共查询到20条相似文献,搜索用时 15 毫秒
1.
Photodynamic therapy (PDT) is a kind of photochemo-therapeutic treatment that exerts its effect mainly through the induction of cell death. Distinct types of cell death may be elicited by different PDT regimes. In this study, the mechanisms involved in the death of human epidermoid carcinoma A431 cells triggered by PDT with Photofrin (a clinically approved photosensitizer) were characterized. Photofrin distributes dynamically in A431 cells; the plasma membranes and Golgi complex are the main target sites of Photofrin after a brief (3 h) and prolonged (24 h) incubation, respectively. Cells with differentially localized Photofrin displayed distinct death phenotypes in response to PDT. The effects of PDT on cells with plasma membrane-localized Photofrin were further studied in details. Cells stopped proliferating post PDT at Photofrin dose >7 micro g/ml, and at higher dose (28 micro g/ml) plasma membrane disruption and cell swelling were observed immediately after PDT. Dramatic alterations of several important signaling events were detected in A431 cells post Photofrin-PDT, including (i) immediate formation of reactive oxygen species (ROS), (ii) rapid activation of c-Jun N-terminal kinase, (iii) delayed activation of caspase-3 and cleavage of polyADP-ribose polymerase and p21-activated kinase 2, and (iv) loss of mitochondrial membrane potential. Intriguingly, the characteristics of typical apoptosis such as phosphatidylserine externalization and DNA fragmentation were not detected in the cell death process caused by this PDT regime. In conclusion, our results show that when plasma membranes are the main targets, Photofrin-PDT can lead to instant ROS formation and subsequent activation of downstream signaling events similar to those elicited by many apoptotic stimuli, but the damage of plasma membranes renders the death phenotype more necrosis like. 相似文献
2.
Photodynamic therapy (PDT), a photochemotherapeutic regimen used to treat several diseases, including cancer, exerts its effects mainly through induction of cell death. Using human epidermoid carcinoma A431 cells as a model, we previously showed that distinct cell death types could be triggered by protocols that selectively delivered Photofrin (a clinically approved photosensitizer) to different subcellular sites (Hsieh et al. [2003] J Cell Physiol 194: 363–375]. Here, the responses elicited by PDT in A431 cells containing intracellular organelle‐localized Photofrin were further characterized. Two prominent cell phenotypes were observed under these conditions: one characterized by perinuclear vacuole (PV) formation 2–8 h after PDT followed by cell recovery or shrinkage within 48 h, and a second characterized by typical apoptotic features appearing within 4 h after PDT. DCFDA‐sensitive reactive oxygen species formed proximal to PVs during the response to PDT, covering areas in which both endoplasmic reticulum (ER) and the Golgi complex were located. Biochemical analyses showed that Photofrin‐PDT also induced JNK activation and altered the protein secretion profile. A more detailed examination of PV formation revealed that PVs were derived from the ER. The alteration of ER structure induced by PDT was similar to that triggered by thapsigargin, an ER Ca2+‐ATPase inhibitor that perturbs Ca2+ homeostasis, suggesting a role for Ca2+ in the formation of PVs. Microtubule dynamics did not significantly affect PV formation. This study demonstrates that cells in which intracellular organelles are selectively loaded with Photofrin mount a novel response to ER stress induced by PDT. J. Cell. Biochem. 111: 821–833, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
3.
《Cell cycle (Georgetown, Tex.)》2013,12(7):729-734
Apoptosis is an important cellular event that plays a key role in pathogeny and therapy ofmany diseases. Apoptosis has been associated with photodynamic therapy (PDT) and itspathway is important in the mechanistic study of PDT. We show that single cell fluorescentimaging can be used to determine the pathway of PDT- induced tumor cell apoptosis. In thisstudy, ASTC-a-1 tumor cells transfected by plasmid DNA SCAT3 were treated by Photofrin-PDT.The intracellular distribution of Photofrin was observed using a confocal microscope. Theactivations of caspase-3 and caspase-8 were dynamically observed using fluorescence resonanceenergy transfer (FRET). Our experimental results show that the Photofrin molecules arelocalized in cell mitochondria, and that after PDT caspase-3 was activated rapidly whilecaspase-8 remained inactive. These results demonstrate that the tumor cell apoptosis inducedby Photofrin-PDT was directly initiated from the mitochondrial pathway. 相似文献
4.
It has been previously demonstrated that 1,25 dihydroxyvitamin D3 (1,25-D3) exerts inhibitory effects in breast cancer cells. The aim of this study was to determine whether mitogen-activated protein kinase (MAPK) pathways are associated with 1,25-D3-induced cell death in breast cancer. We used three breast cell lines which have different sensitivities to 1,25-D3 treatment. Non-malignant MCF-12A cells were more sensitive to 1,25-D3 treatment than malignant MCF-7 cells (growth inhibition IC50 75 nM vs. 100 nM, p < 0.001) while malignant MDA-MB-231 cells were resistant. Moreover, 1,25-D3-induced apoptosis was caspase-dependent in MCF-12A cells and caspase-independent in MCF-7 cells. Following MAPK activation analysis, we found a significant activation of JNK in MCF-12A cells and malignant MCF-7 cells in response to 1,25-D3 treatment. Furthermore, 1,25-D3 treatment stimulated p38 activity in MCF-12A cells and in MCF-7 cells. ERK1/2 activity was unaffected by 1,25-D3 treatment in all breast cells. Importantly, no increased MAPK activity was observed in MDA-MB-231 breast cancer cells which displayed resistance to 1,25-D3-induced apoptosis. Utilising specific pharmacological inhibitors of JNK and p38, it was demonstrated that MCF-12A and MCF-7 cells were protected from death induced by 1,25-D3. These results implicate JNK and p38 signalling in 1,25-D3-induced cancer breast cell death. 相似文献
5.
Caspases, the key enzymes in apoptosis, are synthesized as proenzymes and converted into active form by proteolytic cleavage. The residues on active site reorganize during the activation process as shown in the comparative studies of crystallographic structures of procaspase-7 and its mature form. On the other hand, the proenzyme itself has some activity. Aiming to characterize the activation process, the comparative kinetic study for the pro- and mature caspase-3 was performed. In 1/K(M) versus pH study, a residue with pKa of 6.89+/-0.13 was detected only in caspase-3. While Vmax versus pH kinetic results were consistent with the existence of a residue with pKa of 6.21+/-0.06 in procaspase-3 mutant (D9A/D28A/D175A) but not in caspase-3. In the inactivation assays with diethylpyrocarbonate, a residue (pKa, 6.61+/-0.05) could be determined only for caspase-3 whereas with iodoacetamide a residue with pKa value (6.01+/-0.05) could be assigned only for procaspase-3. Considering that those residues could be protected by caspase-3-specific inhibitor from the inactivation, the modifiers are histidine- and cysteine-specific, respectively, and the involvement of these residues in the characteristic catalytic dyad of caspases, the results indicate that the pKa values of the catalytic histidine and cysteine residues are changed during the activation process. 相似文献
6.
Renata Gonçalves Ariane Zamoner Leila Zanatta Ana Paula Zanatta Aline Pertile Remor Débora da Luz Scheffer Alexandra Latini Fátima Regina Mena Barreto Silva 《Journal of cell communication and signaling》2017,11(3):233-243
1α,25-Dihydroxyvitamin D3 (1,25-D3) is critical for the maintenance of normal male reproduction since reduced fertility is observed in vitamin D-deficient rats. Gamma-glutamyl transpeptidase (GGT) is a membrane-bound enzyme that is localized on Sertoli cells and catalyses the transfer of the gamma-glutamyl residues to an amino acid or peptide acceptor. Sertoli cells are also responsible for providing nutrients, as lactate, to the development of germ cells. The aim of this study was to investigate the effect and the mechanism of action of 1,25-D3 on GGT on Sertoli cell functions from 30-day-old immature rat testis. Results demonstrated that 1,25-D3 stimulates GGT activity at Sertoli cells plasma membrane through a PKA-dependent mechanism of action, which was not dependent of active de novo protein synthesis. The hormone increases glucose uptake, as well as lactate production and release by Sertoli cells without altering the reactive oxygen species (ROS) generation. In addition, 1,25-D3 did not change reduced glutathione (GSH) amount or oxygen consumption, and diminished Sertoli cell death. These findings demonstrate that 1,25-D3 stimulatory effect on GGT activity, glucose uptake, LDH activity and lactate production seem to be an important contribution of Sertoli cells for germ cells nutrition and for a full and active ongoing spermatogenesis. 相似文献
7.
Interdimer processing mechanism of procaspase-8 activation 总被引:12,自引:0,他引:12
The execution of apoptosis depends on the hierarchical activation of caspases. The initiator procaspases become autoproteolytically activated through a less understood process that is triggered by oligomerization. Procaspase-8, an initiator caspase recruited to death receptors, is activated through two cleavage events that proceed in a defined order to generate the large and small subunits of the mature protease. Here we show that dimerization of procaspase-8 produces enzymatically competent precursors through the stable homophilic interaction of the procaspase-8 protease domain. These dimers are also more susceptible to processing than individual procaspase-8 molecules, which leads to their cross-cleavage. The order of the two interdimer cleavage events is maintained by a sequential accessibility mechanism: the separation of the large and small subunits renders the region between the large subunit and prodomain susceptible to further cleavage. In addition, the activation process involves an alteration in the enzymatic properties of caspase-8; while procaspase-8 molecules specifically process one another, mature caspases only cleave effector caspases. These results reveal the key steps leading to the activation of procaspase-8 by oligomerization. 相似文献
8.
Saeki M Irie Y Ni L Itsuki Y Terao Y Kawabata S Kamisaki Y 《The Journal of biological chemistry》2007,282(16):11786-11794
We have previously shown that procaspase-3 exists in a high molecular weight complex in neonatal rat brain. Here, we purify and identify the protein that interacts with procaspase-3 from rat neonatal cortex. We searched binding proteins to procaspase-3 from a cytosolic extract of neonatal rat brain using chromatogram, two-dimensional gel electrophoresis, and far Western immunoblot. Analysis by tandem mass spectrometry identified the protein as a regulatory subunit of calcineurin (calcineurin B). Overexpression of calcineurin B in HEK293 cells potentiated processing of caspase-3 and apoptosis triggered by tumor necrosis factor-alpha and cycloheximide treatment. In a cell-free system, overexpression of calcineurin B in HEK293 cells markedly increased processing of caspase-3 by cytochrome c. Immunodepletion of calcineurin B from cytosolic extracts from Jurkat cells decreased processing of caspase-3 by cytochrome c. Knockdown of calcineurin B by RNA interference resulted in reduced apoptosis in HEK293 cells but not in caspase-3-deficient MCF-7 cells. These results suggest that calcineurin B potentiates the activation of procaspase-3 by accelerating its proteolytic maturation. 相似文献
9.
HeeWon Kang Baek-Soo Han Su-Jeong Kim Young J. Oh 《Apoptosis : an international journal on programmed cell death》2012,17(5):449-462
The evidence implicating a mode of cell death that either favors or argues against caspase-dependent apoptosis is available
in studies that used experimental models of Parkinson’s disease. We sought to investigate the mechanisms by which release
of cytochrome c is not linked to caspase activation during rotenone-induced dopaminergic (DA) neurodegeneration. Unlike caspase activation
in 6-hydroxydopamine-treated cells, both MN9D DA neuronal cells and primary cultures of mesencephalic neurons showed no obvious
signs of caspase activation upon exposure to rotenone. We found that intracellular levels of ATP significantly decreased at
the early phase of neurodegeneration (<~24 h) and therefore external addition of ATP to the lysates obtained at this stage
reconstituted caspase-3 activity. At a later phase of cell death (>~24 h), both decreased levels of ATP and procaspase-9 contributed
to the lack of caspase-3 activation. Under this condition, calpain and the proteasome system were responsible for the degradation
of procaspase-9. Consequently, external addition of ATP and procaspase-9 to the lysates harvested at the later phase was required
for activation of caspase-3. Similarly, caspase-3 activity was also reconstituted in the lysates harvested from cells co-treated
with inhibitors of these proteases and incubated in the presence of external ATP. Taken together, our findings provided a
sequential mechanism underlying how DA neurons may undergo caspase-independent cell death, even in the presence of cytoplasmic
cytochrome c following inhibition of mitochondrial complex I. 相似文献
10.
Putt KS Chen GW Pearson JM Sandhorst JS Hoagland MS Kwon JT Hwang SK Jin H Churchwell MI Cho MH Doerge DR Helferich WG Hergenrother PJ 《Nature chemical biology》2006,2(10):543-550
Mutation and aberrant expression of apoptotic proteins are hallmarks of cancer. These changes prevent proapoptotic signals from being transmitted to executioner caspases, thereby averting apoptotic death and allowing cellular proliferation. Caspase-3 is the key executioner caspase, and it exists as an inactive zymogen that is activated by upstream signals. Notably, concentrations of procaspase-3 in certain cancerous cells are significantly higher than those in noncancerous controls. Here we report the identification of a small molecule (PAC-1) that directly activates procaspase-3 to caspase-3 in vitro and induces apoptosis in cancerous cells isolated from primary colon tumors in a manner directly proportional to the concentration of procaspase-3 inside these cells. We found that PAC-1 retarded the growth of tumors in three different mouse models of cancer, including two models in which PAC-1 was administered orally. PAC-1 is the first small molecule known to directly activate procaspase-3 to caspase-3, a transformation that allows induction of apoptosis even in cells that have defective apoptotic machinery. The direct activation of executioner caspases is an anticancer strategy that may prove beneficial in treating the many cancers in which procaspase-3 concentrations are elevated. 相似文献
11.
HSP27 inhibits cytochrome c-dependent activation of procaspase-9. 总被引:25,自引:0,他引:25
We have previously shown that the small heat shock protein HSP27 inhibited apoptotic pathways triggered by a variety of stimuli in mammalian cells. The present study demonstrates that HSP27 overexpression decreases U937 human leukemic cell sensitivity to etoposide-induced cytotoxicity by preventing apoptosis. As observed for Bcl-2, HSP27 overexpression delays poly(ADP-ribose)polymerase cleavage and procaspase-3 activation. In contrast with Bcl-2, HSP27 overexpression does not prevent etoposide-induced cytochrome c release from the mitochondria. In a cell-free system, addition of cytochrome c and dATP to cytosolic extracts from untreated cells induces the proteolytic activation of procaspase-3 in both control and bcl-2-transfected U937 cells but fails to activate procaspase-3 in HSP27-overexpressing cells. Immunodepletion of HSP27 from cytosolic extracts increases cytochrome c/dATP-mediated activation of procaspase-3. Overexpression of HSP27 also prevents procaspase-9 activation. In the cell-free system, immunodepletion of HSP27 increases LEDH-AFC peptide cleavage activity triggered by cytochrome c/dATP treatment. We conclude that HSP27 inhibits etoposide-induced apoptosis by preventing cytochrome c and dATP-triggered activity of caspase-9, downstream of cytochrome c release. 相似文献
12.
Parent N Sané AT Droin N Bertrand R 《Apoptosis : an international journal on programmed cell death》2005,10(2):313-322
Procaspase-2S has been reported to selectively prevent membrane blebbing and apoptotic body formation in human monocytic-like leukemic U937 cells after etoposide (VP-16) treatment (Droin et al., Oncogene 20. 260–269, 2001). Here, we show that procaspase-2S overexpressed in human B lymphoma Namalwa cells inhibits procaspase-3 processing and activation, preventing cleavage and activation of Rho GTPase-associated ROCK-1 kinase. Failure of ROCK-1 activation in Namalwa cells correlates with a sustained delay in the appearance of membrane blebbing and apoptotic body formation after VP-16 treatment. Reciprocal coimmunoprecipitation experiments indicate that procaspase-2S binds to procaspase-3, but not procaspase-2L and -9 in untreated and VP-16-treated Namalwa cells. These data suggest that procaspase-2S-mediated anti-apoptotic effects are associated with inhibition of the processing and activation of procaspase-3 in VP-16-treated cells. 相似文献
13.
《Biochemical and biophysical research communications》1985,132(1):198-203
We evaluated the viability of 1α,25-dihydroxyvitaminD3-3β-[N-(4-azido-2-nitrophenyl)glycinate] (1,25-(OH)2-D3-ANG), an analog of 1α,25-dihydroxyvitamin D3 (1,25-(OH)2-D3) as a photoaffinity probe for 1,25-(OH)2-D3 receptor in chick intestinal cytosol. A competitive-binding assay revealed that chick intestinal cytosolic 1,25-(OH)2- D3 receptor bound to 1,25-(OH)2-D3-ANG approximately 20-times less effectively than it did to 1,25-(OH)2-D3. Irradiation of 1,25-(OH)2-D3- ANG in the presence of chick intestinal cytosolic preparation significantly diminished subsequent binding to 3H-1,25-(OH)2-D3, suggesting that the photoaffinity analog was covalently attached to the receptor. Therefore the nitroarylazide derivative of 1,25-(OH)2-D3 may be a valuable photoaffinity probe for the characterization of the 1,25-(OH)2-D3 receptor. 相似文献
14.
Tadashi Watanabe Shigeo Nakamura Toshiya Ono Sadaharu Ui Syota Yagi Hiroki Kagawa Hisami Watanabe Tomoyuki Ohe Tadahiko Mashino Masahiro Fujimuro 《Biochemical and biophysical research communications》2014
Primary effusion lymphoma (PEL) is a subtype of non-Hodgkin’s B-cell lymphoma and is an aggressive neoplasm caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients. In general, PEL cells are derived from post-germinal center B-cells and are infected with KSHV. To evaluate potential novel anti-tumor compounds against KSHV-associated PEL, seven water-soluble fullerene derivatives were evaluated as potential drug candidates for the treatment of PEL. Herein, we discovered a pyrrolidinium fullerene derivative, 1,1,1′,1′-tetramethyl [60]fullerenodipyrrolidinium diiodide, which induced apoptosis of PEL cells via a novel mechanism, the caspase-9 activation by suppressing the caspase-9 phosphorylation, causing caspase-9 inactivation. Pyrrolidinium fullerene treatment reduced significantly the viability of PEL cells compared with KSHV-uninfected lymphoma cells, and induced the apoptosis of PEL cells by activating caspase-9 via procaspase-9 cleavage. Pyrrolidinium fullerene additionally reduced the Ser473 phosphorylation of Akt and Ser196 of procaspase-9. Ser473-phosphorylated Akt (i.e., activated Akt) phosphorylates Ser196 in procaspase-9, causing inactivation of procaspase-9. We also demonstrated that Akt inhibitors suppressed the proliferation of PEL cells compared with KSHV-uninfected cells. Our data therefore suggest that Akt activation is essential for cell survival in PEL and a pyrrolidinium fullerene derivative induced apoptosis by activating caspase-9 via suppression of Akt in PEL cells. In addition, we evaluated whether pyrrolidinium fullerene in combination with the HSP90 inhibitor (geldanamycin; GA) or valproate, potentiated the cytotoxic effects on PEL cells. Compared to treatment with pyrrolidinium fullerene alone, the addition of low-concentration GA or valproate enhanced the cytotoxic activity of pyrrolidinium fullerene. These results indicate that pyrrolidinium fullerene could be used as a novel therapy for the treatment of PEL. 相似文献
15.
The programmed cell death 4 (Pdcd4), a translation inhibitor, plays an essential role in tumor suppression, but its role in apoptosis remains unclear. Here we show that Pdcd4 is a critical suppressor of apoptosis by inhibiting the translation of procaspase-3 mRNA. Pdcd4 protein decreased more rapidly through microRNA-mediated translational repression following apoptotic stimuli than did the activation of procaspase-3, cleavage of poly(ADP)ribose polymerase (PARP) by active caspase-3, and nuclear fragmentation. Strikingly, the loss of Pdcd4 by the specific RNA interference increased procaspase-3 expression, leading to its activation and PARP cleavage even without apoptotic stimuli, and sensitized the cells to apoptosis. Thus, our findings provide insight into a novel mechanism for Pdcd4 as a regulator of apoptosis. 相似文献
16.
17.
Objectives: Photodynamic treatment (PDT) of human lung carcinoma cells A549 (p53+/+) and H1299 (p53?/?) induces fast but transient stalling of proteasome activity. We have explored the possibility of prolonging this effect by combining PDT with drugs capable of sustaining the stall, and promote apoptosis of surviving cells. We show that aspirin can be used to accomplish this. Materials and methods: Cells were irradiated at doses ranging from 0.54 to 1.10 J cm?2, and subsequently were incubated with aspirin at either high (10 and 5 mm ) or low concentration (2.5 and 1.5 mm ). Photofrin concentration and incubation time were constant (2.5 μg/ml and 16 h). Under these conditions, we analysed cell viability, colony‐forming efficiency, cycle profile, expression patterns of specific proteins and ubiquitination state, after individual or combined administration. Results: Treatment with either PDT or aspirin, rapidly induced proteasome malfunction and accumulation of cells in G2M, but did not induce apoptosis. However, when aspirin was added to cells (even at low concentrations) after PDT, the proteasome block was sustained. Moreover, significant cytotoxic effects, including apoptosis, were observed along with cytostatic effects (G2M accumulation/decreased colony formation). Conclusions: Combination of PDT and low‐toxicity drugs (such as aspirin) resulted in protracted inhibition of proteasome activity and induced apoptosis even in apoptosis‐resistant cancer cells. 相似文献
18.
Y Takasaki N Horiuchi T Suda 《Biochemical and biophysical research communications》1978,85(2):601-607
Kidney homogenates from chicks fed a vitamin D-deficient diet for 10 days and supplemented with 6.5 nmol of vitamin D3 48 hr prior to sacrifice metabolized -25-hydroxyvitamin D3 (25-OH-D3) to 24,25-dihydroxyvitamin D3 [24,25-(OH)2-D3] and 3 other metabolites (peaks A, C and E). When the homogenates were incubated with purified [3H]-24,25-(OH)2-D3, 3 similar metabolites (peaks A′, C′ and E′) were produced. On high pressure liquid chromatography, peaks A, C and E migrated to exactly the same respective positions as peaks A′, C′ and E′. Kidney homogenates from D-deficient chicks failed to produce these metabolites from [3H]-25-OH-D3 or [3H]-24,25-(OH)2-D3. These results strongly suggest that the new metabolites reported here are synthesized via 24,25-(OH)2-D3 in the kidney of chicks supplemented with vitamin D3. 相似文献
19.
Quinn P. Peterson David R. Goode Diana C. West Joy J.Y. Lee 《Journal of molecular biology》2009,388(1):144-50
The direct induction of apoptosis has emerged as a powerful anticancer strategy, and small molecules that either inhibit or activate certain proteins in the apoptotic pathway have great potential as novel chemotherapeutic agents. Central to apoptosis is the activation of the zymogen procaspase-3 to caspase-3. Caspase-3 is the key “executioner” caspase, catalyzing the hydrolysis of a multitude of protein substrates within the cell. Interestingly, procaspase-3 levels are often elevated in cancer cells, suggesting a compound that directly stimulates the activation of procaspase-3 to caspase-3 could selectively induce apoptosis in cancer cells. We recently reported the discovery of a compound, PAC-1, which enhances procaspase-3 activity in vitro and induces apoptotic death in cancer cells in culture and in mouse xenograft models. Described herein is the mechanism by which PAC-1 activates procaspase-3 in vitro. We show that zinc inhibits the enzymatic activity of procaspase-3 and that PAC-1 strongly activates procaspase-3 in buffers that contain zinc. PAC-1 and zinc form a tight complex with one another, with a dissociation constant of approximately 42 nM. The combined data indicate that PAC-1 activates procaspase-3 in vitro by sequestering inhibitory zinc ions, thus allowing procaspase-3 to autoactivate itself to caspase-3. The small-molecule-mediated activation of procaspases has great therapeutic potential and thus this discovery of the in vitro mechanism of action of PAC-1 is critical to the development and optimization of other procaspase-activating compounds. 相似文献
20.
M Fukushima Y Suzuki Y Toira I Matsunaga K Ochi H Nagano 《Biochemical and biophysical research communications》1975,66(2):632-638
The metabolism of 1α-hydroxyvitamin D3 (1α-OH-D3) was studied in rat liver perfused with [3H]-1α-OH-D3. [3H]-1α-OH-D3 was converted very rapidly to a more polar metabolite, which was identified as 1α,25-dihydroxy-vitamin D3 [1α,25-(OH)2-D3] by co-chromatography with synthetic 1α,25-(OH)2-D3 as well as by gas chromatography-mass spectrometry. [3H]-1α,25-(OH)2-D3 appeared in the perfusate as early as 20 min after addition of [3H]-1α-OH-D3, and its level in the perfusate increased linearly for at least 120 min. These data strongly indicate that 1α-OH-D3 is metabolized to 1α,25-(OH)2-D3, which exerts biological effects on bone and intestine. 相似文献