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1.
To investigate useful biomarkers associated with proximal tubular injury, we assessed changes in levels of a focused set of biomarkers in urine and blood. Male rats administered a single dose or four doses of gentamicin (GM, 240 mg/kg/day) or a single dose of cisplatin (CDDP, 5 mg/kg) were euthanized on days 2 (the day after initial dosing) 5, or 12. At each time point, histopathological examination of the kidney and immunohistochemistry for biomarkers, kidney injury molecule-1 (Kim-1), lipocalin (NGAL), clusterin (CLU), cystatin C (CysC) and β2-microglobulin (β2M) were performed. Biomarker levels were measured in urine and blood. In both treatment groups, degenerated/necrotic proximal tubules and regenerated tubules were mainly observed on days 5 and 12, respectively. At the same time as these tubular injuries, urinary Kim-1, CysC and β2M levels were increased. Moreover, urinary levels of CysC and β2M in GM-treated animals and Kim-1 in CDDP-treated animals increased (on day 2) prior to tubular injury on day 5. This was considered to reflect the characteristics of drug toxicity. Although almost all of the biomarkers in blood were not sufficiently sensitive to detect proximal tubular injury, urinary and plasma β2M levels simultaneously increased. Therefore, in addition to urinary Kim-1, CysC and β2M levels, plasma β2M levels were also considered useful for detecting proximal tubular injury.  相似文献   

2.
The extent and type of renal ultrastructural changes in Beagle dogs varied with the administration of ochratoxin A and citrinin alone and in the two dosage combinations. The three predominant changes were cytoplasmic vacuolation, myelin figure formation and lesions designated as cytoplasmic disarray. These changes were mainly of the endomembane system of the tubular epithelial cells. Cytoplasmic vacuoles were within proximal and distal tubules and collecting ducts and were most numerous in dogs given 10 mg/kg critrinin. Vacuolation of similar distribution, but less severe, was seen in renal tubular cells of dogs given the higher dose of the combined mycotoxins (0.2 mg/kg ochratoxin A + 10 mg/kg citrinin). This damage was limited to the proximal tubular cells in dogs given only ochratoxin A (0.1 or 0.2 mg/kg). Myelin figures were in proximal epithelial cells of dogs given ochratoxin A alone or combined with citrinin. There was cytoplasmic disarray in dogs of all groups except for dogs given 5 mg/kg citrinin. This lesions was usually limited to the proximal tubules. The lesions, however, was found in cells of the distal tubules of dogs given 10 mg/kg citrinin alone.  相似文献   

3.
The aim of our study was to investigate how the distribution and amount of cathepsin B change during acute kidney injury. The research was done on a rat model of acute kidney injury that was induced by nephrotoxic antibiotic gentamicin. Gentamicin was injected at a dose of 40 mg/kg body weight (the first treated group) and 80 mg/kg body weight (the second treated group) for 14 days. Control groups received injections of physiological saline only. One day after the last injection, animals were euthanized, dissected and kidney samples were taken and fixed in 10% buffered formalin. Tissue sections were stained with haematoxylin and eosin, periodic Acid Schiff (PAS) and Oil-red-O. Immunohistochemistry was used for the demonstration of cathepsin B. Vacuolar degeneration of the proximal convoluted tubules was the most prominent pathologic lesion found in the first treated group, while necrosis prevailed in the second treated group in the same localisation. In both treated groups significantly weaker immunohistochemical reaction for cathepsin B was noticed in the proximal convoluted tubules in comparison to the control groups (P < 0.05). The decrease of positive reaction was the largest in the proximal convoluted tubules of the outer renal cortex. Stronger positive reaction for cathepsin B, although not statistically significant, was found in the proximal straight tubules (P > 0.05), as well. However, more numerous cathepsin B-positive large granules appeared in the proximal straight tubules of the second treated group then in the second control group (P < 0.05). We can conclude that the amount of cathepsin B in the affected proximal convoluted tubules significantly decreases along the increased severity of the histopathological lesions of the proximal convoluted tubuls, the amount of enzyme in the well preserved proximal straight tubules increases and more cathepsin B-positive large granules appear in the cytoplasm.  相似文献   

4.
The toxic effects of imidocarb diproprionate (3,3'-bis [2 imidazolin-2yl]-carbanilde diproprionate) were evaluated in adult goats given (intramuscular injection) a lethal dose (6.75 mg/kg). The immediate clinical signs of toxicosis were transient excessive salivation and diarrhea. Anorexia, dyspnea, recumbency, and death occurred between postinjection days (PID) 4 and 8, during which time 7 goats died and 4 moribund goats were euthanatized. There were marked increases in mean serum urea nitrogen concentration and significant increases in serum glutamic oxalacetic transminase activity and in the mean number of circulating neutrophils after PID 4. Renal hyperemia and enlargement were evident by PID1. Serosanguineous fluid in the trachea and major bronchi, pulmonary congestion and edema, hydrothorax, hydroperitoneum, and less frequently hydropericardium were observed on and after day 4. Microscopic renal tubular lesions rapidly progressed from pyknotic epithelial nuclei observed at 6 and 12 hours to acute tubular necrosis of epithelium of the proximal convoluted tubules on days 1 and 2. Pulmonary congestion and edema; hemorrhage into alveoli, bronchioles, and bronchi; and intracytoplasmic lipid vacuoles within the hepatocytes in the periacinar zones of the hepatic lobules were observed on or after day 4. Succinic dehydrogenase and adenosine triphosphatase activities decreased progressively in the epithelial cells of the proximal convoluted tubules. The decreases in cellular enzymatic activity occurred shortly after the appearance of microscopic lesions in the tubular epithelium.  相似文献   

5.
The effects of different doses and dosage regimens on gentamicin pharmacokinetics and tissue residues were determined. Five groups of 12 sheep each were given gentamicin IM: group I, 2 mg of gentamicin sulfate/kg once; group II, 6 mg/kg once; group III, 18 mg/kg once; group IV, 6 mg/kg every 24 hours for 3 doses; and group V, 2 mg/kg every 8 hours for 9 doses. Serum concentrations were determined serially until sheep were killed and necropsied. Three sheep from each group were killed at 1, 4, 8, and 12 days after the last dose was administered. Renal cortex, renal medulla, liver, spleen, lung, skeletal muscle, and skeletal muscle at the injection site were assayed for gentamicin. An exponential equation was fitted to the serum concentrations, and various pharmacokinetic variables were determined. Serum clearance tended to increase as the single dose increased (P = 0.0588). Steady-state volume of distribution increased as the single dose was increased (P less than 0.05). Renal cortex contained the highest concentration of gentamicin which decreased in a biexponential manner. Concentrations in all tissues, except the injection site, were dependent upon the amount of the total dose, not the size of the injected dose (P less than 0.05). Concentrations at the injection site were up to 29 micrograms/g of tissue at 1 day after the last dose was given and were dependent upon the amount of total dose from multiple injections, not on the amount of each injected dose (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)  相似文献   

6.
Gentamicin is frequently used in the treatment of aerobic Gram-negative infections in reptiles. Pharmacokinetic data to ensure proper dosing are scant, especially for large snakes. A pharmacokinetic study of gentamicin was therefore conducted in four blood pythons. Snakes were given intramuscular injections of either 2.5 mg kg-1 or 3.0 mg kg-1 loading dose followed by 1.5 mg kg-1 at 72 and 96 hours. A linear pharmacokinetic relationship between gentamicin serum concentrations and time was demonstrated in each of the four snakes studied. Peak serum concentrations occurred six to 10 hours after injection and ranged from 4.6 to 8.9 micrograms ml-1. Half-life was variable and ranged from 32 to 110 hours. Total body clearance and apparent volume of distribution varied little between the individual snakes studied. There was no evidence of renal toxicity. For blood pythons a loading dose of 2.5 mg kg-1 followed by 1.5 mg kg-1 at 96 hour intervals is recommended. If higher concentrations are desired, a loading dose of 3.0 mg kg-1 followed by 1.5 mg kg-1 at 96 hours can be given. These dosing schedules will provide serum concentrations in excess of the minimum inhibitory concentrations for most aerobic Gram-negative bacilli that are pathogenic in snakes; gentamicin accumulation with subsequent renal dysfunction should not occur.  相似文献   

7.
Eight gopher snakes were given amikacin (5 mg/kg of body weight IM) and were housed at ambient temperatures of 25 C or 37 C. Snakes housed at 37 C had a larger volume of distribution, and a more rapid body clearance of amikacin while the apparent half-life was not changed significantly. The minimum inhibitory concentrations of amikacin against isolated snake pathogens were determined at both temperatures. Bacteria were twice as sensitive at 37 C than at 25 C. The data indicated that amikacin should be given IM at a dose schedule of 5 mg/kg (loading dose) followed by 2.5 mg/kg every 72 hours, and that snakes should be housed near the high end of their preferred optimum ambient temperature during treatment.  相似文献   

8.
Pigs fed a ration, 25% of which was rice culture, of Aspergillus ochraceus lost weight or failed to gain and became depressed. Some pigs died and most developed subcutaneous edema, hydrothorax, hydroperitoneum, pulmonary atelectasis, edema of the mesentery and perirenal edema. Microscopic lesions in addition to edema were primarily renal and consisted of tubular degeneration and necrosis, hyaline tubular casts, interstitial fibrosis and tubular cell regeneration. The first change found after 3 days was cytoplasmic vacuolation of the convoluted and straight segments of the proximal tubules. Necrotic proximal tubules were found after 4 days and after 9 days degeneration and necrosis involved predominantly proximal tubular segments. Pigs fed a ration, 12.5% of which was rice culture, for 8 weeks did not develop perirenal edema but had firm kidneys. Extensive interstitial fibrosis of the cortical labyrinth was the principal change. Within the fibrous connective tissue, some tubules were necrotic and others were atrophied.  相似文献   

9.
Male and female Sprague-Dawley rats were given CGS 21595, a pro-drug that is almost immediately metabolized to CGS 19213, a naphthoquinone that acts as a 5-lipoxygenase inhibitor. The compound was administered by gavage to five groups of Sprague-Dawley rats (group Nos. 1, 5, n = 30; group Nos. 2-4, n = 20) at daily doses of 0, 50, 150, 500, or 1,000 mg/kg for 13 weeks. Rats in the higher dose groups had a reduced weight gain, but significant neurologic signs were not observed. A peripheral neuropathy consisting predominantly of myelin destruction in the spinal nerve roots and sciatic nerves in male rats treated with greater than or equal to 150 mg/kg CGS 21595 and in female rats treated with greater than or equal to 50 mg/kg CGS 21595 for 13 weeks. This lesion was not fully reversible after a recovery period of 4 weeks. Lesions consisted of ballooning of myelin sheaths, infiltration by macrophages, demyelination, and occasional areas of remyelination. Axons were generally preserved, and the brain and spinal cord were not affected. Male and female rats in all treatment groups had cytoplasmic hyaline droplets in the proximal renal tubules. This change was reversible after 4 weeks and was not associated with any other adverse effects on the kidney.  相似文献   

10.
Thirty-two male Swiss ICR mice were injected intraperitoneally with 300 mg 2-bromoethylamine hydrobromide/kg body weight, anesthetized, and perfused with glutaraldehyde-paraformaldehyde solution at 5, 15, 30, 60, 90, 120, 150, and 180 minutes after treatment. Eight control mice were injected intraperitoneally with sterile diluent, and one was perfused at each of the same time periods as the treated mice. Proximal tubule epithelial alterations progressed over time from increased secondary lysosome and myeloid body formation to cellular and mitochondrial swelling and eventually cell necrosis. The glomerular, peritubular, and vasa recta capillaries had endothelial cell swelling and desquamation and platelet aggregation. Bromoethylamine nephrotoxicosis in the male Swiss ICR mouse is an ischemic necrosis of the proximal tubules and papilla initiated by endothelial cell damage and makes an excellent model of chemically induced damage to endothelial cells and tubular necrosis.  相似文献   

11.
Cases of poisoning by oleander (Nerium oleander) were observed in several species, except in goats. This study aimed to evaluate the pathological effects of oleander in goats. The experimental design used three goats per group: the control group, which did not receive oleander and the experimental group, which received leaves of oleander (50 mg/kg/day) for six consecutive days. On the seventh day, goats received 110 mg/kg of oleander leaves four times at one-hourly interval. A last dose of 330 mg/kg of oleander leaves was given subsequently. After the last dose was administered, clinical signs such as apathy, colic, vocalizations, hyperpnea, polyuria, and moderate rumen distention were observed. Electrocardiogram revealed second-degree atrioventricular block. Death occurred on an average at 92 min after the last dosing. Microscopic evaluation revealed renal necrosis at convoluted and collector tubules and slight myocardial degeneration was observed by unequal staining of cardiomyocytes. Data suggest that goats appear to respond to oleander poisoning in a manner similar to other species.  相似文献   

12.
Dose-related changes in the pharmacokinetics of gentamicin sulfate were investigated in 9 sheep given 3, 10, or 20 mg/kg of body weight IV in a crossover design with a 24-day washout period. The pharmacokinetics of the 3 mg/kg single dose were compared with that of the terminal phase pharmacokinetics of 3 mg of gentamicin/kg IV every 8 hours for 7 days in 8 additional sheep. Serum concentrations were monitored for 21 to 24 days after the dose. Polyexponential equations were fit to each data set. The number of exponential terms was determined by optimizing the fit for each data set. The pharmacokinetics of the 3 mg/kg single dose were mainly described by triexponential equations. The 10 mg/kg and the 20 mg/kg single doses and the 3 mg/kg multiple-dose data were described by a tetraexponential equation. The elimination rate constant was significantly smaller (P less than 0.05) after the larger single doses, and the serum gentamicin clearance increased as the dose increased (P less than 0.05). The crossover design sequence had a significant effect on serum gentamicin clearance and the area under the curve normalized to unit dose (P less than 0.01). The final exponential phase was not detectable with the present assay sensitivity under the 3 mg/kg single dose. The triexponential equation underpredicted the terminal serum concentrations determined after the 3 mg/kg multiple dose, whereas the 4 phase equation overpredicted the same terminal serum concentrations, perhaps reflecting saturation of the tissue pools that were mirrored by the serum gentamicin concentrations after 24 hours. The present study emphasized the complexity of the terminal phase gentamicin. pharmacokinetics and acknowledged the need for a long-term washout period when using the crossover design for gentamicin pharmacokinetic studies.  相似文献   

13.
A polybrominated biphenyl fire retardant (Firemaster FF-1) was responsible for the widespread environmental contamination and animal losses in Michigan during 1973 and 1974. In Fischer 344/N rats orally given 30,100,300, and 1,000 mg/kg (5 days/week, 22 total doses) for 4.5 weeks and observed for 90 days after the start of treatment, the LD50 was determined to be 65 mg/kg/day (total 1.43 g/kg) for the female rat and 149 mg/kg/day (total 3.28 g/kg) for the male. All female rats given the dosage of 100 mg/kg/day (22 doses, total 2.20 g/kg) died between 41 and 53 days after the start of treatment, whereas 38% of the males died between 50 and 73 days. Pathologic changes in treated rats were large liver, accentuation of the hepatic lobular markings, and atrophy of thymus and spleen. Microscopically, hepatic changes were characterized by congestion, fatty metamorphosis, and multifocal liquefactive necrosis. Male rats given 100 mg/kg/day and dying after 90 days had subacute to chronic hepatitis with marked focal proliferation of bile ducts. Exposure to Firemaster FF-1 may produce atypical liver nodules in the rat as early as 6 months after they were first given the preparation. Marked hepatotoxic effect persisted in surviving rats when examined after 6 months.  相似文献   

14.
Serum creatinine concentrations, 24-hour endogenous creatinine clearance, and 24-hour urinary gamma-glutamyl transpeptidase (UGGT) activity were measured daily in 6 dogs given nephrotoxic dosages of gentamicin (10 mg/kg of body weight) every 8 hours for 10 days. Mean UGGT activity was significantly increased by day 5 (P less than 0.05) and preceded significant increases in serum creatinine values (greater than 2.0 mg/dl) observed on day 9. Endogenous creatinine clearance remained within normal limits (2.98 +/- 0.96 ml/min/kg) until day 8. Urinalyses performed 8 days after initiation of gentamicin treatment indicated renal tubular damage (granular casts) in 1 of the 6 dogs, and glucosuria in 3 of the 6 dogs. Measurement of UGGT activity was a more sensitive and reliable method of assessing acute renal tubular damage induced by gentamicin than were serum creatinine concentrations or 24-hour endogenous creatinine clearance.  相似文献   

15.
Tumor-promoting effects of ethyl tertiary-butyl ether (ETBE) were investigated in a 2-stage carcinogenesis bioassay with regard to hepatic and renal carcinogenesis in rats. Male 6-week-old Wistar rats were given drinking water containing N-ethyl-N-(2-hydroxyethyl)nitrosamine (EHEN), as an initiator, at a dose of 500 ppm for 2 weeks. Starting one week thereafter, the animals were administered ETBE at dose levels of 0 (control), 100, 300, 500 or 1,000 mg/kg/day by gavage for 19 weeks from week 4 to 22. Necropsy of all rats was performed at week 23, and livers and kidneys were examined histopathologically. Incidences of hepatocellular adenomas, and those of combined hepatocellular adenomas and carcinomas were significantly elevated in rats given 1,000 mg/kg/day ETBE, but not 100‒500 mg/kg/day ETBE, and there was a significant increase in the average numbers of lesions. No significant differences in incidences and average numbers of renal tubule neoplasms were found in rats administered 100‒1,000 mg/kg/day ETBE. However, the average numbers of atypical tubule hyperplasias, considered to be preneoplastic lesions, were significantly increased in rats given ETBE at 1,000 mg/kg/day, but not in rats given 500 mg/kg/day or lower doses. Thus, these results imply that ETBE has hepatic and renal tumor-promoting activities that affect EHEN-induced carcinogenesis in male rats, and the no-observed-effect level is 500 mg/kg/day under the present experimental conditions.  相似文献   

16.
To establish a useful animal model of Itai-Itai disease (IID) of humans, we conducted the following experiments. Experiment 1: Toxic effects of Cd were compared between ovariectomized (OX) and non-OX rats after daily, intravenous injection of cadmium (Cd) chloride for 14 days. In this experiment, we demonstrated that OX rats were more susceptible to Cd-induced nephrotoxicity and hepatotoxicity than non-OX rats. Experiment 2: OX rats were injected with Cd at doses of 1.0 and 2.0 mg/kg, 5 days a week, for 13 weeks. The bone Cd content was gradually increased for 13 weeks in a dose-dependent manner. Calcium and phosphorus contents in the bone and serum levels of parathyroid hormone and osteocalcin were not significantly different between Cd-treated and control rats. Mild osteomalacic lesions in the cortical bones of the midshaft haversian canals as well as chronic nephropathy appeared in the rats of the 2.0 mg/kg group. Experiment 3: OX rats were treated with Cd at doses of 0.5 and 0.05 mg/kg for 70 weeks. The rats of the 0.05 mg/kg group showed slight anemia and mild degeneration of tubular epithelium after 50 weeks of treatment. In the 0.5 mg/kg group, the rats showed definite osteomalacia of bones and nephrosclerosis. The Cd concentration in the bones increased for the first 25 weeks, but was replaced gradually with iron at from 50 to 70 weeks of the administration period. Iron deficiency anemia appeared in the 0.5 mg/kg group at from 12 to 25 weeks, and changed to renal anemia after 50 weeks of administration. The anemia at 50 and 70 weeks was normocytic and normochromic, and serum erythropoietin levels were not elevated in response to the decrease of hemoglobin concentrations of red blood cells. Experiment 4: Ten, OX cynomolgus monkeys were given intravenous injections of 0, 1.0 or 2.5 mg/kg/day Cd, 2 or 3 days per week, for 13 to 15 months. Normocytic and normochromic anemia, renal lesions characterized by tubular atrophy and interstitial fibrosis (Cd nephropathy), and bone lesions characterized by an increase of osteoid and osteopenia (Cd osteopathy) were induced in the monkeys treated with Cd. These results demonstrated that chronic cadmium toxicosis similar to IID of humans was reproducible in rats and monkeys by repeated intravenous injection of Cd and that a disease entity closely resembling IID of humans could be induced in experimental animals by chronic Cd toxicosis without participation of malnutrition, vitamin D deficiency, impaired absorption at the intestinal mucosa or multiparous birth.  相似文献   

17.
Preruminant calves excreted coccidia oocysts in their faeces after 3 weeks of group housing. Two weeks of oral sulphadimidine (SDM) administration, 50 mg/kg on the first day of treatment followed by daily administration of 37.5 mg/kg, under the same housing conditions kept the faeces free of oocysts. Three weeks later, these calves excreted oocysts again. Repetition of the same treatment for 2 weeks controlled the infection again, but a second treatment for 5 days did not suffice. The repeated long treatment affected immunoglobulin levels adversely. SDM given repeatedly at a lower dose rate (30 mg/kg) for 1-week periods with medication-free intervals of 1 week controlled the infection and no adverse effects were noted. In comparison with controls, weight gains were greater in treated calves.  相似文献   

18.
Three groups of eight normal dogs each were orally given prednisone at doses of 0.22 mg/kg of body weight/day, 0.55 mg/kg/day, or 1.1 mg/kg on alternate mornings. Four dogs served as nontreated controls. Samples were obtained from members of each group to determine baseline serum cortisol and ACTH-stimulated cortisol values and histologic features in the lateral thoracic skin before prednisone administration, and after 1, 2, 3, and 4 weeks of administration. Some animals from each group were necropsied after 1, 2, 3, and 4 weeks of prednisone administration. Each course of prednisone administration resulted in adrenocortical atrophy and hypofunction, but adrenocortical suppression was less severe and slower in onset in the group given prednisone on alternate days. Extra-adrenal effects observed were atrophy of the skin and focal, fatty change of the liver. These changes were most evident in dogs given daily pharmacologic doses of prednisone (0.55 mg/kg/day). Fewer extra-adrenal effects were observed in dogs given alternate-day therapy. There were no extra-adrenal lesions in the dogs given equivalent glucocorticoid replacement doses (0.22 mg/kg/day).  相似文献   

19.
Changes in renal function, determined by pharmacokinetics of phenolsulfonphthalein (PSP), and renal morphologic features were examined in adult pony mares given 20 mg of gentamicin sulfate/kg of body weight, IV, q 8 h (group A) n = 7 or isotonic saline solution, IV, q 8 h, n = 5 (group B) for 14 days. Susceptibility of ponies to gentamicin-induced nephrotoxicosis was varied. Two group-A ponies developed acute renal failure and were euthanatized before treatment day 14, whereas 5 group-A A ponies did not develop physical or behavioral abnormalities after 14 days of gentamicin administration. All group-A ponies but none of group-B ponies developed ultrastructural abnormalities of the proximal tubular epithelium, consistent with gentamicin-induced nephrotoxicosis. Significant (P less than 0.05) differences were not detected in pharmacokinetic values of either group. Clearance of PSP was reduced in 4 group-A ponies that developed the most severe gentamicin-induced nephrotoxicosis. Changes in clearance of PSP were significantly (P less than 0.05) correlated with changes in the serum creatinine concentration.  相似文献   

20.
Nineteen cats were given 3 mg of gentamicin sulfate/kg of body weight by rapid IV, SC, or IM injection for baseline values. Serum concentration of gentamicin vs time data were analyzed using a noncompartmental model based on statistical moment theory. One week later, each cat was given 0.5 microgram of Escherichia coli endotoxin/kg, IV. After cats had an increase in rectal temperature of at least 1 C, 3 mg of gentamicin/kg was administered by the same route used the previous week. Serum concentration of gentamicin vs time data were analyzed, and pharmacokinetic values were compared with base-line values. For IV studies, the half-life (t1/2) of gentamicin and the mean residence time were significantly different (P less than 0.05) compared with base line, whereas the total body clearance and apparent volume of distribution at steady state were not. The harmonic mean +/- pseudo SD for the t1/2 of gentamicin after IV administration was 76.8 +/- 12.6 minutes for base line and was 65.2 +/- 12.2 minutes in the same cats given endotoxin. The t1/2 of gentamicin after SC administration was 74.6 +/- 6.2 minutes for base line and was 65.2 +/- 13.6 minutes in the same cats given endotoxin. After IM administration, the t1/2 of gentamicin was 60.3 +/- 10 minutes for base line and was 59.7 +/- 13.6 minutes in the same cats given endotoxin. After IV administration of gentamicin, the arithmetic mean +/- SD for the mean residence time was 102.4 +/- 16.1 minutes for base line vs 79.2 +/- 18.4 minutes in the same cats given endotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)  相似文献   

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