By Cocer Peptides 
Watanni 1 da suka gabata
DUKKANIN LABARI DA BAYANIN KYAUTATAWA DA AKE BAYAR A WANNAN SHAFIN KAWAI DOMIN WATSA BAYANI NE DA MANUFOFIN ILIMI.
Kayayyakin da aka bayar akan wannan gidan yanar gizon an yi niyya ne kawai don binciken in vitro. Binciken in vitro (Latin: *a cikin gilashi*, ma'ana a cikin gilashin gilashi) ana gudanar da shi a wajen jikin mutum. Waɗannan samfuran ba magunguna ba ne, Hukumar Abinci da Magunguna ta Amurka (FDA) ba ta amince da su ba, kuma dole ne a yi amfani da su don hanawa, magani, ko warkar da kowane yanayi na likita, cuta, ko cuta. Doka ta haramta shigar da waɗannan samfuran cikin jikin mutum ko dabba ta kowace hanya.
Dubawa
Ana nuna tsufa ta hanyar raguwa a hankali na ayyukan ilimin lissafin jiki da kuma ƙara yawan kamuwa da cuta. Fahimtar alamomi da halaye na tsufa yana da mahimmanci don bayyana hanyoyin nazarin halittu na tsufa da haɓaka dabarun rage tsufa da rigakafin cututtukan da ke da alaƙa.
Hoto 1. Na'urar rigakafin kumburi.
Alamomi da Halayen Tsufa
(1) Rashin zaman lafiya
Rashin zaman lafiyar al'amuran al'ada shine babban dalilin tsufa. Tarin lalacewar DNA ya samo asali ne daga dalilai masu mahimmanci kamar nau'in oxygen mai amsawa (ROS) wanda aka samar yayin tafiyar matakai na rayuwa, da kuma abubuwan da ba su da kyau kamar hasken ultraviolet da sinadarai. Yayin da kwayoyin halitta suka tsufa, ingancin hanyoyin gyaran DNA yana raguwa, yana haifar da lalacewar DNA da ba a warware ba. Idan ba a gyara karyawar DNA mai madauri biyu da kyau ba, za su iya haifar da rashin daidaituwa na tsarin chromosomal da sake tsara kwayoyin halitta, yana shafar bayyanar kwayoyin halitta da aikin salula. A cikin sel masu tsufa, sauye-sauye a cikin furci na maɓalli na sunadaran a cikin hanyar amsawar lalacewar DNA yana rage haƙurin tantanin halitta ga lalacewar DNA, ta haka yana haɓaka tsarin tsufa. Wannan rashin zaman lafiyar kwayoyin halitta ba wai kawai yana rinjayar aikin salula na al'ada ba amma yana da alaƙa da haɗin gwiwa tare da farawa da ci gaba da cututtuka daban-daban na shekaru kamar ciwon daji da cututtuka na neurodegenerative.
(2) Telomer atrition
Telomeres jerin DNA ne masu maimaitawa a ƙarshen chromosomes waɗanda ke aiki azaman iyakoki, hana haɗuwa da lalata ƙarshen chromosomes. Yayin rarraba tantanin halitta, telomeres a hankali yana raguwa saboda DNA polymerase ba zai iya cika ƙarshen chromosomes ba. Lokacin da telomeres ya gajarta zuwa wani ɗan lokaci, sel suna shiga yanayin tsufa ko kuma su sami apoptosis. Wannan saboda gajeriyar telomeres ana gane su ta hanyar sel azaman lalacewar DNA, don haka kunna wuraren bincike na tantanin halitta don hana ƙarin rarraba tantanin halitta. Telomerase na iya tsawaita tsayin telomere, amma aikinsa ya ragu a yawancin ƙwayoyin somatic. Yayin da shekaru ke ƙaruwa, telomeres na ci gaba da raguwa, suna zama alama mai mahimmanci na senescence na salula. Wasu nazarin sun gano cewa kunna telomerase ko yin amfani da maganin kwayoyin halitta don tsawaita tsayin telomere na iya jinkirta jinkirin salon salula, samar da sabbin fahimta don binciken rigakafin tsufa.
(3) Canje-canjen Epigenetic
Tsarin Epigenetic yana taka muhimmiyar rawa a cikin ƙayyadaddun ƙayyadaddun kwayoyin halitta, kuma tsarin tsufa yana tare da sauye-sauye na epigenetic. Canje-canje a cikin tsarin DNA methylation ɗaya ne daga cikin sauye-sauye na epigenetic na kowa. A lokacin tsufa, gabaɗayan matakan methylation na DNA suna raguwa, amma wasu takamaiman yankuna masu haɓaka kwayoyin halitta suna nuna hypermethylation, wanda ke haifar da yin shuru na waɗannan ƙwayoyin. Kwayoyin da ke da alaƙa da tsarin sake zagayowar tantanin halitta, gyaran DNA, da dai sauransu, sun sami raguwar magana saboda mai haɓaka hypermethylation, ta haka yana shafar ayyukan salula na yau da kullun. gyare-gyaren tarihi kamar acetylation da methylation kuma suna fuskantar canje-canje, suna tasiri tsarin chromatin da samun damar gene. Wadannan sauye-sauye na epigenetic na iya tsara tsarin tafiyar da salon salula irin su yaduwa, bambance-bambance, da tsufa ta hanyar rinjayar maganganun kwayoyin halitta, da kuma sauye-sauye na epigenetic suna nuna wani mataki na sake dawowa, samar da maƙasudai don tsoma baki.
(4) Rashin gina jiki homeostasis
Protein homeostasis shine tushe don kiyaye aikin salula na yau da kullun, wanda ya haɗa da matakai kamar nada furotin, sufuri, da lalata. Da shekaru, hanyoyin gina jiki homeostasis a cikin sel sannu a hankali sun zama marasa daidaituwa. Magana da aikin ƙwayoyin ƙwayoyin cuta kamar su sunadaran girgiza zafi suna raguwa, suna hana sabbin sunadaran da aka haɗe su nadawa daidai, wanda ke haifar da tarin sunadaran da suka ɓace a cikin sel. Ayyukan proteasome da tsarin autophagy-lysosomal suma sun lalace, suna rage ikon su na share ɓoyayyen sunadaran da suka lalace. Tarin waɗannan sunadaran sunadaran da ba na al'ada ba suna samar da tari waɗanda ke rushe tsarin tsarin ilimin halittar jiki na yau da kullun a cikin sel, kunna hanyoyin siginar damuwa na ciki, kuma suna haifar da tsufa na salula. A cikin cututtukan neurodegenerative, sunadaran da ba su da tushe kamar su β-amyloid da furotin tau suna taruwa da yawa, suna haifar da tabarbarewar neuronal da mutuwa, wanda ke da alaƙa da asarar furotin homeostasis yayin tsarin tsufa.
(5) Rage tsarin siginar abinci
Hanyoyin gano abubuwan gina jiki suna taka muhimmiyar rawa wajen haɓakar ƙwayoyin cuta, metabolism, da tsufa. Dauki hanyar mTOR (mammalian manufa na rapamycin) a matsayin misali; yana iya fahimtar yanayin abinci mai gina jiki a cikin sel kuma yana daidaita matakai kamar haɗin furotin, haɓakar tantanin halitta, da autophagy. Lokacin da abubuwan gina jiki suna da yawa, ana kunna mTOR, yana haɓaka haɓakar ƙwayoyin cuta da haɓaka; duk da haka, kunnawa da yawa na hanyar mTOR yana da alaƙa da tsufa, kamar yadda yake hana autophagy, wanda ke haifar da tarin ƙwayoyin cuta da sunadarai masu lalacewa, yayin da kuma inganta amsawar kumburi. Ƙuntataccen kalori na iya hana ayyukan mTOR, kunna autophagy, da share sharar salula, don haka rage tsufa. Hanyar siginar insulin/insulin-like girma factor-1 (IGF-1) Hakanan yana da alaƙa da tsarin abinci mai gina jiki da tsufa; dysregulation na wannan hanyar yana shafar metabolism na salula da tsawon rayuwa. Ta hanyar daidaita hanyoyin gano abubuwan gina jiki, ana iya inganta jihohin rayuwa ta salula, ta haka rage saurin tsufa.
(6) Rashin aikin mitochondrial
Mitochondria, a matsayin gidajen wutar lantarki, suna taka muhimmiyar rawa a tsarin tsufa. Tare da tsufa, tsari da aikin mitochondria suna fuskantar manyan canje-canje. Mitochondrial DNA (mtDNA), rashin kariyar histone kuma yana kusa da wuraren samar da ROS, yana da haɗari ga lalacewar oxidative, yana haifar da tarawar maye gurbin mtDNA. Wadannan maye gurbi suna lalata aikin rukunonin sarkar numfashi na mitochondrial, rage ingancin samar da ATP, da kuma kara samar da ROS. Yawan ROS yana kara lalata mitochondria da sauran kwayoyin halitta a cikin sel, haifar da mugun yanayi. Rashin daidaituwa a cikin mitochondrial kuzarin kawo cikas (ciki har da fusion da fission) kuma yana shafar aikin mitochondrial da rarrabawa. A cikin sel masu hankali, wuce gona da iri na mitochondrial fission yana haifar da gajeriyar mitochondria mai rauni tare da gazawar aiki. Mitochondrial dysfunction-induced makamashi metabolism abnormalities da kuma ƙara oxidative danniya ne key fasali na salon salula da kuma kwayoyin tsufa, a hankali hade da farko da kuma ci gaban daban-daban shekaru da cututtuka kamar cututtukan zuciya da jijiyoyin jini cututtuka da neurodegenerative cututtuka.
(7) Sescence na kwayar halitta
Senescence na salon salula yana nufin asarar iyawar haɓakawa da shiga cikin ingantacciyar kwanciyar hankali, yanayin kamawa mara jurewa. Kwayoyin da ba a gani ba suna nuna halaye na musamman na phenotypic, gami da ƙarar ƙarar tantanin halitta, ƙayyadaddun ilimin halittar jiki, da haɓakar ayyukan β-galactosidase. Hanyoyin da ke haifar da jin daɗin rayuwa sun bambanta, ciki har da rage telomere, lalacewar DNA, da damuwa na oxidative. Kwayoyin ji na ɓoye suna ɓoye jerin cytokines, chemokines, da proteases, suna samar da abin da ke da alaƙa da sirrin phenotype (SASP). SASP ba wai kawai yana haifar da tasirin paracrine akan sel kewaye ba, yana haifar da martani mai kumburi da gyaran matrix na waje, amma kuma yana iya haɓaka fibrosis na nama da samuwar ƙwayar ƙwayar cuta. Yayin da ƙwayar salula na iya kashe ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar cuta.
(8) Ciwon Tuwoyi
Kwayoyin tushe suna da ikon sabunta kansu da bambanta zuwa nau'ikan tantanin halitta daban-daban, suna taka muhimmiyar rawa wajen haɓakawa, kiyayewa, da gyaran kyallen takarda da gabobin. Yayin da tsufa ke ƙaruwa, aikin ƙwayar ƙwayar ƙwayar cuta a hankali yana raguwa, tare da rage ƙarfin sabuntawar kai da ƙayyadaddun yuwuwar bambanta. A lokacin tsarin tsufa, ma'auni na bambance-bambancen ƙwayar hematopoietic zuwa nau'o'in kwayoyin jini daban-daban yana rushewa, yana haifar da rashin aikin tsarin rigakafi. Ƙarfin haɓakawa da bambance-bambancen ƙwayoyin ƙwayoyin cuta na mesenchymal suma suna raunana, suna shafar gyare-gyare da sake farfadowa na kashi, guringuntsi, da adipose kyallen takarda. Abubuwan da ke haifar da gajiyar ƙwayar ƙwayar cuta sun haɗa da canje-canje a cikin microenvironment, dysregulation na hanyoyin siginar ciki, da tara lalacewar DNA. Asarar aikin ƙwayar ƙwayar cuta yana rage ƙarfin gyaran kyallen takarda da gabobin jiki, yana sa su kasa yin tasiri yadda ya kamata ga rauni da cututtuka, wanda ke haifar da tsufa na jiki.
(9) Canje-canje a Sadarwar Intracellular
Sadarwar intercellular yana da mahimmanci don kiyaye homeostasis na kyallen takarda da gabobin. A lokacin tsarin tsufa, sadarwar intracellular yana fuskantar manyan canje-canje. Yayin da shekaru ke ƙaruwa, haɗin haɗin sel yana raguwa, yana shafar musayar abu da watsa sigina tsakanin sel. Bugu da ƙari, aikin tsarin endocrine kuma yana canzawa, yana haifar da rashin daidaituwa na hormonal. Canje-canje a cikin ɓoyewa da aikin hormones kamar insulin da hormone girma suna shafar tsarin metabolism da aikin salula. Kunna hanyoyin siginar kumburi wani muhimmin al'amari ne na sauya hanyar sadarwa ta ciki. Kwayoyin da ba su da hankali suna ɓoye abubuwan SASP waɗanda ke haifar da amsawar kumburi na yau da kullun, lalata sadarwar tsaka-tsaki na al'ada da microenvironment na nama. Waɗannan sauye-sauye a cikin sadarwar salula suna haifar da daidaitawar rashin aiki tsakanin kyallen takarda da gabobin jiki, ta haka ne ke haɓaka ci gaban tsufa.
Haɗin gwiwar Alamar Tsufa da Halaye
Alamomi daban-daban da halayen tsufa ba su keɓe ba amma suna da alaƙa da juna kuma suna da tasiri, tare da haɓaka tsarin tsufa. Rashin zaman lafiya na kwayoyin halitta yana haifar da lalacewar DNA, wanda hakan ke haifar da tsufa na salula da kuma gajiyar kwayar halitta. Telomere attrition kuma yana kunna amsawar lalacewar DNA, yana haifar da rashin zaman lafiyar kwayoyin halitta. Canje-canje na Epigenetic na iya yin tasiri ga maganganun kwayoyin halitta, ta haka ne ke daidaita matakai kamar su gina jiki homeostasis, tsarin gina jiki, da aikin mitochondrial. ROS da ke haifar da rashin aikin mitochondrial na iya kara lalata DNA, yana haifar da rashin zaman lafiya na kwayoyin halitta, yayin da kuma ya shafi hanyoyin siginar salula da kuma canza hanyar sadarwa ta tsakiya. Senescence na kwayar halitta da gajiyawar kwayar halitta suna lalata gyare-gyaren nama da ƙarfin sake haɓakawa, yayin da canje-canje a cikin ƙananan ƙwayoyin nama, bi da bi, suna shafar ƙwayar salula da aikin ƙwayar ƙwayar cuta.
Aikace-aikacen Alamomin tsufa da Halaye a Lafiya da Cuta
(1) Kamar yadda Biomarkers
Alamun tsufa da halaye na iya zama masu alamar halitta don tantance matakin tsufa da matsayin lafiyar mutum. Misali, ta hanyar auna tsayin telomere, tsarin DNA methylation, da alamomin aikin mitochondrial, yana yiwuwa a yi hasashen shekarun ilimin halittar mutum da kuma haɗarin haɓaka cututtukan da suka shafi shekaru zuwa ɗan lokaci. Wadannan alamomin halittu suna taimakawa a farkon gano yuwuwar al'amurran kiwon lafiya, suna ba da tushe don sarrafa lafiyar keɓaɓɓu da sa baki. A cikin rigakafin cututtuka na zuciya da jijiyoyin jini, gano alamun cututtukan da ke da alaƙa da kumburi a cikin jini yana taimakawa gano manyan mutane masu haɗari kuma yana ba da damar matakan sa baki da wuri, kamar gyare-gyaren salon rayuwa ko magungunan ƙwayoyi.
(2) Manufofin Haɓaka Magunguna
Alamomi daban-daban da halaye na tsufa suna ba da ɗimbin manufa don ci gaban ƙwayoyi. Don rashin zaman lafiyar kwayoyin halitta, ana iya samar da magungunan da ke inganta gyaran DNA; don haɓakar telomere, ana iya bincika magungunan da ke kunna telomerase ko kare telomeres; don asarar furotin homeostasis, magungunan da ke inganta aikin chaperone na kwayoyin halitta ko inganta lalata sunadaran suna iya haɓakawa, da dai sauransu. A cikin 'yan shekarun nan, bincike kan rapamycin da analogues da ke niyya da hanyar mTOR ya sami ci gaba mai mahimmanci wajen rage tsufa da kuma tsawaita rayuwa, samar da samfurin nasara don ci gaban magungunan rigakafin tsufa. Don tsufa na salon salula, magungunan haɓakawa waɗanda zasu iya share sel masu hankali ko hana SASP na iya inganta alamun cututtukan da ke da alaƙa da tsufa kuma suna jinkirta tsarin tsufa.
(3) Dabarun Sashi na Lafiya
Dangane da fahimtar alamun tsufa da halaye, ana iya ƙirƙira dabarun sa baki na lafiya daidai. Dangane da shiga tsakani na abinci, ƙuntatawar calorie da abinci na Bahar Rum na iya tsara hanyoyin fahimtar abinci mai gina jiki, inganta yanayin rayuwa, da jinkirta tsufa. Harkokin motsa jiki na iya haɓaka aikin mitochondrial, inganta haɓakar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar kuma ta inganta haɓakar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar kuma ta inganta haɓakar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar cuta, duk waɗannan suna da tasiri mai kyau akan jinkirta tsufa. Yin amfani da antioxidants na iya rage yawan damuwa na oxidative, kare kwayoyin halitta daga lalacewar ROS, da kuma kula da aikin salula na al'ada. Wadannan ingantattun dabarun shiga tsakani na kiwon lafiya suna taimakawa rage saurin tsufa da inganta rayuwar tsofaffi.
Kammalawa
Alamomi da halaye na tsufa sun ƙunshi ɗimbin canje-canje daga kwayoyin halitta zuwa salon salula da matakan nama / gabobin jiki, waɗanda ke da alaƙa da juna kuma suna tasiri ga juna, tare da samar da hadaddun hanyoyin nazarin halittu na tsufa. Fahimtar waɗannan alamomi da halaye suna ba da tushe na ka'idar don rigakafi, ganewar asali, da kuma kula da cututtuka masu alaka da tsufa.
Sources
[1] Pintea A, Manea A, Pintea C, et al. Peptides: 'Yan takara masu tasowa don Rigakafin da Maganin Skin Senescence: Bita[J]. Biomolecules, 2025,15 (1}, LABARI-LAMBA = {88).DOI:10.3390/biom15010088.
[2] Yıldız C, Ozilgen M. Dalilin da yasa ayyukan kwakwalwa na iya lalacewa tare da tsufa: Ƙimar thermodynamic[J]. Jarida ta Duniya na Exergy, 2021.
[3] Joseph AW, Jeevitha Shree DV, Saluja KPS, et al. Binciken Ido don Fahimtar Tasirin Tsufa akan Aikace-aikacen Wayar hannu[C]//, Singapore, 2021. Springer Singapore, 2021-01-01.DOI: 10.1007/978-981-16-0041-8_27.
[4] Joseph AW, Dv J, Saluja KS, et al. Binciken Ido don fahimtar Tasirin Tsufa akan Aikace-aikacen Wayar hannu[J]. Arxiv, 2021, abs/2101.00792. https://api.semanticscholar.org/CorpusID:230435965
[5] Wiesman AI, Rezich MT, O'Neill J, et al. Alamun Epigenetic na Tsufa Suna Hasashen Juyin Juya Halin da ke Hidimar Zaɓar Hankali[J]. Cerebral Cortex, 2020,30(3):1234-1243.DOI:10.1093/cercor/bhz162.
[6] Marron M M. Rashin ƙarfi da ikon tafiya azaman hadedde alamomin tsufa da sa hannunsu na metabolomic, 2019[C]. https://api.semanticcholar.org/CorpusID:202009741
[7] Wang Y, Huang T, Sha X, et al. Samfurin haɗin kai yana bayyana tsarin tsarin tsufa [J]. Ka'idar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittar Halittu & Likitan Modelling), 2018,17.
[8] Juhász D, Németh D. [Canje-canjen ayyukan fahimi a cikin tsufa mai kyau] [J]. Ideggyogyaszati Szemle-Clinical Neuroscience, 2018,71(3-04):105-112.DOI:10.18071/isz.71.0105.
