RET signaling does not modulate MPTP toxicity but is required for regeneration of dopaminergic axon terminals

Activation of the RET (rearranged during transfection) receptor by glial cell-line-derived neurotrophic factor (GDNF) has been identified as an important differentiation and survival factor for dopaminergic neurons of the midbrain in preclinical experiments. These encouraging results have led to clinical trials of GDNF in patients with Parkinson's disease, which have resulted in conflicting findings. To investigate the potential benefit of Ret-dependent signaling on the challenged dopaminergic system, we tested the effect of tissue-selective ablation of the Ret gene on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice, the most widely used animal model for Parkinson's disease. Ablation of Ret did not modify the MPTP-induced loss of dopaminergic neurons in the substantia nigra pars compacta and the dopaminergic innervation of the striatum at 14 days. However, Ret ablation abolished the regeneration of dopaminergic fibers and terminals, as well as the partial recovery of striatal dopamine concentrations, that was observed in control mice between days 14 and 90 after MPTP treatment. We therefore conclude that RET signaling has no influence on the survival of dopaminergic neurons in the MPTP model of Parkinson's disease but rather facilitates the regeneration of dopaminergic axon terminals.     

Melatonin attenuates MPTP-induced dopaminergic neuronal injury associated with scavenging hydroxyl radical

To clarify the relationship between melatonin's hydroxyl radical (*OH) scavenging ability and its protective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neuronal injury, in the present study, the salicylate trapping method combined with high-performance liquid chromatography (HPLC)-electrochemical detection were used to measure the contents of dihydroxybenzoic acid (DHBA) and dopamine (DA) in brain tissues of C57BL/6 mice. Immunocytohistochemistry was used to detect tyrosine hydroxylase (TH)-like positive staining neurons. Results show that MPTP treatment induced an increase in the content of DHBA and decrease in the level of DA as well as the number of TH positive stained neurons in the mouse brain. However, melatonin dose-dependently inhibited the increase of DHBA levels in ventral midbrain tissues, the decrease of DA content and the loss of dopaminergic neurons. Moreover, the relationship between the changes of DHBA and DA levels in the brain of mice following MPTP and melatonin treatment showed a statistically significant negative correlation. Present results suggest that melatonin can ameliorate MPTP-induced dopaminergic neuronal lesions probably, at least partially, because of its inhibition of *OH generation.     

Role of Dopamine Transporter Against MPTP (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine) Neurotoxicity in Mice

We investigated the alterations of dopamine transporter (DAT)-immunopositive cells against MPTP neurotoxicity, in comparison with tyrosine hydroxylase (TH)- immunopositive neurons and glial fibrillary acidic protein (GFAP)-immunopositive cells. This study showed that DAT and TH immunoreactivity was decreased gradually in the striatum and substantia nigra of mice after MPTP treatment. The patterns of the intense TH-immunoreactive fibers and cell bodies were similar to those of DAT-immunoreactive fibers and cell bodies in the striatum and substantia nigra of mice after MPTP treatment. In contrast, GFAP immunoreactivity was increased gradually in the striatum and substantia nigra after MPTP treatment. In our double-labeled immunostaining with anti-DAT and anti-GFAP antibodies, DAT immunoreactivity was observed only in the nigral dopaminergic neurons, but not in the reactive astrocytes. The present results provide further evidence that the functional damage of DAT may precede dopaminergic neuronal death after MPTP treatment, although the decrease in the number of TH-immunopositive neurons was more pronounced than that in the number of DAT-immunopositive neurons. Furthermore, our findings demonstrate that MPTP can selectively injure the dopaminergic neurons which DAT proteins are predominantly distributed on the striatum and substantia nigra. The results provide beneficial information for MPTP-induced neurodegeneration of the nigrostriatal dopaminergic neuronal pathway.     

Estradiol and dehydroepiandrosterone potentiate levodopa-induced locomotor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine monkeys

Six monkeys were rendered hemiparkinsonian with a unilateral injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. These monkeys displayed ipsilateral circling under basal conditions, and after dopaminergic stimulation with levodopa they decreased their ipsilateral circling and started turning to the contralateral side of their lesion. The effect of 17β-estradiol and dehydroepiandrosterone (DHEA) was investigated in these animals. 17β-Estradiol (0.1 mg/kg) added to a threshold dose of levodopa significantly potentiated contralateral circling (mean/30 min) compared to saline or threshold levodopa treatment whereas the duration of circling remained unchanged. DHEA (1–15 mg/kg) alone induced contralateral circling, compared to saline treatment, for 90 min. In addition, DHEA (1–15 mg/kg) potentiated the contralateral circling (mean/30 min) induced by a threshold dose of levodopa and did not change the duration of levodopa circling. A maximal response was observed with 1 or 5 mg/kg of DHEA combined with levodopa depending on the monkey. No correlation was found between the dose for the maximal DHEA response and baseline circling or threshold dose of levodopa. These results suggest that 17β-estradiol or DHEA is able to potentiate locomotor activity of hemiparkinsonian monkeys. The DHEA doses investigated are similar to those presently used in humans. DHEA may be an alternative to 17β-estradiol to modulate dopaminergic activity.     

Melatonin protects against MPTP/MPP+ -induced mitochondrial DNA oxidative damage in vivo and in vitro

The effects of melatonin on the mitochondrial DNA (mtDNA) damage induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridine ion (MPP(+)) were investigated both in vivo and in vitro. MPTP (24 mg/kg, s.c.) induced a rapid increase in the immunoreactivity of 8-hydroxyguanine (8-oxoG), a common biomarker of DNA oxidative damage, in the cytoplasm of neurons in the Substantia Nigra Compact of mouse brain. Melatonin preinjection (7.5, 15 or 30 mg/kg, i.p.) dose-dependently prevented MPTP-induced DNA oxidative damage. In SH-SY5Y cells, MPP(+) (1 mm) increased the immunoreactivity of 8-oxoG in the mitochondria at 1 hr and in the nucleus at 3 hr after treatment. Melatonin (200 microm) preincubation significantly attenuated MPP(+)-induced mtDNA oxidative damage. Furthermore, MPP(+) time-dependently increased the accumulation of mitochondrial oxygen free radicals (mtOFR) from 1 to 24 hr and gradually decreased the mitochondrial membrane potential (Psim) from 18 to 36 hr after incubation. At 72 hr after incubation, MPP(+) caused cell death in 49% of the control. However, melatonin prevented MPP(+)-induced mtOFR generation and Psim collapse, and later cell death. The present results suggest that cytoprotection of melatonin against MPTP/MPP(+)-induced cell death may be associated with the attenuation of mtDNA oxidative damage via inhibition of mtOFR generation and the prevention of Psim collapse.     

Inhibition of sympathetic pathways restores postoperative ileus in the upper and lower gastrointestinal tract

BACKGROUND AND AIM: Postoperative ileus (POI) is a transient bowel dysmotility following abdominal surgery. The effects of adrenergic blocking agents and celiac ganglionectomy were studied in rats to investigate the possible involvement of the adrenergic pathway in whole gastrointestinal (GI) transit in the early and late phases of POI. METHODS: After laparotomy, the terminal ileum was manipulated for 10 min. (51)Cr was administered into the stomach or colon immediately after surgery. In another group, (51)Cr was administered 24 h after surgery. Three hours after (51)Cr was administered, the rats were killed, and GI and colonic transit was calculated as a geometric center (GC). RESULTS: Gastrointestinal transit was significantly delayed 3 h after intestinal manipulation, compared with GI transit in rats that had anesthesia only. Three hours after intestinal manipulation, guanethidine (5 mg/kg) and yohimbine (3 mg/kg) significantly improved delayed GI transit. Celiac ganglionectomy also significantly improved delayed GI transit. Twenty-seven hours after intestinal manipulation, guanethidine, yohimbine and celiac ganglionectomy improved delayed GI transit induced by intestinal manipulation. Colonic transit was delayed 3 h after intestinal manipulation, and delayed colonic transit was partially restored within 27 h of intestinal manipulation. Guanethidine, yohimbine and celiac ganglionectomy improved delayed colonic transit 3 h and 27 h after intestinal manipulation. CONCLUSIONS: Adrenoceptors activated by intestinal manipulation impair the motility of the entire GI tract in both the early and the late phase of POI.     

Effects of a serotonin 5-HT(4) receptor antagonist SB-207266 on gastrointestinal motor and sensory function in humans

BACKGROUND: Serotonin 5-HT(4) receptors are located on enteric cholinergic neurones and may regulate peristalsis. 5-HT(4) receptors on primary afferent neurones have been postulated to modulate visceral sensation. While 5-HT(4) agonists are used as prokinetic agents, the physiological role of 5-HT(4) receptors in the human gut is unknown. AIMS: Our aim was to characterise the role of 5-HT(4) receptors in regulating gastrointestinal motor and sensory function in healthy subjects under baseline and stimulated conditions with a 5-HT(4) receptor antagonist. METHODS: Part A compared the effects of placebo to four doses of a 5-HT(4) receptor antagonist (SB-207266) on the cisapride mediated increase in plasma aldosterone (a 5-HT(4) mediated response) and orocaecal transit in 18 subjects. In part B, 52 healthy subjects received placebo, or 0.05, 0.5, or 5 mg of SB-207266 for 10-12 days; gastric, small bowel, and colonic transit were measured by scintigraphy on days 7-9, and fasting and postprandial colonic motor function, compliance, and sensation during distensions were assessed on day 12. RESULTS: Part A: 0.5, 5, and 20 mg doses of SB-207266 had significant and quantitatively similar effects, antagonising the cisapride mediated increase in plasma aldosterone and acceleration of orocaecal transit. Part B: SB-207266 tended to delay colonic transit (geometric centre of isotope at 24 (p=0.06) and 48 hours (p=0.08)), but did not have dose related effects on transit, fasting or postprandial colonic motor activity, compliance, or sensation. CONCLUSION: 5-HT(4) receptors are involved in the regulation of cisapride stimulated orocaecal transit; SB 207266 tends to modulate colonic transit but not sensory functions or compliance in healthy human subjects.     

Effect of GLP-1 receptor agonist on gastrointestinal tract motility and residue rates as evaluated by capsule endoscopy

AimThis study evaluated the effects of a glucagon-like peptide-1 receptor agonist on gastrointestinal (GI) tract motility and residue rates by examining GI transit time and lumen using capsule endoscopy.Material and methodsGI motility and lumen were assessed by capsule endoscopy before and after liraglutide administration in 14 patients with type 2 diabetes mellitus (T2DM).ResultsGastric transit time in the group with diabetic neuropathy (DN) was 1:12:36 ± 1:04:30 h before liraglutide administration and 0:48:40 ± 0:32:52 h after administration (nonsignificant difference, P = 0.19). Gastric transit time in the non-DN group was 1:01:30 ± 0:52:59 h before administration and 2:33:29 ± 1:37:24 h after administration (significant increase, P = 0.03). Duodenal and small intestine transit time in the DN group was 4:10:34 ± 0:25:54 h before and 6:38:42 ± 3:52:42 h after administration (not significant, P = 0.09) and, in the non-DN group, 3:51:03 ± 0:53:47 h before and 6:45:31 ± 2:41:36 h after administration (significant increase, P = 0.03). The GI residue rate in the DN group was 32.1 ± 24% before administration and 90.0 ± 9.1% after administration (significant increase, P < 0.001), and increased in all patients; in the non-DN group, it was 32.1 ± 35.3% before and 78.3 ± 23.9% after administration (significant increase, P < 0.001), and also increased in all patients.ConclusionLiraglutide causes delayed gastric emptying and inhibits duodenal and small intestine motility. However, these GI movement-inhibiting effects may be decreased or absent in patients with DN-associated dysautonomia.     

Role of cannabinoid receptors in the control of gastrointestinal motility and perception

The identification of endocannabinoids and cannabinoid CB1 receptors in key areas of the intestinal wall, such as cholinergic neurons, supports a role for cannabinoids in the control of gastrointestinal motility. Activation of CB1 receptors inhibits the peristaltic reflex and slows down gastrointestinal and colonic transit. Endocannabinoids play an important inhibitory role in the control of the occurrence of transient lower esophageal sphincter relaxations. Cannabinoid receptor agonists inhibit gastric emptying and intestinal motility in humans. There is strong anatomical support for a role of CB1 receptors in the control of gastrointestinal perception, since these receptors have been identified in key sites of the neuronal circuitry involved in the transmission of visceral pain. Experimental data indicate a visceral antinociceptive action of cannabinoid receptor agonists, which remains to be confirmed in humans.     

Bromocriptine-induced hyperglycemia in nonobese diabetic mice: kinetics and mechanisms of action

The effects of bromocriptine (10 mg/kg), known to inhibit prolactin secretion and lower autoimmune processes, were studied on glucose homeostasis in non-fasted non-obese diabetic mice, a spontaneous model of type 1 diabetes. Hyperglycemia was observed 120 and 240 min after i.p. but not s.c. injection. Bromocriptine administration i.p. led to rapid and marked hyperglycemia characterized by sexual dimorphism with males having higher glycemia than females. Bromocriptine induced a rapid but transient decrease in insulinemia in males only and biphasic increases in glucagon levels and a sustained stimulatory effect on circulating corticosterone in both sexes. Bromocriptine-induced hyperglycemia involved D2-dopaminergic receptors, as demonstrated by the inhibitory effect of the D2-dopamine antagonist, metoclopramide (10 mg/kg). Simultaneous injection of bromocriptine and metoclopramide also blocked the rise in blood corticosterone. In conclusion, by inducing hyperglycemia, i.p. bromocriptine administration to prediabetic autoimmune mice may counteract its beneficial anti-immunostimulatory effects.     

MPTP对小鼠和淀粉样蛋白对大鼠处理后相关脑区NAP1基因表达的影响

目的 研究1－甲基－4－苯基－1，2，3，6－四氢吡啶（MPTP）和β－淀粉样蛋白（Aβ）对小鼠或大鼠相关脑区核小体组装蛋白－1（NAP－1）基因表达的影响。方法 通过MPTP腹腔注射诱导C57BL小鼠产生类似帕金森病症状，Aβ脑室注射诱导SD大鼠产生类似阿尔茨海默病症状，利用逆转录PCR方法检测小鼠黑质与纹状体及大鼠皮质与海马NAP－1mRNA丰度的变化。结果 在小鼠中，MPTP导致黑质NAP－1基因表达显著降低，而对纹状体NAP－1的表达没有明显影响。在大鼠中，Aβ对海马与皮质NAP－1基因的表达均无明显影响。结论 NAP－1很可能参与了MPTP诱导的神经元调亡过程，但在Aβ诱发的神经元凋亡过程中可能不起作用。     

Inhibition of HIV-1 entry by antibodies: potential viral and cellular targets

Vaccine-induced antibodies that interfere with viral entry are the protective correlate of most existing prophylactic vaccines. However, for highly variable viruses such as HIV-1, the ability to elicit broadly neutralizing antibody responses through vaccination has proven to be extremely difficult. The major targets for HIV-1 neutralizing antibodies are the viral envelope glycoprotein trimers on the surface of the virus that mediate receptor binding and entry. HIV-1 has evolved many mechanisms on the surface of envelope glycoproteins to evade antibody-mediated neutralization, including the masking of conserved regions by glycan, quaternary protein interactions and the presence of immunodominant variable elements. The primary challenge in the development of an HIV-1 vaccine that elicits broadly neutralizing antibodies therefore lies in the design of suitable envelope glycoprotein immunogens that circumvent these barriers. Here, we describe neutralizing determinants on the viral envelope glycoproteins that are defined by their function in receptor binding or by rare neutralizing antibodies isolated from HIV-infected individuals. We also describe the nonvariable cellular receptors involved in the HIV-1 entry process, or other cellular proteins, and ongoing studies to determine if antibodies against these proteins have efficacy as therapeutic reagents or, in some cases, as vaccine targets to interfere with HIV-1 entry.     

The role of HIF-1, angiopoietin-2, Dll4 and Notch1 in bleeding gastrointestinal vascular malformations and thalidomide-associated actions: a pilot in vivo study

OBJECTIVE: To investigate plasma levels of hypoxia inducible factor‐1 (HIF‐1), angiopoietin‐2 (Ang‐2), Delta‐like ligand 4 (Dll4) and Notch1 in patients with recurrent gastrointestinal bleeding due to gastrointestinal vascular malformation (GIVM) with or without thalidomide treatment. METHODS: Ten eligible patients with recurrent gastrointestinal bleeding due to GIVM, who received thalidomide 100 mg/d for 4 months, were followed up for 1 year. The effective response was the proportions of patients with yearly bleeding episodes reduced by ≥50% at 1 year after treatment. Plasma levels of HIF‐1, Ang‐2, Dll4 and Notch1 were measured using enzyme‐linked immunosorbent assay in the GIVM thalidomide treatment group before and after treatment (10 patients), the GIVM non‐thalidomide treatment group (25 patients) and the control group (18 participants). RESULTS: In the GIVM thalidomide treatment group, eight patients (8/10) achieved effective response and five (5/10) displayed complete cessation of bleeding. Mean plasma levels of HIF‐1, Ang‐2, Dll4 and Notch1 were all higher in the GIVM thalidomide and non‐thalidomide treatment groups than in the control group (all P < 0.001). However, Ang‐2 decreased more significantly in the effective subgroups (P = 0.003) and no‐bleeding patients (P = 0.008). CONCLUSIONS: HIF‐1, Ang‐2, Dll4 and Notch1 might participate in the formation of GIVM. Thalidomide is an effective and safe treatment agent for GIVM and its associated bleeding. The reduction degree of Ang‐2 after a 4‐month treatment of thalidomide may offer values for evaluating its prognosis and efficacy.     

Role of histamine H3 receptors in control of mouse intestinal motility in vivo and in vitro: comparison with alpha2-adrenoceptors

We tested drugs acting at histamine H₃ receptors in mice on the gastrointestinal transit of a charcoal meal in vivo and on neurogenic contractions of isolated ileal preparations. The agonist (R)--methylhistamine (100 mol/kg) caused a maximum 25% reduction of gastrointestinal transit, an effect mimicked by immepip (100 mol/kg) and antagonized by thioperamide (20 mol/kg) or clobenpropit (20 mol/kg). In the isolated ileum, (R)--methylhistamine (10–100 M) caused a slight, thioperamide-insensitive, reduction (maximum 15%) of electrically evoked cholinergic contractions. In comparison, the ₂-adrenoceptor agonist clonidine (0.1 mol/kg) caused a 35.2% inhibition of the gastrointestinal transit and almost completely reduced (maximum 82% at 1 M) the cholinergic contraction of the isolated ileum, both effects being antagonized by idazoxan (0.4 mol/kg and 1 M, respectively). These results suggest that histamine H₃ receptors, located outside the myenteric plexus, mediate an inhibition of the gastrointestinal transit in vivo. Conversely, the presence of ₂-adrenoceptors in the cholinergic nerve endings and their inhibitory role in the control of gastrointestinal propulsion is confirmed.     

Inhibition of transient lower esophageal sphincter relaxation and gastroesophageal reflux by metabotropic glutamate receptor ligands

BACKGROUND & AIMS: Transient lower esophageal sphincter relaxation (TLESR) is the major mechanism of gastroesophageal acid reflux. TLESR is mediated via vagal pathways, which may be modulated by metabotropic glutamate receptors (mGluRs). Group I mGluRs (mGluR1 and 5) have excitatory effects on neurons, whereas group II (mGluR2 and 3) and group III (mGluR4, 6, 7, and 8) are inhibitory. This study determined the effect of mGluRs on triggering of TLESR and reflux in an established conscious ferret model. METHODS: Esophageal manometric/pH studies were performed in ferrets with chronic esophagostomies. TLESR were induced by a gastric load of 25 mL glucose (pH 3.5) and 30 mL air. RESULTS: In control treated animals, gastric load induced 3.52 +/- 0.46 TLESRs per 47-minute study, 89.7% of which were associated with reflux episodes (n = 16). The mGluR5 antagonist MPEP inhibited TLESR dose dependently, with maximal 71% +/- 7% inhibition at 35 micromol/kg (n = 9; P < .0001). MPEP also significantly reduced reflux episodes (P < .001) and increased basal lower esophageal sphincter pressure (P < .05). MPEP inhibited swallowing dose dependently, suggesting a common action on trigger mechanisms for swallowing and TLESR. The more selective analogue, MTEP, had more potent effects (90% +/- 6% inhibition TLESR at 40 micromol/kg; n = 8; P < .0001). In contrast, the group I agonist DHPG tended to increase TLESR. The group II agonist (2R, 4R)-APDC was ineffective, whereas the group III agonist L-(AP4 slightly reduced TLESR (33% at 11 micromol/kg; P < .05). The selective mGluR8 agonist (S)-3, 4-DCPG inhibited TLESR by 54% at 15 micromol/kg (P < .01). CONCLUSIONS: mGluR5 antagonists potently inhibit TLESR and reflux in ferrets, implicating mGluR5 in the mechanism of TLESR. mGluR5 antagonists are therefore promising as therapy for patients with GERD.     

Inhibition of glucose stimulated insulin secretion by neuropeptide Y is mediated via the Y1 receptor and inhibition of adenylyl cyclase in RIN 5AH rat insulinoma cells

Summary Neuropeptide Y (NPY) has been shown to inhibit insulin secretion from the islets of Langerhans. We show that insulin secretion in the insulinoma cell line RIN 5AH is inhibited by NPY. ¹²⁵I-Peptide YY (PYY) saturation and competition-binding studies using NPY fragments and analogues on membranes prepared from this cell line show the presence of a single class of NPY receptor with a Y1 receptor subtype-like profile. Inhibition of insulin secretion in this cell line by NPY fragments and analogues also shows a Y1 receptor-like profile. Both receptor binding and inhibition of insulin secretion showed the same orders of potency with NPY > [Pro³⁴]-NPY > NPY 3–36 > > NPY 13–36. The Y1 receptor antagonist, BIBP 3226, blocks NPY inhibition of insulin secretion from, and inhibits ¹²⁵I-PYY binding to, RIN 5AH cells. Northern blot analysis using a Y1-receptor specific probe shows that NPY Y1 receptors are expressed by RIN 5AH cells. Y5 receptors are not expressed in this cell line. Neuropeptide Y inhibition of insulin secretion is blocked by incubation with pertussis toxin, implying that the effect is via a G-protein (G_i or G_o) coupled receptor. Neuropeptide Y inhibits the activation of adenylyl cyclase by isoprenaline in RIN 5AH cell lysates, and the stimulation of cAMP by glucagon-like peptide-1 (7–36) amide (GLP-1). It also blocks insulin secretion stimulated by GLP-1, but not by dibutyryl cyclic AMP. Hence, we suggest that NPY inhibits insulin secretion from RIN 5AH cells via a Y1 receptor linked through G_i to the inhibition of adenylyl cyclase. [Diabetologia (1998) 41: 1482–1491] Received: 10 November 1997 and in final revised form: 16 June 1998     

黄芪多糖对大鼠缺氧/复氧诱导的心肌细胞自噬及凋亡抑制作用的机制探讨

目的：探究黄芪多糖（APS）通过调控高迁移率族蛋白1/Toll样受体4/核转录因子-κB(HMGB1/TLR4/NF-κB)信号通路对大鼠缺氧/复氧（H/R）诱导的心肌细胞自噬及凋亡的抑制作用。方法：建立H9C2心肌细胞H/R损伤模型并分为4组：对照组、H/R组、APS组和HMGB1抑制剂组。CCK-8法和EdU染色法检测细胞增殖能力;酶联免疫吸附试验检测细胞肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1β、IL-6含量;透射电镜观察细胞自噬小体的形成;膜联蛋白V-异硫氰酸荧光素/碘化丙啶（AnnexinV-FITC/PI）双染法检测细胞凋亡;实时定量PCR检测细胞HMGB1、TLR4、NF-κB p65 mRNA表达水平;蛋白免疫印迹法检测细胞HMGB1、TLR4、NF-κB p65、B细胞淋巴瘤-2(Bcl-2)、Bcl-2相关X蛋白（Bax）、含半胱氨酸的天冬氨酸蛋白水解酶-3(caspase-3)、P62、微管相关蛋白1A/1B-轻链3(MAP1LC3,缩写为LC3)-Ⅱ蛋白表达水平。结果：与对照组相比,H/R组细胞增殖能力明显减弱,凋亡及自噬水平明显增加,细胞内可见大量自...