Wyniki wyszukiwania

1

Współzależność pomiędzy układami enzymatycznymi a działaniem neuropeptydów

100%

Lipkowski A. W., Misicka A.

Acta Physiologica Polonica

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1989

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tom 40

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nr Supl.34[5-6]

2

my-opioid receptors’ share in cardiorespiratory response to systemic injection of the analgesic chimeric peptide in anaesthetized rats

81%

Wojciechowski P., Szereda-Przestaszewska M., Lipkowski A. W.

Acta Neurobiologiae Experimentalis

|

2011

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tom 71

|

nr 1

3

Alpha,Beta-Hybrides of opioid peptides analogues

81%

Olma A., Podwysocka D., Lipkowski A. W., Kosson P.

Acta Neurobiologiae Experimentalis

|

2011

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tom 71

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nr 1

Endogenous opioid peptides like enkephalins endomorphin, dermorphin and deltorphins are model peptides for the development of new analgesic drugs. Since the discovery of the endogenous opioid peptides, numerous analogues have been synthesized in attempts to develop an analgesic without the serious side effects. A major problem with opioid peptides as drugs is their susceptibility to enzymatic hydrolysis when administrated in vivo. Different chemical approaches, as the incorporation of D-amino acids, unnatural amino acid, α,α-disubstituted amino acids, cyclization, have resulted in more stable analogues. Among the numerous suggestions for modification the substitution of β-amino acids for proteinogenic amino acids represents an interesting possibility. ²-Peptides, oligomers of ²-amino acids are a very actual subject of research. β-Peptides do not bind to the active sites of human peptidases and they are entirely stable against proteolytic degradation. On the other hand β-peptides can mimic α-peptides. This was demonstrated that small β-peptides with their strong folding preferences may be used as pharmaceutically active compounds. In this communication we report the effect on receptor binding single replacements in β3 -hybrides of deltorphin I, µ-selective ligands, tetrapeptide Tyr-D-Ala-Phe-Phe-NH2 (TAPP) and biphaline. Nprotected β3 -homo-amino acids were synthesized using procedures reported in the literature. α-Amino acids are enantiomerically pure, commercially available compounds which have frequently used as starting materials for synthesis of β3 -homo-amino acids. Isomeric optically pure Fmoc and Boc β3 -homo-amino acids were prepared in two-step Arndt-Eistert homologation of N-protected amino acids. The α,β-hybrides of DT I were synthesized by manual solid-phase peptide synthesis (SPPS) using standard techniques. The α,βhybrides of tetrapeptides and biphalin were synthesized in solution. The opioid analogues containing β3 -homo-amino acids were for µ and δ-opioid receptors affinity.

4

Ligands for neuropeptide receptors

81%

Lipkowski A. W., Misicka A., Carr D. B.

Acta Neurobiologiae Experimentalis

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1995

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tom 55

|

nr 5

5

Assessment of antiproliferative potency of opioid peptide analogue biphalin in human glioblastoma cell line T98G

81%

Lazarczyk M., Matyja E., Lipkowski A. W.

Acta Neurobiologiae Experimentalis

|

2009

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tom 69

|

nr 1

Biphalin is a new type of opioid peptide analogue with high analgesic potency that is over 1000-fold greater than morphine, a well-known opiate compound widely utilized in pain management. Because of its less addictive nature than morphine, this substance has been suggested as an useful analgesic drug. Biphalinís high analgesic activity may be related with interaction with all three types of opioid receptors (mu, delta and kappa), belonging to G proteincoupled receptors (GPCR) family. These members of GPCR are expressed by astrocytes, including neoplastic glioma cells. It has been evidenced, that opioid receptors, particularly MOR (mu opioid receptor) and KOR (kappa opioid receptor) are involved in growth regulation of glioma cells. The alteration of tumor cell proliferation might be associated with adenylate cyclase inhibition, that results in decrease of intracellular cAMP level and prevention of PKA activation. The present study was performed on human glioblastoma cell line TG98 to establish the effect of biphalin on neoplastic cell growth and proliferation abilities. The glioma cell line exposed to biphalin at increasing concentrations exhibited the decrease of growth rate, reduction of cell ability to form colonies and alteration of Ki-67 proliferation index. These results suggest that this opioid peptide analogue is promising medicine in simultaneous analgesic and anti-cancer therapy. The work was supported by the Ministry of Science and Education, Grant No. NN401228334 and European Grant Normolife No. LSHC-CT-2006-037733.

6

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Zalozenia technologiczne otrzymywania preparatow z bielma ostropestu plamistego do stosowania jako dodatki przeciwutleniajace

81%

Szczucinska A., Kurzepa K., Kleczkowska P., Lipkowski A. W.

Rośliny Oleiste - Oilseed Crops

|

2006

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tom 27

|

nr 2

357-366

7

Neurotensin NTS1 receptors mediate the cardio-respiratory effects of [Ile 9]PK20, a novel chimeric peptide

81%

Kaczynska K., Szereda-Przestaszewska M., Kleczkowska P., Lipkowski A. W.

Acta Neurobiologiae Experimentalis

|

2013

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tom 73

|

nr 1

Opioids with their large potency in pain relieve have certain undesirable effects like tolerance, dependence and respiratory depression. This is the reason for permanent efforts to create new analgesic compounds devoid of the adverse side effects. PK20 is a novel hybrid of opioidneurotensin peptides synthetized from the C-terminal hexapeptide of neurotensin and endomorphine-2 pharmacophore. This chimeric compound shows clear central and peripheral antinociceptive activity in experimental animals, however nothing is known about the influence of PK20 on respiratory and cardiovascular parameters. The present study was designed to determine the cardiorespiratory effects exerted by an intravenous injection of [Ile9]PK20, analog of PK20 with substitution of tert-leucine by isoleucine9. We also attempted to evaluate whether the effects of the hybrid are mediated by the peripheral neural pathway like vagus nerve. Finally, the contribution of NTS1 neurotensin and opioid receptors in the [Ile9]PK20 cardiorespiratory pattern was tested. Anaesthetized, spontaneously breathing rats were used. Tidal volume was measured at tracheostomy. The timing components of the breathing pattern, arterial blood pressure and heart rate were recorded. Intravenous injection of [Ile9]PK20 at a dose of 100 μg/kg in the intact rats provoked an increase in tidal volume preceded by a prompt shortlived decrease. Immediately after the end of injection brief acceleration of the respiratory rhythm, was ensued by the slowing down of breathing. Changes in respiration were concomitant with a bi-phasic response of the blood pressure: immediate increase was followed by prolonged hypotension. Bilateral midcervical vagotomy eliminated both: tidal volume and respiratory rate responses. Blockade of NTS1 receptors with an intravenous dose of 500 μg/kg of SR 142948, significantly lessened post-[Ile9]PK20 cardiorespiratory effects. Naloxone hydrochloride – antagonist of opioid receptors – failed to block [Ile9]PK20-evoked responses. This study depicts that [Ile9]PK20 acting through neurotensin NTS1 receptors augments the tidal component of the breathing pattern through the vagal pathway. This latter mediates also the respiratory timing response to the drug. Blood pressure effects evoked by an intravenous injection of [Ile9]PK20 occur besides the vagal pathway and might result from activation of the central and peripheral vascular NTS1 receptors. In summary the respiratory effects appeared not to be profound. However, considerable and extended hypotension evoked by [Ile9]PK20 sets the main disadvantage of an analgesic compound.

8

Peripheral antinociceptive effect of biphalin in a mouse model of cancer pain

81%

Lesniak A., Bochynska-Czyz M., Sacharczuk M., Lipkowski A. W.

Acta Neurobiologiae Experimentalis

|

2013

|

tom 73

|

nr 1

It is generally accepted that classical opioids exert their antinociceptive effect mainly when binding to opioid receptors located in the central nervous system. However, a growing body of evidence points to the relevance of peripheral opioid receptors in periphery pathology, including cancer. A cancer is very often the cause of pain resulting from peripheral metastasis. The peripheral component of antinociception induced by a dimeric enkephalin analog – biphalin showing limited blood-brainbarrier permeability may prove important in cancer pain therapy. An additional advantage of biphalin is a possibility to treat pain symptoms with reduction of side-effects – a result of the central action of some other opioid analgesics, e.g. morphine. We examined the peripheral and central analgesic effect of biphalin in a murine skin cancer pain model developed by an intraplantar inoculation of B16T0 melanoma cells. Animals developed robust thermal hypersensitivity in the tumor-bearing paw compared to PBS-injected individuals. Biphalin produced stronger analgesia in the tumor-bearing paw than morphine upon a comparable central effect. Our results suggest that biphalin analgesia manifested in the periphery is linked to a less effective transport through the bloodbrain barrier. We speculate that the centrally effective dose of biphalin equipotent to morphine simultaneously produces analgesia via peripheral opioid receptors. Thus, biphalin may become useful in cancer pain treatment as an alternative drug executing a local as well as a central analgesic response with limited undesirable side-effects.

9

Neuropeptide analogues as prospective new medicines for cancer pain treatment: Opioid-tachykinin chimera

81%

Lipkowski A. W., Kosson D., Klinowiecka A., Misicka A.

Acta Neurobiologiae Experimentalis

|

2009

|

tom 69

|

nr 1

Multidrug therapies became routine approach in modern medical treatment protocols. However, simple combinations of drugs have disadvantages, including differences in pharmacological profi les of single drug component. Therefore, over twenty years ago we have proposed development of multitarget medicines as a new avenue of drug discovery. Identifi cation of numerous endogenous components that participate in the formation, transmission, modulation and perception of pain signals offers numerous strategies for the development of new analgesics. One of them is hybridization of opioid pharmacophores with tachykinin receptor ligands. Tachykinins, like substance P (SP) produces both hyperalgesia and, at low doses, a naloxone-sensitive analgesia. Very likely, these opposite effects of SP in the spinal cord, are mediated through activation of various self-regulatory mechanisms. Modulation of tachykinin receptor system is probably signifi cant component of tolerance and dependence development. Therefore, various new opioid agonisttachykinin antagonist and opioid agonist-tachykinin agonist have been synthesized and tested to develop new medicines for chronic pain treatment. The presentation will focus on new group of opioid agonist-tachykinin agonist that expresses strong analgesic activity even after peripheral application. These new compounds are interesting candidates for treatment of chronic pain because they express very low tolerance development properties. Presented studies have been supported in part with EU grant Normolife (LSHC-CT-2006-037733)

10

The protective effect of TRH and its analogues on staurosporine-but not doxorubicin-induced apoptosis in primary cortical neurons

81%

Jantas D., Jaworska-Feil L., Lipkowski A. W., Lason W.

Acta Neurobiologiae Experimentalis

|

2009

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tom 69

|

nr 1

In the present study we investigated the infl uence of thyrotropinreleasing hormone (TRH, pGlu-His-Pro-NH2) and its more stable analogues: CG-3703 (Montirelin), RGH-2202 (L-6-keto-piperidine-2carbonyl-L-leucyl-L-prolinamide) and Z-TRH (Z-pGlutamyl-Histydyl-Proline) on neuronal apoptosis evoked by staurosporine ñ or doxorubicin, agents activating mitochondrial or extracellular (FAS) apoptotic cell death, respectively. We showed that TRH (0.001ñ10 μM) in U-shape concentration dependent way (effective concentrations: 0.01 and 0.1 μM) partially attenuated the staurosporine (0.5 μM) ñ but not doxorubicin (0.5 μM)-evoked cell damage in mouse 7 DIV cortical neurons only when added 24 h before toxin administration. The TRH analogues (MON, RGH, Z-TRH) were also effective in lower concentration (0.001 μM) than TRH in attenuation of the staurosporine-induced LDH release. Moreover, that benefi cial effect of TRH and its analogues was not accompanied with its infl uence on caspase-3 activity, though the attenuation of number of apoptotic cells was observed in Hoechstís staining. Furthermore, we found that neither PI3-K (wortmannin 10 μM, LY294002 1 μM) nor MAPK/ERK1/2 (PD098059 1 uM and U0126 1 μM) inhibitors were able to abolish protection served by TRH and MON. There was no protection observed when peptides were added concomitantly with staurosporine and doxorubicin. The obtained data showed ameliorating effect of pretreatment with low concentrations of TRH and its analogues on neuronal cell death mediated by agent activating mitochondrial pathway of apoptosis. That effect seems to be caspase-3-independent and does not engage the PI3-K/ Akt and MAPK/ERK1/2 cellular prosurvival pathways. Supported by grant No. 2PO5A15530 from the Ministry of Education and Science (Warsaw, Poland)

11

Antinociceptive interaction of substance P and dermorphin applied intrathecally

81%

Kosson P., Klinowiecka A., Lipkowski A. W.

Acta Neurobiologiae Experimentalis

|

2009

|

tom 69

|

nr 1

In the clinic, multidrug therapies become standard of modern successful therapies. However, the different pharmacodynamic profi le of the drugs creates limits of using of a mixture. The discovery of numerous endogenous components which participate in the formation, transmission, modulation and perception of pain signals offers numerous strategies for the development of new analgesic. One of them is Substance P (SP). This undecapeptide Arg-Pro-Lys-Pro-Gln-Gln-PhePhe-Gly-Leu-Met-NH2 is widely distributed throughout the central nervous system and is highly expressed on areas that are critical for the regulation of pain infl ux, affective behavior and stress. For activation of the receptor neurokinin-1 (NK-1) the C-terminal sequence of SP is essential but not all the effects of SP are mediated through the Cterminal fragment. N-terminal fragment, such as SP(1-7) induces antinociception and desensitization of several SP-induced behaviors. SP has been suggested to modulate the expression of opiate tolerance and withdrawal behaviours in rodents. This communication will present the results of creating the mixture SP and dermorphin administered together at the same time, because it is very important to describe pharmacological mechanism of these two compounds. This is the fi rst step to design new analgesics hybrids where in one molecule we have two different pharmacophores: C-terminal fragment of substance P and N- terminal fragment replaced with dermorphin. Presented studies have been supported with EU grant Normolife (LSHC-CT-2006-037733)

12

Synthesis and cell cancer growth inhibiting properties of somatostatin analogs

81%

Dyniewicz J., Bochynska-Czyz M., Lipkowski A. W.

Acta Neurobiologiae Experimentalis

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2011

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tom 71

|

nr 1

Somatostatin (SST) is a tetradecapeptide that was originally characterized as a physiological inhibitor of growth hormone. In addition, SST has another multiple functions. It regulates endocrine and exocrine secretion, possesses antiproliferative properties and acts as a neurotransmitter/neuromodulator. These diverse physiological effects are mediated by a family of G-protein-coupled receptors, called somatostatin receptors sst1 - sst5. Nowadays, there are several cyclic synthetic somatostatin analogues (eg octreotide, lanreotide), clinically used for cancer therapy and gastrointestinal disorders, that primarily interact with receptor sst2 and sst5. Our goal is to synthesize a linear tetrapeptide which would have activity like somatostatin. The base of analogs’ structures are, key for somatostatin activity, aminoacids residues like. Results of this experiments will be present on the poster.

13

Przeciwbakteryjne efekty współdziałania antybiotyków beta-laktamowych i tioglikozydów ekstrahowanych ze śruty rzepaku

81%

Makulec-Niewiarowska I., Lipkowski A. W., Marczak E. D., Baranowska B.

Rośliny Oleiste - Oilseed Crops

|

1996

|

tom 17

|

nr 1

14

Synthesis and binding properties of deltorphin I analogues containing [R] and [S]-alpha-hydroxymethylnaphtylalanine

81%

Olma A., Gniadzik A., Lipkowski A. W., Lachwa M.

Acta Biochimica Polonica

|

2001

|

tom 48

|

nr 4

New analogues of deltorphin I (DT I), in which the phenylalanine residue in position 3 is substituted with amphiphilic a,a-disubstituted amino acid enantiomers, (R) and (S)-a-hydroxymethylnaphtylalanine, were synthesized and tested for u and δ opioid receptor affinity and selectivity. Although both analogues have lower affinity to δ receptors than DT I, they both expressed specificity to δ receptors.

15

Induction of areactivity of rat lymphocytes stimulated by myelin antigens

71%

Michalkiewicz J., Zielinska J., Kwiatkowska-Pazer B., Krzepa K., Lipkowski A. W.

Acta Neurobiologiae Experimentalis

|

2006

|

tom 66

|

nr 4

16

Is pig spinal cord hydrolysate safe for treatment Experimental Allergic Encephalomyelitis in rats?

71%

Kasarello K., Katkiewicz M., Kurzepa K., Kwiatkowska-Patzer B., Lipkowski A. W.

Acta Neurobiologiae Experimentalis

|

2011

|

tom 71

|

nr 1

EAE (Experimental Allergic Encephalomyelitis) is the animal model of Multiple Sclerosis, an autoimmune and neurodegenerative human disease. Proposed method for autoimmune diseases treatment is to evoke oral tolerance, which is lack of response to fed antigen. Our previous experiments showed that pig spinal cord hydrolysate, which is source of myelin antigens is able to evoke oral tolerance in EAE rats. The aim of our study was to investigate, if treatement with pig spinal cord hydrolysate has any toxic effects on rats. Twelve female Lewis rats were fed with pig spinal cord hydrolysate (500mg/kg) or PBS (control group, 0,5ml per rat) each day for one month. One day after the last day of feeding animals were sacrified, and the main organs were collected. Organs were fixed in 10% formalin, postfixed in paraffin, cut into slices and stained with hematoxylin and eosin. Slices were analysed using the light microscope. Every spleen, thymus and adrenal gland was weighted to count relative mass. Number of spleen megakaryocytes in 1mm2 was counted. There were no changes observed in any brain, heart, stomach, intestine, uterus and ovary preparations. We observed single changes in rats liver, kidney, thymus, mesenteric lymph node, adrenal gland, and in the number of spleen megakaryocytes, but not corelated with experimental group. The fact that we did not find any significant changes in rat organs can confirm that pig spinal cord hydrolysate is safe for rats. Supported by N302 009 32/1139 grant.

17

Effects of Lactococus lactis producing myelin peptides on histopathological changes in spinal cord of rats with Experimental Allergic Encephalomyelitis

71%

Kasarello K., Szczepankowska A. K., Patzer-Kwiatkowska R., Bardowski J., Lipkowski A. W.

Acta Neurobiologiae Experimentalis

|

2013

|

tom 73

|

nr Suppl.1

Experimental Allergic Encephalomyelitis (EAE) is the animal model of Multiple Sclerosis (MS), human autoimmunological disease that causes neurodegeneration. The autoimmune base of the disease leads to treatment searching in immunological mechanisms. Earlier we proposed the application of pig spinal cord hydrolysate as a mean to induce oral tolerance. The positive effects observed in EAE rats, stimulated us to develop bacteria that may express active peptide related to myelin fragment. For our experiments we used mixture of Lactococcus lactis producing fragments of three main myelin peptides, MBP (MBP 85-97), PLP (PLP 139-151) and MOG (MOG 35-55). We fed female Lewis rats with spectrum of bacteria doses, from 101 to 108 cells/ rat daily, for twenty days, from day −10 to 9. At the day 0 we evoked EAE in rats. Based on the results obtained from clinical symptoms, we selected two doses, 103 and 106 bacteria cells/rat for investigation of histopathological changes in spinal cord of animals. We observed slighter inflammatory cells infiltration in spinal cord in EAE rats fed with both doses of bacteria in comparison to non-fed ones. Supported by N302 00932/1139 grant.

18

Antiproliferative properties of opioid-tachykinin hybride peptides on human glioblastoma cell line T98G

71%

Lazarczyk M., Matyja E., Lipkowski A. W., Yamamoto T., Hruby F. J.

Acta Neurobiologiae Experimentalis

|

2006

|

tom 66

|

nr 4

19

Blood-brain barrier permeability and analgesic activity of morphine and endomorphine-1 in mice bred for swim-stress induced analgesia

71%

Klinowiecka A., Kosson P., Sacharczuk M., Gajkowska B., Lipkowski A. W.

Acta Neurobiologiae Experimentalis

|

2009

|

tom 69

|

nr 1

In 1983 prof. Boguslaw Sadowski from Institute of Genetic and Animal Breeding in Jastrzebiec developed genetic mouse lines selectively bred for high (HA) and low (LA) swim-stress induced analgesia. Selected animals differ in sensitivity to both, pain or stress responses. Many experiments were conducted but the mechanism which is responsible for different sensitivity to both, pain and stress in these animals has been unknown till today. We hypothesized that difference in blood-brain barrier (BBB) permeability is the reason of different response of HA and LA mice. According to our hypothesis the β-endorphins which are released on the periphery after stressful stimuli, can cross the BBB and reach the brain, and analgesia is observed. The aim of the studies is to present the analgesic activity of opioid compounds in selected mice to examine their BBB permeability. This communication will also present infl uence of stress on analgesic activity of the given compounds. Different analgesic potency of alkaloid and opioid peptide in selected mice was a premise to conduct an ultramicroscopic studies which displayed pathological changes in morphology of BBB in HA and LA mice. These fi ndings may explain different analgesic potency of the given compounds. These animals may well simulate human high and low sensitivity to both, pain or stress response. Presented studies have been supported with EU grant Normolife (LSHC-CT-2006-037733)

20

Utylizacja odpadu nasion ostropestu plamistego II. Biologicznie czynne peptydy z odpadu nasion ostropestu plamistego

71%

Baranowska B., Kurzepa K., Marczak E., Szczucinska A., Lipkowski A. W.

Rośliny Oleiste - Oilseed Crops

|

2003

|

tom 24

|

nr 2

725-732

Ograniczanie wyników

Współzależność pomiędzy układami enzymatycznymi a działaniem neuropeptydów

my-opioid receptors’ share in cardiorespiratory response to systemic injection of the analgesic chimeric peptide in anaesthetized rats

Alpha,Beta-Hybrides of opioid peptides analogues

Ligands for neuropeptide receptors

Assessment of antiproliferative potency of opioid peptide analogue biphalin in human glioblastoma cell line T98G

Zalozenia technologiczne otrzymywania preparatow z bielma ostropestu plamistego do stosowania jako dodatki przeciwutleniajace

Neurotensin NTS1 receptors mediate the cardio-respiratory effects of [Ile 9]PK20, a novel chimeric peptide

Peripheral antinociceptive effect of biphalin in a mouse model of cancer pain

Neuropeptide analogues as prospective new medicines for cancer pain treatment: Opioid-tachykinin chimera

The protective effect of TRH and its analogues on staurosporine-but not doxorubicin-induced apoptosis in primary cortical neurons

Antinociceptive interaction of substance P and dermorphin applied intrathecally

Synthesis and cell cancer growth inhibiting properties of somatostatin analogs

Przeciwbakteryjne efekty współdziałania antybiotyków beta-laktamowych i tioglikozydów ekstrahowanych ze śruty rzepaku

Synthesis and binding properties of deltorphin I analogues containing [R] and [S]-alpha-hydroxymethylnaphtylalanine

Induction of areactivity of rat lymphocytes stimulated by myelin antigens

Is pig spinal cord hydrolysate safe for treatment Experimental Allergic Encephalomyelitis in rats?

Effects of Lactococus lactis producing myelin peptides on histopathological changes in spinal cord of rats with Experimental Allergic Encephalomyelitis

Antiproliferative properties of opioid-tachykinin hybride peptides on human glioblastoma cell line T98G

Blood-brain barrier permeability and analgesic activity of morphine and endomorphine-1 in mice bred for swim-stress induced analgesia

Utylizacja odpadu nasion ostropestu plamistego II. Biologicznie czynne peptydy z odpadu nasion ostropestu plamistego