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Bibenzyls, a kind of important plant polyphenols, have attracted growing attention for their broad and remarkable pharmacological activities. However, due to the low abundance in nature, uncontrollable and environmentally unfriendly chemical synthesis processes, these compounds are not readily accessible. Herein, one high-yield bibenzyl backbone-producing Escherichia coli strain was constructed by using a highly active and substrate-promiscuous bibenzyl synthase identified from Dendrobium officinale in combination with starter and extender biosynthetic enzymes. Three types of efficiently post-modifying modular strains were engineered by employing methyltransferases, prenyltransferase, and glycosyltransferase with high activity and substrate tolerance together with their corresponding donor biosynthetic modules. Structurally different bibenzyl derivatives were tandemly and/or divergently synthesized by co-culture engineering in various combination modes. Especially, a prenylated bibenzyl derivative ( 12) was found to be an antioxidant that exhibited potent neuroprotective activity in the cellular and rat models of ischemia stroke. RNA-seq, quantitative RT-PCR, and Western-blot analysis demonstrated that 12 could up-regulate the expression level of an apoptosis-inducing factor, mitochondria associated 3 (Aifm3), suggesting that Aifm3 might be a new target in ischemic stroke therapy. This study provides a flexible plug-and-play strategy for the easy-to-implement synthesis of structurally diverse bibenzyls through a modular co-culture engineering pipeline for drug discovery.
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OBJECTIVE To evaluate efficacy， safety and cost-effectiveness of edaravone dexborneol and compound porcine cerebroside ganglioside in the treatment of acute ischemic stroke， and to provide decision-making reference for clinical treatment selection. METHODS The medical records of 488 patients with acute ischemic stroke hospitalized from Jan. 2021 to Dec. 2021 were collected and divided into two groups according to the treatment plan， i.e. 268 patients in edaravone dexborneol group， and 220 patients in compound porcine cerebroside ganglioside group. After baseline levels of the two groups were balanced using propensity score matching method， curative effect was evaluated according to the changes of NIHSS scores before and after treatment； the occurrence of adverse drug reactions in patients were collected from the hospital adverse reaction reporting system； from the perspective of China’s health system， the cost-effectiveness of the two options were analyzed， and one-way sensitivity analysis was conducted. RESULTS After the propensity score matching， 125 patients were included in the edaravone dexborneol group and compound porcine cerebroside ganglioside group， respectively. The response rates were 81.6% and 74.4%， respectively， with no significant difference. The average costs were 13 560.30 yuan and 14 958.68 yuan， respectively； the cost of edaravone dexborneol group was lower than that of compound porcine cerebroside ganglioside group. No adverse reaction reporting information was retrieved in both groups. Results of one-way sensitivity analysis showed that other drug costs in compound porcine cerebroside ganglioside group was relatively sensitive parameters. CONCLUSIONS Short-term efficacy and safety of edaravone dexborneol are equivalent to those of compound porcine cerebroside ganglioside in treating acute ischemic stroke. But edaravone dexborneol regimen had lower cost and is a more economical scheme.
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OBJECTIVE@#To evaluate the mechanisms underlying the protective effect of Chinese herbal medicine Fructus broussonetiae (FB) in both mouse and cell models of Alzheimer's disease (AD).@*METHODS@#APP/PS1 mice treated with FB for 2 months and vehicle-treated controls were run through the Morris water maze and object recognition test to evaluate learning and memory capacity. RNA-Seq, Western blotting, and immunofluorescence staining were also conducted to evaluate the effects of FB treatment on various signaling pathways altered in APP/PS1 mice. To further explore the mechanisms underlying FB's protective effect, PC-12 cells were treated with Aβ@*RESULTS@#FB-treated mice showed improved learning and memory capacity on both the Morris water maze and object recognition tests. RNA-seq of hippocampal tissue from APP/PS1 mice showed that FB had effects on multiple signaling pathways, specifically decreasing cell apoptotic signaling and increasing AKT and β-catenin signaling. Similarly, FB up-regulated both AKT and β-catenin signaling in PC-12 cells pre-treated with Aβ@*CONCLUSIONS@#FB exerted neuroprotective effects on hippocampal cells of APP/PS1 mice, as well as improved cell viability in an in vitro model of AD. The protective actions of FB occurred via the upregulation of AKT/β-catenin signaling.
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As the first most common cause of death in China,stroke has become a public health problem that seriously affects national economy and people′s livelihood. Unfortunately,only 3% to 5% of stroke patients receive tissue plasminogen activator(tPA)treatment,the only pharmacological therapy ap?proved for ischemic stroke,and no drug is available for hemorrhagic stroke. Therefore,there is an ur?gent need to develop new drugs for stroke therapy. Despite the awareness that neuroprotective agents could be a common strategy for the treatment of both ischemic and hemorrhagic stroke,numerous neu?roprotective agents have showed failure in clinical trials. Combined with the current therapeutic strategies and drug development of stroke,this paper elaborated the stroke injury mechanisms and corresponding clinical drug research targeting excitotoxicity,oxidative and nitrosative stress,and inflammation. From a new perspective,this paper has proposed a novel therapeutic strategy targeting inherent defense mechanisms against stroke,with nicotinamide phosphoribosyltransferase(Nampt)- nicotinamide ade?nine dinucleotide defense system as an example to present our experimental evidence that Nampt can serve as an anti-stroke target and nicotinamide mononucleotide as an anti-stroke agent under development. It is hoped that the bottleneck of stroke therapy can be overcome with unremitting efforts so as to reduce the financial burden and mental stress,and bring benefits to people around the world.
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Nerve agent not only inhibit acetylcholinesterase ( AChE) at an early stage, but also induce prolonged and progressive neuroinflammation and delayed neurodegeneration.Recently, the US National Institute of Health ( NIH) has sponsored some major programs of toxic mechanisms and treatment of nerve agents, which aims at the development of quick and effective treatment to acute intoxication and delayed effect.The experimentally effective new antidotes mainly include AChE-targeting drugs, broad-spectrum reactivators and scavengers, antiinflamatory and nerve protection drugs.
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Background Minocycline possesses neuroprotective effect in a variety of animal models and clinical trials of central nervous system,but whether it works on optic nerve injury remains unclear.Objective This study aimed to observe the protective effects of minocycline on retinal ganglion cells (RGCs) in the early stage of optic nerve crush and explore its mechanism.Methods One hundred and thirty-six clean C57BL/6J mice were randomly divided into normal control group,normal saline solution group and minocycline group.The optic nerve crush injury models were induced in the left eyes of the mice in the normal saline solution group and minocycline group by a cross-action forceps for 3 seconds.Minocycline was injected intraperitoneally in the minocycline group firstly 45 mg/kg(0.4 ml) and followed by 22.5 mg/kg per day after 24 hours until sacrifice of the animals,and the equivalent volume of normal saline solution was injected in the same way in the normal saline solution group.The mice were euthanized at 4,7,11,14 days postoperatively and the left eyeballs were collected.Retinal flat mounts and DAPI staining was used to observe and compare the change of RGCs density among different groups and various time points.Apoptosis of mice RGCs were assessed by TdT-mediated dUTP nick end labeling (TUNEL).Real-time polymerase chain reaction (real-time PCR) was used to detect the expression of CD11b mRNA in retinal microglials.Results DAPI staining in retinal flat mounts showed that the average RGCs density was (77.50±2.38)/0.01 mm2 and (70.00±2.94) /0.01 mm2 in the 4th and 7th day after modeling in the normal saline solution group,and those in the minocycline group were (88.75 ± 2.36) /0.01 mm2 and (81.00 ± 3.92)/0.01 mm2,with significant differences between the two groups (t4d =-6.708,P＜0.01 ;t7d =--4.491,P＜0.01).The apoptotic RGCs were (12±1)/mm and (4±1)/mm in the normal saline solution,which were significantly more than (4±1)/mm and (1±0)/mm in the minocycline group (t4 d =12.832,P＜0.01 ; t7d =3.455,P =0.026).However,no significant difference was found in apoptotic RGCs in postoperative 11 days and 14 days between the normal saline solution group and the minocycline group (P =0.708,0.777).The expressing levels of CD11 b mRNA in the retinal microglials were significantly higher in the 4th and 7th day in the normal saline solution group than those in the minocycline group (t4 d =8.312,P＜0.01 ;t7d=5.407,P＜0.01),but were not significantly different in the 11st and 14th day after modeling between the two groups (P=0.055,0.170).Conclusions Minocycline can play a neuroprotective effect on RGCs in the early stage of optic nerve crush in mice by inhibiting microglia activation and decreasing RGCs apoptosis.
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Many events can cause the irreversible damage of optical nerve.Conventional treatment of visual nerve damage is medicine therapy.However,each drug shows its advantages and disadvantages.Chitosan is a polysaccharide with positive charge and good biocompatibility,and it prosses the antioxidant,antiapoptosis and antineuritic effects,so it is thought to play a neuroprotective role for multiple causative neuropathies.The progress in neuroprotective mechanism of chitosan was reviewed in this paper.
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OBJECTIVE: To assess the effect of bone marrow mononuclear cells (BMMNCs) transplantation in the expression of nuclear factor-kappaB (NF-kappaB) in spinal cord injury (SCI) in rats. METHODS: BMMNCs were isolated from tibia and femur by a density gradient centrifugation. After establishment of acute transection SCI, rats were divided into experiment (BMMNCs), experiment control (0.1 M PBS infused) and sham surgery groups (laminectomy without any SCI). Locomotor function was assessed weekly for 5 weeks post-injury using BBB locomotor score and urinary bladder function daily for 4 weeks post-injury. Activity of NF-kappaB in spinal cord was assessed by immunohistochemistry and reverse transcriptase polymerase chain reaction. RESULTS: At each time point post-injury, sham surgery group had significantly higher Basso, Beattie, Bresnahan locomotor and urinary bladder function scores than experiment and experiment control group (p<0.05). At subsequent time interval there were gradual improvement in both experiment and experiment control group, but experiment group had higher score in comparison to experiment control group (p<0.05). Comparisons were also made for expression of activated NF-kappaB positive cells and level of NF-kappaB messenger RNA in spinal cord at various time points between the groups. Activated NF-kappaB immunoreactivity and level of NF-kappaB mRNA expression were significantly higher in control group in comparison to experiment and sham surgery group (p<0.05). CONCLUSION: BMMNCs transplantation attenuates the expression of NF-kappaB in injured spinal cord tissue and thus helps in recovery of neurological function in rat models with SCI.