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onsdag 15 oktober 2025

Käärmeenmyrkyissä piilee syövänvastaisia ominaisuuksia

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  • Molecular Biomarkers for Cancer Diagnosis and Therapy


    • Nur Zawanah Zabidi,
    Nurhamimah Misuan,
    Isra Ahmad Farouk,
    Sunil Kumar Lal &
    Michelle Khai Khun Yap 
    Abstract
    Cancer is a life debilitating fatal disease that affects millions of lives annually across the world. The current cancer treatments include invasive surgical procedures or the use of non-selective cytotoxic drugs to inhibit tumour growth and metastasis. Snake venom proteins exhibit highly selective cytotoxicity to tumour cells, thus are excellent candidates for anti-cancer therapeutics. In this chapter, we discuss snake venom proteins that have been discovered to have anti-cancer properties alongside the biodiversity of venom and medically important snakes from Elapidae and Viperidae families. Snake venoms three-finger toxins, lectins, metalloproteinases, serine proteinases, disintegrins, l-amino acid oxidases and phospholipases A2 are venom proteins described prominently for anti-cancer properties. In addition, mechanistic actions of anti-cancer activities such as apoptosis, anti-angiogenesis and necroptosis have also been elaborated. In addition, drug delivery formulations for these proteins are also discussed, including the uses of liposomes, gold nanoparticles, mesoporous silica nanoparticles and recombinant adenovirus. Lastly, we discuss commercially available anti-cancer drugs, such as Captopril and Enalapril, along with other clinically developed drugs. Overall, we aim to provide a chapter that enhances understanding of the therapeutic application of snake venom proteins for anti-cancer.
     
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    Myrkkykäärmeet käärmeiden taxonomiassa

    Animals, Poisonous and Venomous

    https://doi.org/10.1016/B978-0-12-386454-3.00984-2

    Snakes

    Introduction

    There are approximately 3000 types of snakes that exist around the world, with an estimated 600 types that are venomous. Reports from databases of the World Health Organization estimate a range of 20 000–94 000 deaths occurring, annually, from snakebites. Snakes exist on every continent, with the exception of Antarctica.

    Toxicity

    Snakes are classified in the phylum Chordata, subphylum Vertebrata, class Reptilia, order Squamata, suborder Serpentes. There are 14 families, but Colubridae, Elapidae, Hydrophidae, Viperidae, Crotalinae, and Viperinae are the families and subfamilies of poisonous snakes (see Fig. 3). The dose and exposure to venom vary due to the complexity of multiple components, the amount injected, and the type of snakebite. Approximately 20–25% all pit viper bites and 50% of Coral Snake bites are dry bites. “Dry bites” result when venom is prematurely discharged from the fangs before they puncture the skin, (UF Wildlife, 2020). When envenomations occur in humans, effects vary from cytotoxic, neurotoxic, and hemotoxic events, which are dependent on species, seasonal, and geographic factors (Resiere et al., 2022).

    Viperinae are the families and subfamilies of poisonous snakes (see Figure 3).

     COLUBRIDAE  https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/colubridae 

    ELAPIDAE  https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/elapidae

    HYDROPHIDAE 

    HYDROPHIINAE  https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/hydrophiinae

    VIPRIDAE https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/viperidae

     

    Colubridae

    The Colubridae family is the largest snake family. It contains approximately 2000 species. Many colubrids are technically considered venomous but very few are considered dangerous to humans. Human deaths have been attributed to the boomslang (Dispholidus typus), keel snake (Rhabdophis spp.), and twig snakes (Thelotornis spp.). Medically important colubrids possess rear fangs, which are not as developed as elapid or viper fangs. In order to inject significant amounts of venom they frequently have to ‘chew’ on their victims. The venom of colubrids has not been studied as extensively as elapids and vipers and relatively little is known about it. Surprisingly, some of the same toxins found in elapid venom have been isolated from certain colubrids. However, clinical experience with colubrid envenomation is more consistent with a hemotoxic venom, similar to vipers, which can cause significant coagulopathy. Like other snakebites, the care of colubrid envenomations begins with supportive care measures. Considering the reports of coagulopathy after envenomation from boomslang and keel snakes, laboratory parameters should be closely followed. Though antivenom therapy is again the definite treatment, few colubrid antivenoms are commercially produced. An equine-derived boomslang antivenom and goat-derived Rhabdophis tigrinus antivenom are available. There is currently no Thelotornis spp. antivenom in production.

     

    Elapids

    The family Elapidae includes cobras, mambas, and sea snakes (see Marine Envenomations). In North America, the family is represented by the coral snake Micrurus spp. (Color Plate 8-14). The venom of many members of the elapid family is predominantly neurotoxic. The bite of an elapid such as a coral snake can produce local pain (but usually not swelling), headache, nausea, paresthesias, cranial nerve involvement, altered mental status, and respiratory failure. As with pit viper bites, medical care should be sought immediately. Treatment involves administration of a Micrurus-specific antivenin as soon as possible. Some evidence suggests that pressure and immobilization of the wound area until antivenin can be administered is beneficial for the outcome of elapid bites. This treatment method is shown in Figure 8-33.

    Coral snake bites also cause significant morbidity and mortality in cats and dogs. As with human beings, neurotoxic effects predominate and treatment is based on the use of antivenin.10

     

    Hydrophiids = family HYDROPHIIDAE

    The hydrophiids or sea snakes are widely distributed throughout equatorial and tropical regions of the Indian and Pacific oceans, from the coast of Africa to America. There is some evidence that they have navigated the Panama canal and are colonising the Caribbean (Warrell, personal communication). They are closely related to the Elapids, having a similar venom and fang apparatus. Medically important genera include Enhydrina, Hydrophis, Pelamis, and Laticauda.

    Viperids = family VIPERIDAE

    Viperids are amongst the best known and probably medically most important venomous snakes. They are divided into two subfamilies, Viperinae and Crotalinae. The latter encompasses all the pit vipers, so called because they have highly developed paired heat-sensing organs on the anterior part of the head in pits. These allow them to more effectively locate and strike warm blooded preys at night. All vipers have a very well-developed anteriorly placed proteroglyphous fang structure. The fangs are on a modified maxilla which is capable of considerable rotation, allowing the fang to be folded against the roof of the mouth when not in use. This has enabled development of larger fangs than in other venomous snakes of equivalent size and in some vipers fang length may exceed 2 cm. 

    The subfamily Viperinae is found in Africa, Asia and Europe. Medically important Genera include Vipera, Bitis, Echis, Cerastes, Causus.

      The subfamily Crotalinae is found in Asia and the Americas. Medically important Genera include Crotalus, Trimeresurus, Agkistrodon, Sistrurus, Calloselasma, Bothrops, Bothriechis, Bothriopsis, Lachesis, Porthidium. There are no vipers naturally occurring in Australia or New Guinea.

    Crotalids

    Three genera of crotalids are Crotalus (Rattlesnake), Sistrurus (Massasauguas or pigmy rattlesnakes), and Agkistrodon (Copperhead and Cottonmouth). Crotalids (‘Pit Vipers’) have triangular heads, elliptical pupils, a single row of subcaudal scales behind the anal plate, and facial pits which serve as heat sensors. Crotalids have hinged front fangs ∼2 cm in length, which are curved and hollowed. Rattlesnakes usually have a rattle – keratin scales at the end of the tail that produce a rattling sound when rubbed together. Venom glands are located posterior to the eyes and connected to fangs by venom ducts. Identifiable characteristics of copperheads are the rust-colored heads, and a white buccal cavity is noteworthy of cottonmouths or ‘water moccasins’.

    Envenomation from a crotalid bite leaves one or more puncture wounds with a potential for progressive edema and ecchymosis. Crotalid venom contains a mixture of proteins, lipids, and metals. The venom forms fibrin polymers, which are susceptible to normal fibrinolysis and phagocytosis. It is represented by falling fibrinogen levels. Copperhead venom has a weak effect on this series of events in coagulation, resulting in lower morbidity after envenomation.

    Initial pain at the site of the bite may be followed with a ‘metallic sensation’ in the mouth. Victims may become weak, and experience nausea, diarrhea, diaphoresis, and chills. Edema may begin around the bite area or may be delayed. Observation of the site for edema is a clue as to whether or not a ‘dry bite’ has occurred; that is, that no venom was injected into the site. Envenomation is most serious if venom is injected directly into joints, muscles, or veins. Hemorrhagic blisters and tissue destruction are possible. Neurotoxicity from rattlesnakes (but generally not from cottonmouths or copperheads) may be manifested as fasciculations, which are fine continuous contractions. In some cases, systemic neurotoxicity may involve respiratory failure. In the most serious cases, massive envenomation may lead to serious bleeding, hypotension, shock, multiple organ failure, and a high incidence of mortality.

    Despite popular belief, crotalid envenomation does not generally result in life-threatening symptoms. Maintaining a patent airway, intravenous access, clinical observation of edema and the bite area, adequate laboratory work, and the use of antivenin when necessary are the essentials of treatment in snakebite envenomation. Antivenin should only be used in moderate to severe envenomations, usually within 8 h postenvenomation. This is an equine-derived product and thus skin testing for sensitivity is usually performed after the decision that antivenin is necessary has been made. Serum sickness may occur from the antivenin. Hospital monitoring, wound care, and patient follow-up are important for the recovery of these patients.

     

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    Käärmeen myrkyissä on matrixmetalloproteinaaseja osatekijänä, JPost käärmeluettelo maailman käärmeistä . Pubmed haku "Snake poison"

    Löysin  valtavan hyvän kuvasarjan ja selityksiä maailman  vaarallisimmista käärmeistä JPostin sivuilta. Yhden niistä näin vuonna 1967 meidän kibbutsiparakkimme oven lähistöllä, mutta joku oli jo  tappanut sen.  En ollut koskaan nähnyt niin vaaleaa ja jokseenkin kookasta käärmettä. Suomen käärmeet eivät ole niin vaaleit ja isohkoja.  Selaan esiin sen nimen tähän uudestaan: 

     https://www.cleverst.com/worldwide/slithers-cp-ob/38?utm_content=00ae4d84163b0e0e55dc8e9906ac13a173&utm_source=outbrainjk&utm_campaign=cl-slithers-l-sv01-all-0w-rl-20065d&utm_term=Jpost&utm_medium=00f4dac2ae0c272820894de89c581036b0&ap={timestamp}&utm_bid=0.009&utm_l=1&utm_t=scroll&dicbo=v4-p7owy6o-1081424984-0

    sain nimiluettelosta ainakin 58 merkattua muistiin MMPvihkooni. 15.10.2025  

     

    Liitän linkin  Wikipediasta käärmeen myrkistä ja toxiineista: https://en.wikipedia.org/wiki/Snake_venom

     

    Pub Med haku Snake poison ,  viimeisimmät 10  artikkelia sitaattina. 

    9,491 results

    Socioeconomic and ecological drivers of snakebite incidence in Mexico: A spatial analysis of risk factors.
    Rangel-Camacho R, Yáñez-Arenas C, Chippaux JP, Martín G. PLoS Negl Trop Dis. 2025 Oct 10;19(10):e0013582. doi: 10.1371/journal.pntd.0013582. eCollection 2025 Oct. PMID: 41071848 Free PMC article.
    Our methodological approach integrated three critical components: environmental suitability indices for venomous snake species derived from refined species distribution models, socioeconomic vulnerability metrics, and healthcare accessibility parameters. ...CONCLUSIONS: Ou …
    Phytochemical Profiling of Silver Cockscomb (Celosia argentea L.) using Spectroscopic Techniques and Antioxidant Activity Determination.
    Sharma P, Saini S, Hasanpuri P, Kataria N, Sharma A. Chem Biodivers. 2025 Sep 22:e01029. doi: 10.1002/cbdv.202501029. Online ahead of print. PMID: 40982607
    Celosia argentea (Amaranthaceae) is a medicinal plant traditionally used to treat various disorders, such as urinary disorders, jaundice, diabetes, fever, antidote for snake poison, mouth sores, and eyesight improvement. Based on its ethnomedicinal significance, the …
    Digital Health Intervention in Snakebite Management: Scoping Review.
    Dash A, Kerketta S, Mallick G, Menon J, Kanungo S, Pati S. J Med Internet Res. 2025 Sep 17;27:e71378. doi: 10.2196/71378. PMID: 40961360 Free PMC article.
    Data extraction focused on app features (snake identification, first aid protocols), accessibility (operating system compatibility, cost), multilingual support, and user feedback. ...All 16 apps provided first aid protocols, with most including snake identification …
    Comparative analysis of hemotoxic, myotoxic, and inflammatory profiles of Calloselasma rhodostoma and Trimeresurus insularis venoms in mice.
    Aphrodita A, Sentono DN, Yudha DS, Purwestri YA, Nuringtyas TR, Raharjo S, Wahid I, Rahmi SN, Wahyudi ST, Sofyantoro F. Narra J. 2025 Aug;5(2):e1874. doi: 10.52225/narra.v5i2.1874. Epub 2025 Apr 21. PMID: 40951459 Free PMC article.
    Snakebite envenomation remains a significant medical concern, particularly in tropical regions where venomous snakes such as Calloselasma rhodostoma and Trimeresurus insularis are prevalent. Both venoms are known for their potent hemotoxic, myotoxic, and inflammatory effec …
    Guillain-Barre Syndrome Secondary to Snake Bite: A Report of a Rare and Fatal Case.
    Dhamelia PM, Mokariya DR, Anand JS, Futela P, Murawska Baptista A, Singla A. Am J Case Rep. 2025 Sep 13;26:e948917. doi: 10.12659/AJCR.948917. PMID: 40944946 Free PMC article.
    He had been recently hospitalized a few weeks ago for snake-bite-associated neuroparalysis that had gradually resolved without any complications before discharge. .
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    torsdag 31 juli 2025

    ADAM12 proteiinin ja HIF-tekijöiden osuus rintasyövässä

     https://www.pnas.org/doi/full/10.1073/pnas.2020490118

    Hypoxia-inducible factor-dependent ADAM12 expression mediates breast cancer invasion and metastasis

    Ru Wang https://orcid.org/0000-0002-2768-1753, Ines Godet https://orcid.org/0000-0002-4889-5144, Yongkang Yang, +9 , and Gregg L. Semenza gsemenza@jhmi.eduAuthors Info & Affiliations
    Contributed by Gregg L. Semenza, April 1, 2021 (sent for review October 5, 2020; reviewed by Adrian Harris and Jonathan Sleeman)
    May 5, 2021
    118 (19) e2020490118
    https://doi.org/10.1073/pnas.2020490118

     Tässä voisi huomauttaa , että rintasyöpäpotilaille kuten muilekin on liikunnasta hyötyä kudoshappitilanteen pitämsieksi  normaalina. 

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    måndag 28 juli 2025

    Olennainen uusi tieto ADAM-perheenjäsenistä terapioiden kannalta . (A Disintegrin And Metalloproteinase = ADAM)

     https://pubmed.ncbi.nlm.nih.gov/?term=ADAM-members&sort=date

    10 results

    ADAMs contribute to triple negative breast cancer via mTORC1 pathway: targeting ADAM-mTOR axis improves efficacy.
    Liu S, Chen H, Gagea M, Federico L, Zhang F, Gomez J, Do KA, Symmans WF, Hortobagyi GN, Mills GB, Gonzalez-Angulo AM, Tripathy D. Cancer Lett. 2025 Aug 28;626:217775. doi: 10.1016/j.canlet.2025.217775. Epub 2025 May 6. PMID: 40339955 Free article.
    The A Disintegrin and Metalloproteinase (ADAM) family plays a vital role in cancer pathophysiology. Previous studies focused on single ADAM members. However, none of these have entered into the clinical arena as diagnostics or therapeutics for breast cancer. In this …
    Prior authorizations in dermatology and impact on patient care: An updated survey of US dermatology providers and staff by the American Academy of Dermatology.
    Petitt CE, Kiracofe E, Adamson A, Barbieri JS. Dermatol Online J. 2021 Jan 15;27(1):13030/qt990631n9. PMID: 33560787 Free article.
    -based dermatologists (N=3,000) and the Association of Dermatology Administrators/Managers (ADAM) members (N=718). RESULTS: Respondents reported 24% of patients require PAs. Dermatologists and staff spend a mean of 3.3 hours/day on PAs. ...
    Molecular design and structural optimization of potent peptide hydroxamate inhibitors to selectively target human ADAM metallopeptidase domain 17.
    Wang Z, Wang L, Fan R, Zhou J, Zhong J. Comput Biol Chem. 2016 Apr;61:15-22. doi: 10.1016/j.compbiolchem.2015.12.003. Epub 2015 Dec 8. PMID: 26709988
    The ADAM metallopeptidase domain 17 (ADAM17 or TACE) and its close relative ADAM10 are two of the most important ADAM members that share high conservation in sequence, structure and function, but exhibit subtle difference in regulation of downstream cell signaling e …
    Retinoids induce integrin-independent lymphocyte adhesion through RAR-α nuclear receptor activity.
    Whelan JT, Wang L, Chen J, Metts ME, Nasser TA, McGoldrick LJ, Bridges LC. Biochem Biophys Res Commun. 2014 Nov 28;454(4):537-42. doi: 10.1016/j.bbrc.2014.10.120. Epub 2014 Oct 31. PMID: 25450689
    Interestingly, adhesion occurs independent of integrin function, and mutant studies demonstrate that atRA-induced adhesion to ADAM members required a distinct binding interface(s) as compared to integrin recognition. ...
    Structure of human ADAM-8 catalytic domain complexed with batimastat.
    Hall T, Shieh HS, Day JE, Caspers N, Chrencik JE, Williams JM, Pegg LE, Pauley AM, Moon AF, Krahn JM, Fischer DH, Kiefer JR, Tomasselli AG, Zack MD. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012 Jun 1;68(Pt 6):616-21. doi: 10.1107/S1744309112015618. Epub 2012 May 22. PMID: 22684055 Free PMC article.
    ADAM-8 has an overall fold similar to those of other ADAM members, including a central five-stranded beta-sheet and a catalytic Zn(2+) ion. ...
    TGFβ induces proHB-EGF shedding and EGFR transactivation through ADAM activation in gastric cancer cells.
    Ebi M, Kataoka H, Shimura T, Kubota E, Hirata Y, Mizushima T, Mizoshita T, Tanaka M, Mabuchi M, Tsukamoto H, Tanida S, Kamiya T, Higashiyama S, Joh T. Biochem Biophys Res Commun. 2010 Nov 19;402(3):449-54. doi: 10.1016/j.bbrc.2010.09.130. Epub 2010 Oct 8. PMID: 20934403
    Membrane-anchored heparin-binding EGF-like growth factor (proHB-EGF) ectodomain is cleaved by a disintegrin and metalloproteinase (ADAM) members and is implicated in epidermal growth factor receptor (EGFR) transactivation. ...
    ADAM gene expression and regulation during human osteoclast formation.
    Verrier S, Hogan A, McKie N, Horton M. Bone. 2004 Jul;35(1):34-46. doi: 10.1016/j.bone.2003.12.029. PMID: 15207739
    In this study, we identified the expression and the regulation of ADAM members (a disintegrin and metalloprotease) at both gene and protein levels during human osteoclast differentiation and activity. ...
    ADAMs, a disintegrin and metalloproteinases, mediate shedding of oxytocinase.
    Ito N, Nomura S, Iwase A, Ito T, Kikkawa F, Tsujimoto M, Ishiura S, Mizutani S. Biochem Biophys Res Commun. 2004 Feb 20;314(4):1008-13. doi: 10.1016/j.bbrc.2003.12.183. PMID: 14751233
    Immunohistochemical analysis in human placenta demonstrated strong expression of ADAM12 in syncytiotrophoblasts, while little expression of ADAM9 was detected throughout the placenta. Our results suggest ADAM members, at least including ADAM12, are involved in P-LAP …
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    MMP perheestä on runsaasti artikkelia , myös uuden pandemiauhkaviruksenkin suhteen.

     

    50,794 results

    Emerging highly pathogenic H5N1 influenza triggers fibrotic remodeling in human airway organoids.
    Rothan H, Mostafa A, Bayoumi M, Ye C, Barre RS, Allué-Guardia A, Nogales A, Torrelles JB, Martinez-Sobrido L. Emerg Microbes Infect. 2025 Dec;14(1):2532684. doi: 10.1080/22221751.2025.2532684. Epub 2025 Jul 25. PMID: 40712003
    In this study, we modelled infection with a highly pathogenic recombinant human A/Texas/37/2024 H5N1 (rHPh-TX H5N1) strain using human airway organoids (HAO) to investigate viral replication, innate immune response, infection-induced fibrogenesis, and potential ther …
    Morphological and Molecular Evaluation of a Gel Based on Hyaluronic Acid and Spermidine for Oral Regenerative Purposes.
    Henin D, Canciani E, Carmagnola D, Ferrero S, Pellegrini G, Perrotta M, Sirello R, Dellavia C, Gagliano N. Cells. 2025 Jul 9;14(14):1047. doi: 10.3390/cells14141047. PMID: 40710300
    BACKGROUND: Oral wound healing is a complex process influenced by extracellular matrix (ECM) remodeling and cellular migration. Hyaluronic acid (HA) and spermidine (SP) have shown regenerative potential, but their combined effects on oral tissues remain unexplored. ...METH …
    D-Limonene Exhibits Antiproliferative Activity Against Human Colorectal Adenocarcinoma (Caco-2) Cells via Regulation of Inflammatory and Apoptotic Pathways.
    Alghamdi AAA. Curr Issues Mol Biol. 2025 May 18;47(5):370. doi: 10.3390/cimb47050370. PMID: 40699769 Free article.
    This study investigated the antiproliferative potential of D-limonene, a natural compound, on human colorectal adenocarcinoma (Caco-2) cells and analyzed its underlying mechanisms. ...Furthermore, in a concentration-dependent way, D-limonene therapy decreased the levels of …
    The role of matrix metalloproteinases in the modulation of aqueous humor in glaucoma patients.
    Teodor C, Ramona BI, Ovidiu B, Casiana SM, Laurenţiu L, Daciana DŞ, Andrei C, Diana BA. Rom J Ophthalmol. 2025 Apr-Jun;69(2):208-211. doi: 10.22336/rjo.2025.33. PMID: 40698094 Free PMC article. Review.
    Matrix metalloproteinases are crucial proteolytic enzymes involved in the degradation and remodeling of the extracellular matrix within the ocular structures. ...This review summarizes current findings on the role of matrix metalloproteinases in …
    Bisphenol A suppresses colon epithelial cell responses via G0/G1-phase arrest, MAPK and PI3K/AKT pathway modulation, and MMP-2/9 Inhibition by upregulating p21WAF1.
    Song JH, Lee D, Hwang B, Kim S, Kim J, Park S, Choo S, Hwang SK, Kim H, Yun SJ, Choi YH, Kim WJ, Moon SK. Sci Rep. 2025 Jul 23;15(1):26698. doi: 10.1038/s41598-025-11700-9. PMID: 40695970 Free article.
    We explored the adverse effects of BPA on human colonic epithelial cells in vitro by performing comprehensive viability, proliferation, invasion, and migration assays on HCT 116 and HCT-8 cells. ...Furthermore, BPA treatment significantly reduced the induction of matrix …
    NFIC suppressed the epithelial ovarian cancer via modulating the balance of PTEN/TGFbeta1/EGR1/BRD4 and SP1/EZH2 induced Inhibition of TBX2/MMPs signaling.
    Ren Y, Xu R, Zhang D, Su L, Jin Y, Li N, Wang Y. Sci Rep. 2025 Jul 22;15(1):26593. doi: 10.1038/s41598-025-09653-0. PMID: 40695900 Free article.
    Additionally, TBX2 inhibits PTEN and promotes MMPs. BRD4 promotes H3K27AC, which leads to TGFbeta1 expression, while H3K27me3 inhibits TGFbeta1 expression. ...In vitro, NFIC inhibited the expression of TBX2, nucleus SP1, EZH2, and MMPs, and promoted the expression o …
    Basement membrane perforations guide anterior-posterior axis formation.
    Chen DY, Claussen NH, Titus S, Hu W, Weatherbee BAT, Mandelbaum RS, Scott RT Jr, Seli E, Streichan SJ, Zernicka-Goetz M. Nat Commun. 2025 Jul 22;16(1):6763. doi: 10.1038/s41467-025-61441-6. PMID: 40695803 Free article.
    Here, we use targeted perturbations to demonstrate that asymmetric perforations in the basement membrane guide DVE migration. During implantation, matrix metalloproteinases in extra-embryonic tissues create uneven basement membrane perforations, establishing directi …
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