Mitochondria targeting drugs for neurodegenerative diseases—Design,mechanism and application

Neurodegenerative diseases (NDDs) such as Alzheimer''s disease (AD) and Parkinson''s disease (PD) are a heterogeneous group of disorders characterized by progressive degeneration of neurons. NDDs threaten the lives of millions of people worldwide and regretfully remain incurable. It is well accepted that dysfunction of mitochondria underlies the pathogenesis of NDDs. Dysfunction of mitochondria results in energy depletion, oxidative stress, calcium overloading, caspases activation, which dominates the neuronal death of NDDs. Therefore, mitochondria are the preferred target for intervention of NDDs. So far various mitochondria-targeting drugs have been developed and delightfully some of them demonstrate promising outcome, though there are still some obstacles such as targeting specificity, delivery capacity hindering the drugs development. In present review, we will elaborately address 1) the strategy to design mitochondria targeting drugs, 2) the rescue mechanism of respective mitochondria targeting drugs, 3) how to evaluate the therapeutic effect. Hopefully this review will provide comprehensive knowledge for understanding how to develop more effective drugs for the treatment of NDDs.KEY WORDS: Neurodegenerative diseases, Mitochondria, Targeting drug, Apoptosis, Reactive oxygen species, Adenosine triphosphate, Mitochondrial membrane potential, Evaluation     

肺总顺应性的容量反应性研究

目的 探讨肺总顺应性(C)的容量反应性以及高血压对其反应能力的影响。方法 选择广东省广州市红十字会医院行择期平卧位手术的患者65例为研究对象,记录患者机械通气后不同时点[5 min(t₁)、10 min(t₂)、15 min(t₃)、20 min(t₄)、25 min(t₅)、30 min(t₆)]的C、气道平台压(p_plat)、气道峰压(p_peak)、心率(HR)、平均动脉压(MAP)、心排血量(CO)、每搏量变异度(SVV)、每搏输出量(SV)。计算不同时间段[T₁(5～10 min)、T₂(>10～15 min)、T₃(>15～20 min)、T₄(>20～25 min)、T₅(>25～30 min)]患者C、SV、SVV的变化量(△C、△SV、△SVV)。采用日本科林动脉硬...     

微小RNA-199a靶向调控沉默信息调节因子1对脑梗死大鼠神经元凋亡的影响

目的 探讨微小RNA-199a(miR-199a)对脑梗死大鼠神经元凋亡的影响及对沉默信息调节因子1(SIRT1)的调控作用。方法 构建脑梗死大鼠实验模型,将60只大鼠随机分为假手术组、脑梗死组、miR-199a抑制组、miR-199a阴性对照组、miR-199a抑制+SIRT1抑制组,每组12只。通过神经行为学评估判断大鼠神经功能变化,采用苏木精-伊红(HE)染色法观察各组大鼠脑组织神经元病理变化,采用流式细胞术检测脑皮质神经元凋亡情况,采用荧光定量聚合酶链反应(PCR)检测各组脑组织中miR-199a、SIRT1 mRNA表达水平,并通过蛋白质印迹法(Western blot)检测各组脑组织SIRT1、活化型半胱氨酸天冬氨酸蛋白酶-3(Cleaved caspase-3)蛋白表达量。采用双荧光素酶报告基因系统验证miR-199a和SIRT1的靶向调控关系。结果 与假手术组相比,脑梗死组大鼠脑组织出现变性、神经元坏死情况,神经元凋亡率、Cleaved caspase-3蛋白表达量、神经学评分和miR-199a表达量升高,SIRT1 mRNA和SIRT1蛋白表达量降低,差异有统计学意义...     

The kinase p38α functions in dendritic cells to regulate Th2-cell differentiation and allergic inflammation

Dendritic cells (DCs) play a critical role in controlling T helper 2 (Th2) cell-dependent diseases, but the signaling mechanism that triggers this function is not fully understood. We showed that p38α activity in DCs was decreased upon HDM stimulation and dynamically regulated by both extrinsic signals and Th2-instructive cytokines. p38α-specific deletion in cDC1s but not in cDC2s or macrophages promoted Th2 responses under HDM stimulation. Further study showed that p38α in cDC1s regulated Th2-cell differentiation by modulating the MK2−c-FOS−IL-12 axis. Importantly, crosstalk between p38α-dependent DCs and Th2 cells occurred during the sensitization phase, not the effector phase, and was conserved between mice and humans. Our results identify p38α signaling as a central pathway in DCs that integrates allergic and parasitic instructive signals with Th2-instructive cytokines from the microenvironment to regulate Th2-cell differentiation and function, and this finding may offer a novel strategy for the treatment of allergic diseases and parasitic infection.     

自身免疫多内分泌腺病综合征与成人隐匿性自身免疫性糖尿病

成人隐匿性自身免疫性糖尿病(LADA)可同时伴有肾上腺、甲状腺、性腺等其他内分泌腺的自身免疫性疾病,而成为自身免疫多内分泌腺病综合征(APS)中的一个表现,其共同土壤为免疫耐受的破坏。文章从APS的角度探讨LADA的研究价值。     

Extremely high serum CA19-9 level along with elevated D-dimer in assisting detection of ruptured ovarian endometriosis

BackgroundTo clarify clinical importance of serum CA19-9, CA-125, and plasma D-dimer (D-D) levels in detecting spontaneously ruptured ovarian endometriosis (OE).Materials and MethodsWe retrospectively examined 173 patients with endometriosis out of 735 cases of OE between 2013 and 2019. Among these, 21 cases were diagnosed as “spontaneously ruptured” after surgery, while the remaining cases were unruptured. Venous blood was collected pre-operatively to detect CA19-9, CA-125, and D-D levels. A receiver operating characteristic curve analysis was applied to test clinical value of each marker.ResultsAmong the 21 patients with ruptured OE, 16 had a history of pelvic cysts, 19 claimed sudden onsets of lower abdominal pain, and fluid accumulation were detected in cul-de-sac in only six participants by ultrasound. For serological investigation, both CA19-9 and D-D were significantly elevated in the ruptured OE group (343.09 ± 367.67 U/ml vs. 36.84 ± 40.01 U/ml, 3.39 ± 4.90 mg/L vs. 0.43 ± 0.29 mg/L, both p < .0001). The area under curve (AUC) value for the combination of CA19-9 and D-D was 0.975 (95% CI, 0.939 − 0.993), with specificity of 96.69%, and sensitivity of 85.71%. The combination of CA-125, CA19-9 and D-D showed the highest AUC value that up to 0.976 (95% CI, 0.940–0.993), with sensitivity of 95.24%, and specificity of 87.50%.ConclusionThe combination of CA19-9 and D-D can be chosen as an effective and economical indicators to identify patients with spontaneously ruptured OE in pre-operation assessment. However, from the perspective of differential diagnosis, the combination of CA-125, CA19-9 and D-D is the best choice.

Key messages

• Taking into account the economic effect, the combination of CA19-9 and D-D can be chosen as an effective indicators to identify patients with spontaneously ruptured OE in pre-operation assessment.
• From the perspective of differential diagnosis, the combination of CA-125, CA19-9 and D-D is the best choice to identify patients with spontaneously ruptured OE.

     

Targeted peptide-modified oxidized mesoporous carbon nanospheres for chemo-thermo combined therapy of ovarian cancer in vitro

Ovarian cancer remains one of serious hazards to human health due to many drawbacks of existing available treatment options. In this study, a multifunctional chemo-thermo combined therapy nanoplatform (OMCNPID) was successfully prepared, which is composed of I₆P₈ peptide as a targeting moiety to interleukin-6 receptors (IL-6Rs), oxidized mesoporous carbon nanospheres (OMCN) as a near infrared (NIR)-triggered drug carrier and doxorubicin (DOX) as a chemotherapeutic drug and fluorescent agent. The synthesized multifunctional nanoplatform displayed high storage capacity for drugs and excellent photothermal properties. Besides, DOX was rapidly released from OMCNPID at the condition of low pH and NIR laser irradiation due to the dissociation of DOX from graphitic cores of OMCN. In vitro experimental results verified that OMCNPID could be markedly taken up by SKOV-3 monolayer cells and tumor spheroids, and revealed a remarkable synergistic chemo-photothermal effect against ovarian cancer. All the results demonstrated that OMCNPID is a pH/NIR dual-stimulus responsive nanoplatform and can achieve efficient chemo-thermo combined therapy.     

Precise immunological evaluation rationalizes the design of a self-adjuvanting vaccine composed of glycan antigen,TLR1/2 ligand,and T-helper cell epitope

Sialyl-Tn (STn), overexpressed on various tumors, has been investigated for its application in anti-cancer vaccine therapy. However, Theratope, an STn-based vaccine, failed in the phase III clinical trial due to poor immunogenicity and epitope suppression by the foreign carrier protein. We therefore developed a self-adjuvanting STn based-vaccine, a conjugate of clustered STn (triSTn) antigen, TLR1/2 ligand (Pam₃CSK₄), and T-helper (Th) cell epitope, and found that this three-component self-adjuvanting vaccine effectively resulted in the production of anti-triSTn IgG antibodies. We herein analyzed immune responses induced by this self-adjuvanting vaccine in detail. We newly synthesized two-component vaccines, i.e., Pam₃CSK₄- or Th epitope-conjugated triSTn, as references to evaluate the immune-stimulating functions of Pam₃CSK₄ and Th epitope. Immunological evaluation of the synthesized vaccine candidates revealed that Pam₃CSK₄ was essential for antibody production, indicating that the uptake of triSTn antigen by antigen-presenting cells (APCs) was promoted by the recognition of Pam₃CSK₄ by TLR1/2. The function of the Th epitope was also confirmed. Th cell activation was important for boosting antibody production and IgG subclass switching. Furthermore, flow cytometric analyses of immune cells, including T cells, B cells, dendritic cells, and other monocytes, were first employed in the evaluation of self-adjuvanting vaccines and revealed that the three-component vaccine was able to induce antigen-specific immune responses for efficient antibody production without excessive inflammatory responses. Importantly, the co-administration of Freund''s adjuvants was suggested to cause excessive myeloid cell accumulation and decreased plasma cell differentiation. These results demonstrate that vaccines can be designed to achieve the desired immune responses via the bottom-up construction of each immune element.

Detailed analysis of a three-component self-adjuvanting vaccine revealed that conjugate vaccines can be designed to achieve the desired immune responses via bottom-up construction of the necessary immune elements.