Physical exercise and traumatic brain injury: is it question of time?

Is it better to be safe than sorry?This Hamletic dilemma has always stimulated medical-scientific debates in numerous fields of biomedicine.And among these,the preventive-therapeutic approach to the treatment of brain trauma is one of the most striking examples.Traumatic brain injury(TBI)is a leading cause of brain damage among young and elderly populations with a very high hospitalization and death rate.TBI is characterized by two pathologically distinct but strictly consequential phases:a first characterized by an immediate and highly variable mechanical dysfunction of the brain tissue,which involves widespread cell death and tissue degeneration,followed by a second phase which can last from days to even years depending on the severity of the TBI and the patient’s pre-existing health status.Secondary processes,including inflammatory phenomena,oxidative stress associated with metabolic,vascular,and neuro-modulatory deficits,are very often responsible for neuro-motor and psychological deficits leading to long-term disabilities(Kaur and Sharma,2018).

Molecular and cellular changes in the post-traumatic spinal cord remodeling after autoinfusion of a genetically-enriched leucoconcentrate in a mini-pig model

Post-traumatic spinal cord remodeling includes both degenerating and regenerating processes,which affect the potency of the functional recovery after spinal cord injury(SCI).Gene therapy for spinal cord injury is proposed as a promising therapeutic strategy to induce positive changes in remodeling of the affected neural tissue.In our previous studies for delivering the therapeutic genes at the site of spinal cord injury,we developed a new approach using an autologous leucoconcentrate transduced ex vivo with chimeric adenoviruses(Ad5/35)carrying recombinant cDNA.In the present study,the efficacy of the intravenous infusion of an autologous genetically-enriched leucoconcentrate simultaneously producing recombinant vascular endothelial growth factor(VEGF),glial cell line-derived neurotrophic factor(GDNF),and neural cell adhesion molecule(NCAM)was evaluated with regard to the molecular and cellular changes in remodeling of the spinal cord tissue at the site of damage in a model of mini-pigs with moderate spinal cord injury.Experimental animals were randomly divided into two groups of 4 pigs each:the therapeutic(infused with the leucoconcentrate simultaneously transduced with a combination of the three chimeric adenoviral vectors Ad5/35‐VEGF165,Ad5/35‐GDNF,and Ad5/35‐NCAM1)and control groups(infused with intact leucoconcentrate).The morphometric and immunofluorescence analysis of the spinal cord regeneration in the rostral and caudal segments according to the epicenter of the injury in the treated animals compared to the control mini-pigs showed:(1)higher sparing of the grey matter and increased survivability of the spinal cord cells(lower number of Caspase-3-positive cells and decreased expression of Hsp27);(2)recovery of synaptophysin expression;(3)prevention of astrogliosis(lower area of glial fibrillary acidic protein-positive astrocytes and ionized calcium binding adaptor molecule 1-positive microglial cells);(4)higher growth rates of regeneratingβIII-tubulin-positive axons accompanied by a higher number of oligodendrocyte transcription factor 2-positive oligodendroglial cells in the lateral corticospinal tract region.These results revealed the efficacy of intravenous infusion of the autologous genetically-enriched leucoconcentrate producing recombinant VEGF,GDNF,and NCAM in the acute phase of spinal cord injury on the positive changes in the post-traumatic remodeling nervous tissue at the site of direct injury.Our data provide a solid platform for a new ex vivo gene therapy for spinal cord injury and will facilitate further translation of regenerative therapies in clinical neurology.

Rabbit models of dry eye disease: comparative analysis

AIM:To report ocular changes in rabbits after the implementation of three different induction methods to create dry eye(DE)conditions and provides evidence of DErelated disease evolution.METHODS:Experimental methods were divided into 3 models.The first model used involved triple injection of complete Freund’s adjuvant,50µL each,also called the meibomian gland dysfunction(MGD)model.In the second model,DE conditions were created by the resection of nictitating membranes(NM),Harderian glands(HG),and main lacrimal glands(LG),also called the LGR model.The third model involved the topical administration of benzalkonium chloride(BAK)0.1%solution.The Schirmer test,ocular surface staining with fluorescein,and tear breakup time tests were implemented before and after excision.After euthanasia,the ocular tissues were dissected.Cornea,conjunctiva,and meibomian glands were treated with periodic acid–Schiff(PAS)staining and haematoxylin–eosin staining.RESULTS:The MGD model triggered inflammation of meibomian glands.It detected changes in the lipid layer of the tear film.The bilateral resection of NM,HG,and LG reduced the watering layer of the tear film.The topical administration of BAK of 0.1%solution impacted the mucosal layer of the tear film.CONCLUSION:Different changes are observed with different DE syndrome models.The composition of the tear film differ depending on which part of the eye is targeted.More studies need to be done to confirm whether an increased thickness of the cornea has any impact on the DE disease.

Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations:lessons from recent clinical trials

We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors.Specifically,we discussed randomized clinical trials in subjects with Alzheimer's disease,Huntington's disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations,and glucocerebrosidase-associated Parkinson's disease.Learning potential lessons to improve future therapeutic approaches is the aim of this review.Two long-term,controlled trials on three anti-β-amyloid monoclonal antibodies(solanezumab,gantenerumab and crenezumab)in subjects carrying Alzheimer's disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits.A major trial on tominersen,an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington's disease,was prematurely interrupted because the drug failed to show higher efficacy than placebo and,at highest doses,led to worsened outcomes.A 28-week trial of tofersen,an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy.A trial of venglustat,a potent and brain-penetrant glucosylceramide synthase inhibitor,in Parkinson's disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo.We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies,antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type variants.

Development of sorghum mutants with improved in vitro protein digestibility by CRISPR/Cas9 editing of kafirin genes

Sorghum(Sorghum bicolor(L.) Moench) is a major world crop that is a reliable source of fodder and food grain in arid regions. However, unlike other cereals, sorghum grain has low nutritional value, owing mainly to the resistance of its storage proteins(kafirins) to protease digestion. Changing the composition of kafirins or their primary structure may address this problem. To induce mutations in kafirin-encoding genes that were expected to disturb their accumulation in endosperm cells, we used a genome-editing approach. By Agrobacterium-mediated genetic transformation of immature embryos of cv. Avans, we obtained 14 transgenic plants with genetic constructs for site-directed mutagenesis of the k1C5 and g KAF1 genes encoding 22 k Da a-and 28 kDa γ-kafirins, respectively. Sequencing of 5 regenerants obtained by using k1C5-addressing vector revealed two plants with mutations. T_1 progeny of these mutants had higher in vitro digestibility of endosperm proteins(86%–92%), in comparison with the donor Avans(63%–67%). The kernels of these plants had a thick vitreous endosperm. A mutant with increased in vitro protein digestibility and vitreous endosperm, carrying a mutation in the target sequence, was also obtained by use of the gKAF1-addressing vector. Thus, using genome editing technology, we have obtained mutants with improved kafirin digestibility that can be used in sorghum breeding.

On the interaction of a donepezil-huprine hybrid with synthetic membrane models

Alzheimer's disease is the most prevalent type of dementia today,discovered and described by Alois Alzheimer in 1907.According to the World Alzheimer Report 2021,75%of people with dementia worldwide are undiagnosed,equivalent to 41 million people(Gauthier et al.,2021).With each passing year,the number of people affected by these diseases is increasing,and the estimates of suffering from them in the future are growing.

Introduction to the special issue on celebrating the 15th anniversary of JIOHS and the 70th anniversary of HUST

Since launching in 2008,Journal of Innovative Optical Health Sciences(JIOHS)has been published for 15 years umtil 2022.Supported by the founding advisor Prof.Britton Chance and other founding Editorial Members,JIOHS was quickly embraced by the biomedical optics community,especially in Asia.Authors submitted some of their high quality papers to JIOHS,which led to a constant Impact Factor(IF)increase frcom the first IF 0.632 to IF 2396(Journal Citation Report 2021).

TRIM72‑mediated degradation of the short form of p62/SQSTM1 rheostatically controls selective autophagy in human cells

Dear Editor,Autophagy is an evolutionarily conserved catabolic process that involves the sequestration and transport of organelles,macromolecules,or invading microorganisms to lysosomes for degradation[1].Sequestosome 1(p62/SQSTM1)was the first protein shown to bind target-associated ubiquitin(Ub)and LC3 conjugated to the phagophore membrane,thus,acting as an important autophagy receptor for ubiquitinated targets[2].

Premature aging of skeletal stem/progenitor cells rather than osteoblasts causes bone loss with decreased mechanosensation

A distinct population of skeletal stem/progenitor cells(SSPCs)has been identified that is indispensable for the maintenance and remodeling of the adult skeleton.However,the cell types that are responsible for age-related bone loss and the characteristic changes in these cells during aging remain to be determined.Here,we established models of premature aging by conditional depletion of Zmpste24(Z24)in mice and found that Prx1-dependent Z24 deletion,but not Osx-dependent Z24 deletion,caused significant bone loss.However,Acan-associated Z24 depletion caused only trabecular bone loss.Single-cell RNA sequencing(sc RNA-seq)revealed that two populations of SSPCs,one that differentiates into trabecular bone cells and another that differentiates into cortical bone cells,were significantly decreased in Prx1-Cre;Z24^(f/f)mice.Both premature SSPC populations exhibited apoptotic signaling pathway activation and decreased mechanosensation.Physical exercise reversed the effects of Z24depletion on cellular apoptosis,extracellular matrix expression and bone mass.This study identified two populations of SSPCs that are responsible for premature aging-related bone loss.The impairment of mechanosensation in Z24-deficient SSPCs provides new insight into how physical exercise can be used to prevent bone aging.

Aldo-keto reductase family member C3(AKR1C3)promotes hepatocellular carcinoma cell growth by producing prostaglandin F2α

Hepatocellular carcinoma(HCC)is a leading cause of death worldwide.Current therapies are effective for HCC patients with early disease,but many patients suffer recurrence after surgery and have a poor response to chemotherapy.Therefore,new therapeutic targets are needed.We analyzed gene expression profiles between HCC tissues and normal adjacent tissues from public databases and found that the expression of genes involved in lipid metabolism was significantly different.The analysis showed that AKR1C3 was upregulated in tumors,and high AKR1C3 expression was associated with a poorer prognosis in HCC patients.In vitro,assays demonstrated that the knockdown of AKR1C3 or the addition of the AKR1C3 inhibitor indomethacin suppressed the growth and colony formation of HCC cell lines.Knockdown of AKR1C3 in Huh7 cells reduced tumor growth in vivo.To explore the mechanism,we performed pathway enrichment analysis,and the results linked the expression of AKR1C3 with prostaglandin F2 alpha(PGF2a)downstream target genes.Suppression of AKR1C3 activity reduced the production of PGF2a,and supplementation with PGF2a restored the growth of indomethacin-treated Huh7 cells.Knockdown of the PGF receptor(PTGFR)and treatment with a PTGFR inhibitor significantly reduced HCC growth.We showed that indomethacin potentiated the sensitivity of Huh7 cells to sorafenib.In summary,our results indicate that AKR1C3 upregulation may promote HCC growth by promoting the production of PGF2α,and suppression of PTGFR limited HCC growth.Therefore,targeting the AKR1C3-PGF2a-PTGFR axis may be a new strategy for the treatment of HCC.

Galangin induces apoptosis of hepatocellular carcinoma cells via the mitochondrial pathway

AIM:To investigate the mechanism by which galangin,a polyphenolic compound derived from medicinal herbs,induces apoptosis of hepatocellular carcinoma(HCC) cells.METHODS:The 3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay was used to measure cell viability.Apoptosis was evaluated by in situ uptake of propidium iodide and Hoechst 33258 and was then detected by fluorescence microscopy.Protein expressions were detected by Western blotting.To confirm the apoptotic pathway mediated by galangin,cells were transfected by bcl-2 gene to overexpress Bcl-2 or siRNA to down-regulate Bcl-2 expression.RESULTS:Galangin(46.25-370.0 μmol/L) exerted an anti-proliferative effect,induced apoptosis,and decreased mitochondrial membrane potential in a dose and time-dependent manner.Treatment with galangin induced apoptosis by translocating the pro-apoptotic protein Bax to the mitochondria,which released apoptosis-inducing factor and cytochrome c into the cytosol.Overexpression of Bcl-2 attenuated galangin-induced HepG2 cell apoptosis,while decreasing Bcl-2 expression enhanced galangin-induced cell apoptosis.CONCLUSION:Our data suggests that galangin mediates apoptosis through a mitochondrial pathway,and may be a potential chemotherapeutic drug for the treatment of HCC.

Paracrine and endocrine actions of bone——the functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts

The skeleton is a dynamic organ that is constantly remodeled. Proteins secreted from bone cells, namely osteoblasts, osteocytes,and osteoclasts exert regulation on osteoblastogenesis, osteclastogenesis, and angiogenesis in a paracrine manner. Osteoblasts secrete a range of different molecules including RANKL/OPG, M-CSF, SEMA3A, WNT5A, and WNT16 that regulate osteoclastogenesis. Osteoblasts also produce VEGFA that stimulates osteoblastogenesis and angiogenesis. Osteocytes produce sclerostin（SOST） that inhibits osteoblast differentiation and promotes osteoclast differentiation. Osteoclasts secrete factors including BMP6, CTHRC1, EFNB2, S1P, WNT10B, SEMA4D, and CT-1 that act on osteoblasts and osteocytes, and thereby influencea A osteogenesis. Osteoclast precursors produce the angiogenic factor PDGF-BB to promote the formation of Type H vessels, which then stimulate osteoblastogenesis. Besides, the evidences over the past decades show that at least three hormones or ＂osteokines＂from bone cells have endocrine functions. FGF23 is produced by osteoblasts and osteocytes and can regulate phosphate metabolism. Osteocalcin（OCN） secreted by osteoblasts regulates systemic glucose and energy metabolism, reproduction, and cognition. Lipocalin-2（LCN2） is secreted by osteoblasts and can influence energy metabolism by suppressing appetite in the brain.We review the recent progresses in the paracrine and endocrine functions of the secretory proteins of osteoblasts, osteocytes, and osteoclasts, revealing connections of the skeleton with other tissues and providing added insights into the pathogenesis of degenerative diseases affecting multiple organs and the drug discovery process.

Berberine promotes the development of atherosclerosis and foam cell formation by inducing scavenger receptor A expression in macrophage

Berberine 被识别通过低密度脂蛋白(LDL ) 的正式就职在人和仓鼠降低浆液胆固醇水平在肝的房间的受体。在阻止动脉粥样硬化评估它的潜力，在在 apolipoprotein 电子 deficient 的动脉粥样硬化开发的 berberine 的效果(apoE ?/?) 老鼠被调查。在 apoE ?/ ？鼠标，在 vivo 导致的 berberine 泡沫房间形成和支持的动脉粥样硬化开发。berberine 导致的泡沫房间形成也在老鼠 RAW264.7 房间，以及在老鼠和人的主要巨噬细胞被观察。由导致 scavenger 受体 A (SR -- 一) 在巨噬细胞的表示， berberine 增加了修改 LDL (DiO-Ac-LDL ) 的举起。导致 Berberine 的 SR -- 表情也在动脉粥样硬化患者在 vivo 并且在房间在巨噬细胞泡沫房间被观察损害。在 RAW264.7 房间的分析显示 berberine 导致了 SR -- 由压制 PTEN 表示的表情，它导致了持续 Akt 激活。我们的结果建议那在减轻动脉粥样硬化评估减少胆固醇的混合物的潜力，它涉及动脉粥样硬化开发的房间上的效果例如巨噬细胞，应该也被考虑。泡沫房间形成的提升能抵销阴沉的浆液胆固醇的有益的效果。

Tom70 mediates activation of interferon regulatory factor 3 on mitochondria

细胞内部的 RNA 病毒被受体 retinoic 察觉到酸可诱导的基因 1 (RIG-I )/melanoma 联系区别的基因 5 (MDA5 ) 在线粒体上触发 MAVS 信号建筑群的形成。因而，这导致坦克绑定 kinase 的激活 1 (TBK1 ) 并且干扰素的 phosphorylation 规章的因素 3 (IRF3 ) ，哪个组成地与 cytosolic 女伴 Hsp90 联系。MAVS 怎么激活 TBK1/IRF3，仍然保持大部分未知。在这研究，我们识别了外部膜的 translocases 70 (Tom70 ) ， mitochondrial 进口受体，在 RNA 病毒感染之上与 MAVS 交往。宫外的表示或 Tom70 击倒能分别地提高或损害调停 IRF3 的基因表示。机械学地， Tom70 的 clamp 领域(R192 ) 与 Hsp90 的 C 终端主题(EEVD ) 交往，因此招募 TBK1/IRF3 到线粒体。这个相互作用的混乱或 Tom70 的错误地点严厉地损害 TBK1 和 IRF3 的激活。而且，招待抗病毒的回答显著地被增加或残废当面或 Tom70 的缺席。一起，我们的学习作为连接 MAVS 到 TBK1/IRF3 的一个批评适配器描绘 Tom70，表明那线粒体与天生的免疫是 evolutionarily 综合的。

p73β inhibits transcriptional activities of enhancer I and X promoter in hepatitis B virus more efficiently than p73α

AIM: p73, as a novel member of a family of p53-related transcription factors, shares redundant functions with p53, such as the abilities of inducing apoptosis and suppressing growth. It is well known that p53 can repress HBV expression and transcription efficiently. The aim of this paper is to investigate the transcriptional effect of p73α and p73β on hepatitis B virus (HBV) and to understand the correlation between HBV and p73.METHODS: To construct an x-gene inactivated HBV plasmid which was cotransfected with p73α or p73β expression vectors into HepG2 cells. After transiently transfecticn, HBV surface antigen (HBsAg) and HBV e antigen (HBeAg) were detected by ELISA. Viral transcripts synthesized by HBV were evaluated by Northern blotting analysis. The activities of HBV regulatory elements, including enhancer Ⅰ/X promoter (ENI/Xp) and enhancer Ⅱ/core promoter (ENⅡ/Cp) were monitored by luciferase assays.RESULTS: Both p73α and p73β could repress HBsAg and HBeAg expression by downregulating the ENⅠ/Xp and ENⅡ/Cp activities. But p73β exerted stronger inhibition on the activity of ENI/Xp than p73α, resulting in much lower level of viral transcripts and the antigens expression.CONCLUSION: p73β as a novel member of p53 family can efficiently inhibit HBV transcription mainly through downregulating the activities of the HBV ENI/Xp regulatory elements.

A nuclear import inhibitory peptide ameliorates the severity of cholecystokinin-induced acute pancreatitis

AIM: To assess the effect of our novel cell-permeable nuclear factor-kappaB (NF-κB) inhibitor peptide PN50 in an experimental model of acute pancreatitis. PN50 was produced by conjugating the cell-penetrating penetratin peptide with the nuclear localization signal of the NF-κB p50 subunit.METHODS: Pancreatitis was induced in male Wistar rats by administering 2×100 μg/kg body weight of cholecystokininoctapeptide (CCK) intraperitoneally (IP) at an interval of 1 h. PN50-treated animals received 1 mg/kg of PN50 IP 30 min before or after the CCK injections. The animals were sacrificed 4 h after the first injection of CCK.RESULTS: All the examined laboratory (the pancreatic weight/body weight ratio, serum amylase activity,pancreatic levels of TNF-α and IL-6, degree of lipid peroxidation, reduced glutathione levels, NF-κB binding activity, pancreatic and lung myeloperoxidase activity) and morphological parameters of the disease were improved before and after treatment with the PN50 peptide.According to the histological findings, PN50 protected the animals against acute pancreatitis by favoring the induction of apoptotic, as opposed to necrotic acinar cell death associated with severe acute pancreatitis.CONCLUSION: Our study implies that reversible inhibitors of stress-responsive transcription factors like NF-κB might be clinically useful for the suppression of the severity of acute pancreatitis.

Molecular mechanisms of ＂off-on switch＂ of activities of human IDH1 by tumor-associated mutation R132H

人的 cytosolic NADP-IDH (IDH1 ) 最近被发现了涉及 tumorigenesis。尤其是，到目前为止识别的导出肿瘤的 IDH1 变化主要发生在 Arg132，和变化 R132H 是最流行的。这个变化损害酶的氧化 IDH 活动，但是显示把伪 - ketoglutarate (伪 K G ) 变换成 2-hydroxyglutarate 的新减小功能。这里，我们报导有或没有 isocitrate (ICT ) 的 R132H 变异的 IDH1 的结构跳了。和 mutagenesis 的结构的数据和生物化学的数据揭示一个以前未定义的起始的 ICT 有约束力的状态并且证明那项 IDH 活动要求一个 conformational 变化到一关门预先转移状态。Arg132 在催化反应起多重功能的作用；特别地， R132H 变化从起始的 ICT 有约束力的状态妨碍 conformational 变化到预先转移状态，导致 IDH 活动的缺陷。我们的结果第一次描述那有中间的符合构造，对应于一个起始的 ICT 有约束力的状态并且 R132H 变化能在这符合构造套住酶，因此使潜在地肿瘤镇压的 IDH 活动的鈥渙f f 开关鈥 ? 的分子的机制清楚些。而且，我们为获得的 伪K G 减小活动证明了 Tyr139 的必要性并且建议 Tyr139 可以由从 NADPH 在一个氢化物阴离子的转移期间在 伪K G 的 C2 原子上补偿增加的否定费用到 伪K G 起一个重要作用，它提供新卓见进 鈥渙n 开关鈥?的机制假设地由这个变化的 IDH1 的 oncogenic 减小活动。