significantly increased with increasing curcumin concentration and time course （P 〈 0.05）; BACE1 mRNA and protein expression and Aβ40/42 production significantly decreased with increasing curcumin concentration and time course （P 〈 0.05）. The changes in PPARy and BACE1 expression during Aβ production could be reversed by the PPARy antagonist GW9662. These findings indicate that curcumin reduced Aβ production by activating PPARy expression and inhibiting BACE1 expression in a concentration- and time-dependent manner.

Inhibition of protein degradation increases the Bt protein concentration in Bt cotton

Bacillus thuringiensis(Bt)cotton production is challenged by two main problems,i.e.,the low concentration of Bt protein at the boll setting stage and the lowest insect resistance in bolls among all the cotton plant’s organs.Therefore,increasing the Bt protein concentration at the boll stage,especially in bolls,has become the main goal for increasing insect resistance in cotton.In this study,two protein degradation inhibitors(ethylene diamine tetra acetic acid(EDTA)and leupeptin)were sprayed on the bolls,subtending leaves,and whole cotton plants at the peak flowering stage of two Bt cultivars(medium maturation Sikang 1(SK1))and early maturation Zhongmian 425(ZM425)in 2019 and 2020.The Bt protein content and protein degradation metabolism were assessed.The results showed that the Bt protein concentrations were enhanced by 21.3 to 38.8%and 25.0 to 38.6%in the treated bolls of SK1 and ZM425 respectively,while they were decreased in the subtending leaves of these treated bolls.In the treated leaves,the Bt protein concentrations increased by 7.6 to 23.5%and 11.2 to 14.9%in SK1 and ZM425,respectively.The combined application of EDTA and leupeptin to the whole cotton plant increased the Bt protein concentrations in both bolls and subtending leaves.The Bt protein concentrations in bolls were higher,increasing by 22.5 to 31.0%and 19.6 to 32.5%for SK1 and ZM425,respectively.The organs treated with EDTA or/and leupeptin showed reduced free amino acid contents,protease and peptidase activities and significant enhancements in soluble protein contents.These results indicated that inhibiting protein degradation could improve the protein content,thus increasing the Bt protein concentrations in the bolls or/and leaves of cotton plants.Therefore,the increase in the Bt protein concentration without yield reduction suggested that these two protein degradation inhibitors may be applicable for improving insect resistance in cotton production.

Major royal-jelly proteins intake modulates immune functions and gut microbiota in mice

In this study,we investigated the effects of major royal jelly proteins(MRJPs)on the estrogen,gut microbiota,and immunological responses in mice.Mice given 250 or 500 mg/kg,not 125 mg/kg of MRJPs,enhanced the proliferation of splenocytes in response to mitogens.The splenocytes and mesenteric lymphocytes activated by T-cell mitogens(Con A and anti-CD3/CD28 antibodies)released high levels of IL-2 but low levels of IFN-γand IL-17A.The release of IL-4 was unaffected by MRJPs.Additionally,splenocytes and mesenteric lymphocytes activated by LPS were prevented by MRJPs at the same dose as that required for producing IL-1βand IL-6,two pro-inflammatory cytokines.The production of IL-1β,IL-6,and IFN-γwas negatively associated with estrogen levels,which were higher in the MRJP-treated animals than in the control group.Analysis of the gut microbiota revealed that feeding mice 250 mg/kg of MRJPs maintained the stability of the natural intestinal microflora of mice.Additionally,the LEf Se analysis identified biomarkers in the MRJP-treated mice,including Prevotella,Bacillales,Enterobacteriales,Gammaproteobacteria,Candidatus_Arthromitus,and Shigella.Our results showed that MRJPs are important components of royal jelly that modulate host immunity and hormone levels and help maintain gut microbiota stability.

The pathogenic mechanism of TAR DNA-binding protein 43(TDP-43)in amyotrophic lateral sclerosis

The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex,basal ganglia,brainstem,and spinal cord,and commonly involves the muscles of the upper and/or lower extremities,and the muscles of the bulbar and/or respiratory regions.However,as the disease progresses,it affects the adjacent body regions,leading to generalized muscle weakness,occasionally along with memory,cognitive,behavioral,and language impairments;respiratory dysfunction occurs at the final stage of the disease.The disease has a complicated pathophysiology and currently,only riluzole,edaravone,and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized countries.The TAR DNA-binding protein 43 inclusions are observed in 97%of those diagnosed with amyotrophic lateral sclerosis.This review provides a preliminary overview of the potential effects of TAR DNAbinding protein 43 in the pathogenesis of amyotrophic lateral sclerosis,including the abnormalities in nucleoplasmic transport,RNA function,post-translational modification,liquid-liquid phase separation,stress granules,mitochondrial dysfunction,oxidative stress,axonal transport,protein quality control system,and non-cellular autonomous functions(e.g.,glial cell functions and prion-like propagation).

Impact of apolipoprotein E isoforms on sporadic Alzheimer's disease:beyond the role of amyloid beta

The impact of apolipoprotein E(ApoE)isoforms on sporadic Alzheimer's disease has long been studied;however,the influences of apolipoprotein E gene(APOE)on healthy and pathological human brains are not fully understood.ApoE exists as three common isoforms(ApoE2,ApoE3,and ApoE4),which differ in two amino acid residues.Traditionally,ApoE binds cholesterol and phospholipids and ApoE isoforms display diffe rent affinities for their receptors,lipids transport and distribution in the brain and periphery.The role of ApoE in the human depends on ApoE isoforms,brain regions,aging,and neural injury.APOE E4 is the strongest genetic risk factor for sporadic Alzheimer's disease,considering its role in influencing amyloid-beta metabolism.The exact mechanisms by which APOE gene variants may increase or decrease Alzheimer's disease risk are not fully understood,but APOE was also known to affect directly and indirectly tau-mediated neurodegeneration,lipids metabolism,neurovascular unit,and microglial function.Consistent with the biological function of ApoE,ApoE4 isoform significantly alte red signaling pathways associated with cholesterol homeostasis,transport,and myelination.Also,the rare protective APOE variants confirm that ApoE plays an important role in Alzheimer's disease pathogenesis.The objectives of the present mini-review were to describe classical and new roles of various ApoE isoforms in Alzheimer's disease pathophysiology beyond the deposition of amyloid-beta and to establish a functional link between APOE,brain function,and memory,from a molecular to a clinical level.APOE genotype also exerted a heterogeneous effect on clinical Alzheimer's disease phenotype and its outcomes.Not only in learning and memory but also in neuro psychiatric symptoms that occur in a premorbid condition.Cla rifying the relationships between Alzheimer's disease-related pathology with neuropsychiatric symptoms,particularly suicidal ideation in Alzheimer's disease patients,may be useful for elucidating also the underlying pathophysiological process and its prognosis.Also,the effects of anti-amyloid-beta drugs,recently approved for the treatment of Alzheimer's disease,could be influenced by the APOE genotype.

GmSTF accumulation mediated by DELLA protein GmRGAs contributes to coordinating light and gibberellin signaling to reduce plant height in soybean

Plant height influences plant architecture,lodging resistance,and yield performance.It is modulated by gibberellic acid(GA)metabolism and signaling.DELLA proteins,acting as central repressors of GA signaling,integrate various environmental and hormonal signals to regulate plant growth and development in Arabidopsis.We examined the role of two DELLA proteins,GmRGAa and GmRGAb,in soybean plant height control.Knockout of these proteins led to longer internodes and increased plant height,primarily by increasing cell elongation.GmRGAs functioned under different light conditions,including red,blue,and far-red light,to repress plant height.Interaction studies revealed that GmRGAs interacted with the blue light receptor GmCRY1b.Consistent with this,GmCRY1b partially regulated plant height via GmRGAs.Additionally,DELLA proteins were found to stabilize the protein GmSTF1/2,a key positive regulator of photomorphogenesis.This stabilization led to increased transcription of GmGA2ox-7b and subsequent reduction in plant height.This study enhances our understanding of DELLA-mediated plant height control,offering Gmrgaab mutants for soybean structure and yield optimization.

Responses of growth performance,antioxidant function,small intestinal morphology and mRNA expression of jejunal tight junction protein to dietary iron in yellow-feathered broilers

This study aimed to investigate the dose-effect of iron on growth performance,antioxidant function.intestinal morphology,and mRNA expression of jejunal tight junction protein in 1-to21-d-old yellow-feathered broilers.A total of 7201-d-old yellow-feathered maleb roilers were allocated to 9 treatments with 8 replicate cages of 10 birds per cage.The dietary treatments were consisted of a basal diet(contained 79.6 mg Fe kg^(-1))supplemented with 0,20,40,60,80,160,320,640,and 1,280 mg Fe kg^(-1)in the form of FeSO_(4)·7H_(2)O.Compared with the birds in the control group,birds supplemented with 20mg Fe kg^(-1)had higher average daily gain(ADG)(P<0.0001).Adding 640 and 1,280 mg Fe kg^(-1)significantly decreased ADG(P<0.0001)and average daily feed intake(ADFI)(P<0.0001)compared with supplementation of 20mg Fe kg^(-1).Malondialdehyde(MDA)concentration in plasma and duodenum increased linearly(P<0.0001),but MDA concentration in liver and jejunum increased linearly(P<0.05)or quadratically(P<0.05)with increased dietary Fe concentration.The villus height(VH)in duodenum and jejunum,and the ratio of villus height to crypt depth(V/C)in duodenum decreased linearly(P?0.05)as dietary Feincreased.As dietary Fe increased,the jejunal relative mRNA abundance of claudin-1 decreased linearly(P=0.001),but the jejunal relative mRNA abundance of zona occludens-1(ZO-1)and occludin decreased linearly(P?0.05)or quadratically(P?0.05).Compared with the supplementation of 20 mg Fe kg^(-1),the supplementation of640 mg Fe kg^(-1)or higher increased(P?0.05)MDA concentrations in plasma,duodenum,and jejunum,decreased VH in the duodenum and jejunum,and the addition of 1,280 mg Fe kg^(-1)reduced(P?0.05)the jejunal tight junction protein(claudin-1,ZO-1,occludin)mRNA abundance.In summary,640 mg of supplemental Fe kg^(-1)or greater was associated with decreased growth performance,increased oxidative stress,disrupted intestinal morphology,and reduced mRNA expression of jejunal tight junction protein.

Calmodulins and calmodulin-like proteins-mediated plant organellar calcium signaling networks under abiotic stress

Plant calmodulins(CaMs)and calmodulin-like proteins(CMLs)mediate Ca~(2+)signaling in response to abiotic stresses.Manipulation of this signaling in crops could increase stress tolerance.We review methods for detecting Ca~(2+)signals,regulatory roles of Ca Ms and CMLs,binding targets,and Ca~(2+)networks under abiotic stress in organelles.

Emulsifying property,antioxidant activity,and bitterness of soybean protein isolate hydrolysate obtained by Corolase PP under high hydrostatic pressure

Enzymatic hydrolysis of proteins can enhance their emulsifying properties and antioxidant activities.However,the problem related to the hydrolysis of proteins was the generation of the bitter taste.Recently,high hydrostatic pressure(HHP)treatment has attracted much interest and has been used in several studies on protein modification.Hence,the study aimed to investigate the effects of enzymatic hydrolysis by Corolase PP under different pressure treatments(0.1,100,200,and 300 MPa for 1-5 h at 50℃)on the emulsifying property,antioxidant activity,and bitterness of soybean protein isolate hydrolysate(SPIH).As observed,the hydrolysate obtained at 200 MPa for 4 h had the highest emulsifying activity index(47.49 m^(2)/g)and emulsifying stability index(92.98%),and it had higher antioxidant activities(44.77%DPPH free radical scavenging activity,31.12%superoxide anion radical scavenging activity,and 61.50%copper ion chelating activity).At the same time,the enhancement of emulsion stability was related to the increase of zeta potential and the decrease of mean particle size.In addition,the hydrolysate obtained at 200 MPa for 4 h had a lower bitterness value and showed better palatability.This study has a broad application prospect in developing food ingredients and healthy foods.

Effect of sodium starch octenyl succinate-based Pickering emulsion on the physicochemical properties of hairtail myofibrillar protein gel subjected to multiple freeze-thaw cycles

A Pickering emulsion based on sodium starch octenyl succinate(SSOS)was prepared and its effects on the physicochemical properties of hairtail myofibrillar protein gels(MPGs)subjected to multiple freeze-thaw(F-T)cycles were investigated.The whiteness,water-holding capacity,storage modulus(G')and texture properties of the MPGs were significantly improved by adding 1%-2%Pickering emulsion(P<0.05).Meanwhile,Raman spectral analysis demonstrated that Pickering emulsion promoted the transformation of secondary structure,enhanced hydrogen bonds and hydrophobic interactions,and promoted the transition of disulfide bond conformation from g-g-g to g-g-t and t-g-t.At an emulsion concentration of 2%,theα-helix content decreased by 10.37%,while theβ-sheet content increased by 7.94%,compared to the control.After F-T cycles,the structure of the MPGs was destroyed,with an increase in hardness and a decrease in whiteness and water-holding capacity,however,the quality degradation of MPGs was reduced with 1%-2%Pickering emulsion.These findings demonstrated that SSOS-Pickering emulsions,as potential fat substitutes,can enhance the gel properties and the F-T stability of MPGs.

Crosstalk between Wnt and bone morphogenetic protein signaling during osteogenic differentiati

Mesenchymal stem cells(MSCs)originate from many sources,including the bone marrow and adipose tissue,and differentiate into various cell types,such as osteoblasts and adipocytes.Recent studies on MSCs have revealed that many transcription factors and signaling pathways control osteogenic development.Osteogenesis is the process by which new bones are formed;it also aids in bone remodeling.Wnt/β-catenin and bone morphogenetic protein(BMP)signaling pathways are involved in many cellular processes and considered to be essential for life.Wnt/β-catenin and BMPs are important for bone formation in mammalian development and various regulatory activities in the body.Recent studies have indicated that these two signaling pathways contribute to osteogenic differen-tiation.Active Wnt signaling pathway promotes osteogenesis by activating the downstream targets of the BMP signaling pathway.Here,we briefly review the molecular processes underlying the crosstalk between these two pathways and explain their participation in osteogenic differentiation,emphasizing the canonical pathways.This review also discusses the crosstalk mechanisms of Wnt/BMP signaling with Notch-and extracellular-regulated kinases in osteogenic differentiation and bone development.

Interplay between the glymphatic system and neurotoxic proteins in Parkinson’s disease and related disorders:current knowledge and future directions

Parkinson’s disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins,includingα-synuclein,amyloid-β,and tau,in addition to the impaired elimination of these neurotoxic protein.Atypical parkinsonism,which has the same clinical presentation and neuropathology as Parkinson’s disease,expands the disease landscape within the continuum of Parkinson’s disease and related disorders.The glymphatic system is a waste clearance system in the brain,which is responsible for eliminating the neurotoxic proteins from the interstitial fluid.Impairment of the glymphatic system has been proposed as a significant contributor to the development and progression of neurodegenerative disease,as it exacerbates the aggregation of neurotoxic proteins and deteriorates neuronal damage.Therefore,impairment of the glymphatic system could be considered as the final common pathway to neurodegeneration.Previous evidence has provided initial insights into the potential effect of the impaired glymphatic system on Parkinson’s disease and related disorders;however,many unanswered questions remain.This review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson’s disease and related disorders.The focus of this review is on identifying the manifestations and mechanisms of interplay between the glymphatic system and neurotoxic proteins,including loss of polarization of aquaporin-4 in astrocytic endfeet,sleep and circadian rhythms,neuroinflammation,astrogliosis,and gliosis.This review further delves into the underlying pathophysiology of the glymphatic system in Parkinson’s disease and related disorders,and the potential implications of targeting the glymphatic system as a novel and promising therapeutic strategy.

Optimizing the Bacillus thuringiensis(Bt)protein concentration in cotton:Coordinated application of exogenous amino acids and EDTA to reduce spatiotemporal variability in boll and leaf toxins

During the boll formation stage,cotton bolls exhibit the lowest expression of Bacillus thuringiensis(Bt)insecticidal proteins.Resistance to insects varies notably among different organs,which poses challenges for controlling cotton bollworms.Consequently,an experimental strategy was designed in the 2020-2021 cotton growing season to coordinate the enhancement of protein synthesis and the attenuation of degradation.Two Bt cultivars of Gossypium hirsutum,namely the hybrid Sikang 3 and the conventional Sikang 1,were used as test materials.Three treatments were applied at the peak flowering period:CK(the control),T1(amino acids),and T2(amino acids and EDTA).The results show that,in comparison to the CK group,the Bt protein contents were significantly increased in both cotton bolls and their subtending leaves under the T1 and T2 treatments.The maximum levels of increase observed were 67.5%in cotton bolls and 21.7%in leaves.Moreover,the disparity in Bt protein content between cotton bolls and their subtending leaves notably decreased by 31.2%.Correlation analysis suggested that the primary physiological mechanisms for augmenting Bt protein content involve increased protein synthesis and reduced protein catabolism,which are independent of Bt gene expression levels.Stepwise regression and path analysis revealed that elevating the soluble protein content and transaminase activity,while reducing the catabolic enzyme activities,are instrumental in enhancing the Bt protein content.Consequently,the coordinated application of amino acids and EDTA emerges as a strategy that can improve the overall resistance of Bt cotton and mitigate the spatiotemporal variations in Bt toxin concentrations in both cotton bolls and leaves.

Protein tyrosine phosphatase non-receptor Ⅱ:A possible biomarker of poor prognosis and mediator of immune evasion in hepatocellular carcinoma

BACKGROUND The incidence of primary liver cancer is increasing year by year.In 2022 alone,more than 900000 people were diagnosed with liver cancer worldwide,with hepatocellular carcinoma(HCC)accounting for 75%-85%of cases.HCC is the most common primary liver cancer.China has the highest incidence and mortality rate of HCC in the world,and it is one of the malignant tumors that seriously threaten the health of Chinese people.The onset of liver cancer is occult,the early cases lack typical clinical symptoms,and most of the patients are already in the middle and late stage when diagnosed.Therefore,it is very important to find new markers for the early detection and diagnosis of liver cancer,improve the therapeutic effect,and improve the prognosis of patients.Protein tyrosine phosphatase non-receptor 2(PTPN2)has been shown to be associated with colorectal cancer,triple-negative breast cancer,non-small cell lung cancer,and prostate cancer,but its biological role and function in tumors remain to be further studied.AIM To combine the results of relevant data obtained from The Cancer Genome Atlas(TCGA)to provide the first in-depth analysis of the biological role of PTPN2 in HCC.METHODS The expression of PTPN2 in HCC was first analyzed based on the TCGA database,and the findings were then verified by immunohistochemical staining,quantitative real-time polymerase chain reaction(qRT-PCR),and immunoblotting.The value of PTPN2 in predicting the survival of patients with HCC was assessed by analyzing the relationship between PTPN2 expression in HCC tissues and clinicopathological features.Finally,the potential of PTPN2 affecting immune escape of liver cancer was evaluated by tumor immune dysfunction and exclusion and immunohistochemical staining.RESULTS The results of immunohistochemical staining,qRT-PCR,and immunoblotting in combination with TCGA database analysis showed that PTPN2 was highly expressed and associated with a poor prognosis in HCC patients.Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that PTPN2 was associated with various pathways,including cancer-related pathways,the Notch signaling pathway,and the MAPK signaling pathway.Gene Set Enrichment Analysis showed that PTPN2 was highly expressed in various immune-related pathways,such as the epithelial mesenchymal transition process.A risk model score based on PTPN2 showed that immune escape was significantly enhanced in the high-risk group compared with the low-risk group.CONCLUSION This study investigated PTPN2 from multiple biological perspectives,revealing that PTPN2 can function as a biomarker of poor prognosis and mediate immune evasion in HCC.

Effects of improved amino acid balance diet on lysine mammary utilization, whole body protein turnover and muscle protein breakdown on lactating sows

Background The study objective was to test the hypothesis that low crude protein(CP)diet with crystalline amino acids(CAA)supplementation improves Lys utilization efficiency for milk production and reduces protein turnover and muscle protein breakdown.Eighteen lactating multiparous Yorkshire sows were allotted to 1 of 2 isocaloric diets(10.80 MJ/kg net energy):control(CON;19.24%CP)and reduced CP with“optimal”AA profile(OPT;14.00%CP).Sow body weight and backfat were recorded on d 1 and 21 of lactation and piglets were weighed on d 1,14,18,and 21 of lactation.Between d 14 and 18,a subset of 9 sows(CON=4,OPT=5)was infused with a mixed solution of 3-[methyl-2H3]histidine(bolus injection)and[13C]bicarbonate(priming dose)first,then a constant 2-h[13C]bicarbonate infusion followed by a 6-h primed constant[1-13C]lysine infusion.Serial blood and milk sampling were performed to determine plasma and milk Lys enrichment,Lys oxidation rate,whole body protein turnover,and muscle protein breakdown.Results Over the 21-d lactation period,compared to CON,sows fed OPT had greater litter growth rate(P<0.05).Compared to CON,sows fed OPT had greater efficiency of Lys(P<0.05),Lys mammary flux(P<0.01)and whole-body protein turnover efficiency(P<0.05).Compared to CON,sows fed OPT tended to have lower whole body protein breakdown rate(P=0.069).Muscle protein breakdown rate did not differ between OPT and CON(P=0.197).Conclusion Feeding an improved AA balance diet increased efficiency of Lys and reduced whole-body protein turnover and protein breakdown.These results imply that the lower maternal N retention observed in lactating sows fed improved AA balance diets in previous studies may be a result of greater partitioning of AA towards milk rather than greater body protein breakdown.