152 results about "Pancreatic islets" patented technology

Disclosed herein are compositions and methods related to differentiation of stem cells into pancreatic islet cells. In some embodiments, the methods provided herein relate to generation of pancreatic β cell, α cell, δ cells, and EC cells in vitro. In some embodiments, the disclosure provides pharmaceutical compositions including the cells generated according to the methods disclosed herein, as well as methods of treatment making use thereof.

The invention relates to the technical field of biological pharmacy, in particular to application of a recombinant protein DEL-1 in preparation of a medicine for resisting pancreatic beta cell inflammation. The recombinant protein DEL-1 has a remarkable inhibition effect on pancreatic beta cell inflammatory response induced by high glucose and high fat. Experiments show that in an islet beta cell inflammation model constructed by combining high glucose with palmitic acid, DEL-1 can significantly reduce the expression level of inflammatory factors such as IL-1beta, IL-6, TNF-alpha and the like. The DEL-1 is proved to have a definite effect of resisting pancreatic beta cell inflammation.

The invention discloses a composite combined preparation for synergistically treating and conditioning diabetes, relates to the technical field of foods, health foods or dietary supplements for adjuvant therapy and health care of diabetes, and in particular relates to a composite combined preparation for synergistically treating and conditioning diabetes. The preparation comprises albumin peptide, saussurea involucrata culture, vitamin B1, vitamin B2, wheat oligopeptide, corn oligopeptide, collagen peptide, mulberry leaf extract, rhizoma polygonati extract, sea-buckthorn extract, isomaltitol, maltodextrin, ginseng extract and bitter gourd extract. Through the synergistic effect of all the components, comprehensive auxiliary conditioning on diabetes is realized from multiple targets of maintaining colloid osmotic pressure and nutrition, regulating glycolipid metabolism in multiple ways, protecting pancreatic beta cell functions, enhancing insulin sensitivity, preventing nerve and blood vessel complications, meeting special diet requirements and the like. The composition can be prepared into food, health-care food or dietary supplement and other dosage forms.

The invention relates to an islet repair ICK mode oral polypeptide optimization system taking VDAC1 as a target based on ESM2 and a genetic algorithm, and the system comprises a mutation module which is used for carrying out mutation and recombination by adopting the genetic algorithm according to original protein sequence data to generate an initial population; the prediction module is used for respectively inputting the protein sequence data of the initial population into a protein dimer dissociation energy prediction model, a protein toxicity prediction model and a protein cell penetrability prediction model to obtain a dissociation energy prediction value delta G, a toxicity probability value T and a cell membrane passing transmission probability Ed; and the optimization module is used for acquiring the optimal individual performance of the highest fitness score to output the Pareto optimal sequence index, and recording the hotspot residue distribution and the site mutation frequency at the same time. On the basis of keeping the biological activity of the original sequence, the key drug properties are improved in a breakthrough manner.

The present application relates to a kind of pharmaceutical composition for treating type 2 diabetes and its application.The pharmaceutical composition includes icariin, hydroxymethyl coumarin and cinnamaldehyde, by three-component synergistic effect, simultaneously act on insulin resistance, pancreatic beta cell apoptosis and systemic metabolic inflammation three type 2 diabetes core pathological links, auxiliary reduce serum lipid level, and reduce drug-related liver injury risk, good safety.Animal experiment results show that three-drug combination group can effectively reduce blood sugar (decrease about 50%), significantly improve islet structure atrophy, restore hepatocyte index arrangement, reduce glomerular hypertrophy, significantly reduce serum TG and CHOL level (P<0.05) and inflammatory factor IL-6 and TNF-alpha level (P<0.05), and avoid the hepatotoxicity risk (ALT / AST restores to close to normal level) of hydroxymethyl coumarin.The present application is composed of three kinds of natural monomers with clear structure, and has clear components and controllable quality, which provides a more optimal comprehensive treatment strategy for the treatment of type 2 diabetes and its complications.

The present disclosure relates to a method of generating pancreatic lineage cells, e.g. islet-like cell aggregates comprising pancreatic beta cells, comprising the steps of providing a single cell suspension of a population of endocrine progenitor cells (EP), allowing the EP cells in the single cell suspension to form 3D structures, and culturing the cells under conditions allowing differentiation into pancreatic mono-hormonal beta cells. The present disclosure also relates to islet-like cell aggregates obtainable by said method and their medical use.

The invention discloses nutrition-balanced flour assisting in pancreas islet repair as well as a preparation method and application of the nutrition-balanced flour. The nutrition-balanced flour is prepared from the following raw materials in parts by mass: 40-60 parts of whole grains, 10-15 parts of beans, 5-15 parts of vital gluten, 7-10 parts of potatoes, 7-10 parts of vegetables, 5-8 parts of bacteria and algae, 5-8 parts of nut seeds, 3-5 parts of medicinal and edible food and 3-5 parts of beer yeast. The invention provides more comprehensive nutrition powder containing whole grains, beans, potatoes, nuts and the like, and further comprises common food with the effect of reducing blood sugar and medicinal and edible food which has the effect of reducing blood sugar and can prevent diabetic complications, and the nutrition flour has the following functions: balanced nutrition is provided for the body; blood sugar reduction is assisted; the islet cells are assisted to repair; and diabetic complications are prevented. The invention relates to an application of nutrition-balanced flour assisting in pancreas islet repair. The flour is used for making steamed buns, dumplings, steamed stuffed buns, wontons, noodles, cakes, biscuits or other flour products.

The present disclosure provides methods of amplifying tissue samples derived from humans for purposes of treating certain diseases. The method comprises: isolating a small amount of associated tissue by biopsy or other tissue acquisition methods; the tissue is amplified in vitro, and meanwhile, natural functions are reserved; and re-implanting the amplified tissue to alleviate human disease. One example includes ex vivo expansion of human pancreatic islet tissue and reimplantation of the expanded cells into an individual with Type 1 diabetes for treatment and long term relief or cure of disease.

This invention discloses a traditional Chinese medicine composition for reversing type 2 diabetes and its preparation method, belonging to the field of traditional Chinese medicine technology. It comprises the following raw materials in parts by weight: Astragalus membranaceus 25-35 parts, Rehmannia glutinosa 20-30 parts, Trichosanthes kirilowii 15-25 parts, Anemarrhena asphodeloides 10-20 parts, Coptis chinensis 8-15 parts, Salvia miltiorrhiza 15-25 parts, Ligusticum chuanxiong 8-15 parts, Paeonia lactiflora 10-20 parts, Pueraria lobata 20-30 parts, Atractylodes lancea 10-20 parts, Poria cocos 15-25 parts, Alisma plantago-aquatica 10-20 parts, Ophiopogon japonicus 15-25 parts, Schisandra chinensis 5-15 parts, and Glycyrrhiza uralensis 3-10 parts. This invention strictly follows the principles of traditional Chinese medicine's principal, assistant, adjuvant, and guide herb combination, comprehensively addressing the four methods of invigorating qi and nourishing yin, clearing heat, resolving blood stasis, and eliminating turbidity. It regulates the body's metabolism from the root cause, significantly controlling blood sugar and improving insulin resistance, while also protecting pancreatic function, thus solving the problems of single herb combinations and limited efficacy in traditional Chinese medicine.

The application provides an islet-vascular co-culture system based on a microfluidic chip, a building method and application, and the building method of the islet-vascular co-culture system comprises the following steps: S1, preparing microfibers loaded with islets; S2, preparing an assembled chip, the assembled chip comprises a containing cavity, first microchannel networks and second microchannel networks are symmetrically arranged on two sides of the containing cavity, and the first microchannel networks and the second microchannel networks are respectively communicated with a liquid inlet and a liquid outlet at an end away from the containing cavity; S3, controlling the flow of the liquid inlet to be 6-8 muL / min to carry out dynamic culture. The application can simulate the key structure and characteristics of islet tissue, can evaluate a diabetes treatment drug in vitro, can bridge the gap between in vitro and in vivo models, and can provide new tools and methods for the fields of drug development, disease model construction and personalized medical treatment.

The invention provides a core-shell structure microgel system. The core-shell structure microgel system comprises a core and a shell coating the core, the core is composed of a composite hydrogel of methacrylated gelatin and methacrylated chitosan; the shell is formed by double crosslinking of polyethylene glycol diacrylate and alginate. The core serves as a functional core, provides a highly simulated natural extracellular matrix and maintains pancreas islet activity, and the shell serves as a barrier to protect the core, regulate material exchange and provide mechanical support. The core-shell structure microgel system allows diffusion of glucose, oxygen and insulin and blocks immune globulin, cell factors and immune cells, so that fibrosis wrapping is reduced to the greatest extent.

The application relates to a construction method of a Mettl3 transgenic mouse model with specific knockout, enriches the understanding of the function and action mechanism of Mettl3 in mature pancreatic islet beta cells, and provides a new thought and target for the pathogenesis and treatment of diabetes.

The invention belongs to the field of new application of medicines, and particularly relates to application of triptolide in preparation of medicines for treating diabetic vascular obstruction complications. Diabetes vascular obstruction is a common serious complication of diabetes and can cause various tissue injuries such as cardiovascular diseases, nephropathy and retinopathy. Experiments prove that the triptolide can remarkably improve the problems of blood vessel blockage, blood flow slowing, abnormal neovascularization and the like caused in a high-glucose environment, and meanwhile, the expression of blood glucose related indexes (such as Glucose and HbA1c) and inflammatory factors (such as TNF-alpha and IL-1beta) is reduced. In addition, triptolide can also protect pancreas from high glucose damage and improve functions of pancreatic beta cells. According to the invention, the clinical application range of the triptolide is expanded, and a new candidate substance is provided for drug treatment of diabetic vascular complications.

The invention relates to a preparation method and application of ganoderma lucidum and coix seed mycoplasm, and belongs to the technical field of traditional Chinese medicine and health food processing. According to the preparation method of the lucid ganoderma and coix seed mycoplasm, the lucid ganoderma and coix seed mycoplasm is obtained through liquid fermentation by taking coix seeds as a fermentation substrate and lucid ganoderma as a fermentation strain. The ganoderma lucidum and coix seed mycoplasm composition is obtained through a ganoderma lucidum and coix seed two-way fermentation technology, functional ingredients are increased, and the ganoderma lucidum and coix seed mycoplasm composition has the effects of enhancing immunity, protecting pancreas islet beta cells and improving glycolipid metabolism. The invention develops the application of the traditional Chinese medicine composition in the fields of food and health care products.

This invention relates to the regulation of pancreatic islet cell differentiation by regulatory factors related to N6-adenosine methylation modification of mRNA. Specifically, it relates to the use of (a) the ALKBH5 gene, or its protein, or its promoter; and / or (b) the YTHDF2 gene, or its protein, or its inhibitor, for the preparation of compositions or formulations for (1) promoting the differentiation of endodermal cells into pancreatic islet precursor cells and / or islet organoids; and / or (2) preventing and / or treating diabetes. The ALKBH5 of this invention regulates the N6-adenosine methylation modification of mRNA by... 6 Modification A controls the in vitro differentiation process of human pancreatic cells. Furthermore, the method of this invention holds promise as an effective method for in vitro culture of pancreatic islet cells, and could subsequently be applied to the treatment of diabetes.

The invention relates to a device for distributing and receiving a population of pancreatic islets heterogeneous in size, the device comprising a matrix having a first face opposite a second face, characterized in that the matrix comprises concentric channels centered on a center O, the channels have an opening for receiving the pancreatic cells, the opening leading out onto the first face, the opening extending over the entire length (L) of the channel, the opening having a width (I) taken along the section Si, the device being configured such that the widths of the opening of two adjacent channels have an equal or increasing value moving away from the center O and such that the widths of the opening of a channel closest to the center O and of a channel furthest from the center O have an increasing value moving away from the center O. The invention relates to the field of implantable devices, in particular artificial pancreas devices.

The invention discloses a preparation rich in polygonatum sibiricum polypeptide and application of the preparation in diabetes mellitus. The composition is prepared from rhizoma polygonati polypeptide, semeglutide, astaxanthin, an active agent and a ferroptosis mixture. Pharmacodynamic experiments show that in a diabetic mouse model, fasting blood glucose can be remarkably reduced, the serum insulin level can be increased, renal function indexes can be improved, and expression of NLRP3 inflammation pathway related proteins (NLRP3, Caspase-1 and IL-1beta) in pancreatic tissue can be remarkably inhibited. By integrating multiple mechanisms of blood glucose reduction, oxidation resistance, inflammation resistance, ferroptosis resistance and the like, multi-target collaborative intervention is realized, the pharmaceutical composition is remarkably superior to a single component in the aspects of blood glucose reduction, pancreas islet function protection and complication alleviation, and a new clinical strategy is provided for treatment of diabetes mellitus, especially type 1 diabetes mellitus.

This invention is applied in the field of medicine, namely in endocrinology, and can be used in the treatment of type 1 diabetes. The invention proposes a combination containing a dipeptidyl peptidase 4 (DPP-4) inhibitor, a proton pump inhibitor (PP1), and γ-aminobutyric acid or γ-aminobutyric acid receptor agonist. This unique combination and dosage of drugs leads to the regeneration (recovery) of pancreatic β-cells, which occurs with a dramatic reduction in insulin requirements up to a total cessation of insulin in some individuals and is intended for the treatment of type 1 diabetes mellitus.

The application discloses corn silk glucan, a structure formula of which is [→4)-β-D-Glcp-(1→]n, wherein n is 6-60, and a molecular weight range is 1-9.8 kDa. By extracting effective components in corn silk, an extract is obtained, the extract is precipitated by 30-90% ethanol, corn silk crude polysaccharide is obtained, and after the corn silk crude polysaccharide is dissolved, the corn silk crude polysaccharide is sequentially subjected to biological membrane dialysis, ion exchange resin column and HPLC-ELSD separation and purification, and corn silk glucan is obtained. The corn silk glucan and zeaxanthin are compounded to form a glucan compound, the glucan compound can stabilize insulin and improve the activity of the insulin in mouse islet cells, and the glucan compound has 2-5 times stronger hypoglycemic activity than that of zeaxanthin alone, and therefore, the glucan compound has important significance for researching new hypoglycemic drugs or health-care food for assisting hypoglycemia.

The invention relates to the technical field of medical data processing, in particular to a multi-modal data fusion diabetes risk prediction system after acute pancreatitis, and the method comprises the steps: obtaining the feature data and treatment indexes of each dimension of a target patient and a plurality of reference patients after acute pancreatitis; obtaining a weighted similarity index according to the difference between the feature data of the target patient and the feature data of each reference patient in the same dimension; according to the treatment index of each reference patient and the distribution difference of the overall reference patients, a boundary feature length is obtained in combination with weighted similar indexes; fitting the treatment indexes of the reference patients whose diagnosis time lengths are greater than the demarcation characteristic length and less than or equal to the demarcation characteristic length respectively to obtain a pancreas islet compensation function curve; and obtaining a diabetes risk prediction result of the target patient according to a deviation condition between the treatment index of the target patient and the pancreas islet compensation function curve. According to the invention, the accuracy of the risk prediction result of the patient in the compensatory state is good.

The invention belongs to the technical field of polypeptide preparation and biological medicine, and particularly relates to a preparation method of Jingzhaotoxin polypeptide IX (JZTX-IX) and application of Jingzhaotoxin polypeptide IX in treatment of diabetes mellitus. A chilobrachys jingzhao toxin polypeptide IX coding gene, a 6 * His tag nucleotide sequence, a thrombin restriction enzyme cutting site nucleotide sequence and an MBP hydrotropy tag nucleotide sequence are connected to a prokaryotic expression vector for prokaryotic expression, and the expressed polypeptide is purified to obtain the chilobrachys jingzhao toxin polypeptide IX protein. The target polypeptide with high purity, complete disulfide bond folding and uniform conformation is obtained, so that the high purity and biological activity of the target polypeptide are ensured. On the basis, the treatment activity of the JZTX-IX on diabetes mellitus especially type II diabetes mellitus is found and verified, and the JZTX-IX can remarkably reduce fasting blood glucose of mice with the type II diabetes mellitus, improve glucose tolerance and insulin sensitivity, relieve polydipsia and polyuria symptoms and promote insulin secretion and islet cell proliferation.

This invention discloses a method for constructing a type 2 diabetes mouse model combining artificial intelligence prediction and multi-target knockout. The method involves acquiring and standardizing multi-omics data and baseline phenotypic data of mice to form a standardized modeling dataset; constructing an interaction map covering pancreatic β-cell function based on this data; selecting target target combinations and target phenotypic prediction results; generating construction instructions and submitting them to a controlled facility for multi-gene knockout modification to obtain modified mice and modification receipts; obtaining measured phenotypic data of the modified mice based on the modification receipts; comparing this data with the target phenotypic prediction results to generate phenotypic deviation metrics and phenotypic determination results; and registering the target target combinations, prediction results, measured phenotypic data, and modification receipts when the phenotypic determination results are satisfactory to form a type 2 diabetes composite mouse model. This invention achieves closed-loop optimization of AI-driven multi-target genetic modification, improving the efficiency and accuracy of constructing animal models of complex metabolic diseases.

The present application relates to the technical field of mRNA vaccine, and specifically discloses a proinsulin mRNA vaccine for protecting the function and quantity of pancreatic beta cells. The vaccine is composed of a lipid nanoparticle (LNP) and an mRNA wrapped by the LNP; the mRNA is an mRNA sequence encoding proinsulin, and all uridines in the mRNA sequence are replaced by N1-methyl pseudouridine. The mRNA vaccine of the present application realizes the dual protection of the quantity and function of pancreatic beta cells, compared with the existing intervention means which only focus on blood glucose control or immune regulation, the present application delays the occurrence process of type 1 diabetes from the root, and provides a new technical scheme and drug selection for the prevention and early intervention of type 1 diabetes.

The application discloses a temperature-sensitive hydrogel with a diabetes treatment effect, a kit, a use method and application thereof, and belongs to the technical field of diabetes treatment drugs. The temperature-sensitive hydrogel is formed by mixing a human umbilical vein endothelial cell suspension, a mixed solution with a final concentration of 15-20% of P407 and a final concentration of 0.6-0.8% of sodium hyaluronate, a final concentration of 50 ng / mL of vascular endothelial growth factor, a final concentration of 10 ng / mL of basic fibroblast growth factor, a final concentration of 0.5-2% of lidocaine hydrochloride, a final concentration of 100-200 mg / mL of tumor necrosis factor alpha monoclonal antibody and a final concentration of 2-5% of islet cell-alginic acid gel fiber segments with a length of less than 1 mm. The temperature-sensitive hydrogel is safe, non-toxic, low in immunogenicity, low in cost and good in treatment effect. The reagent is combined with sterile consumables to form a kit, and the kit is convenient to use and can be better applied to the treatment of diabetes.

The invention discloses a compound polysaccharide preparation for treating diabetes and application thereof, and belongs to the technical field of biomedicine. The compound polysaccharide preparation is composed of compound polysaccharide A and compound polysaccharide B according to the mass ratio of 1: 1. The compound polysaccharide A is prepared from abelmoschus esculentus and chlorella through alkaline ultrasonic extraction and 10-100kDa ultrafiltration classification; the compound polysaccharide B is prepared by performing enzymolysis and hot water extraction on grifola frondosa and sarcodon aspratus. Experiments prove that the preparation can significantly improve insulin secretion and glucose uptake ability of islet cells, effectively reduce fasting blood-glucose of type 2 diabetes model mice and synchronously improve triglyceride and total cholesterol levels through strong synergistic interaction among the components. The preparation disclosed by the invention is natural in source, safe and efficient, so that a new choice is provided for medicine development of type 2 diabetes mellitus.

The present invention relates to a test kit for performing an assay to detect and measure at least one autoantibody molecule in a subject developing type 1 diabetes (T1D). The invention more specifically relates to a recombinant antigen molecule fused to a bioluminescent reporter protein to detect an autoantibody molecule against a self-antigen. Said self-antigen is preferably expressed by pancreatic islet beta cells and include insulin, proinsulin, Glutamate decarboxylase 65, islet antigen 2, and Zinc transporter 8. More specifically, the present invention relates to an assay comprising a set of at least three recombinant antigen molecules in a single composition, the antigen molecules being selected from the list comprising recombinant human Glutamate decarboxylase 65, recombinant human islet antigen 2, recombinant human Zinc transporter 8, recombinant human insulin, and recombinant human proinsulin. The invention further relates to methods for determining the presence and / or level of at least one autoantibody molecule in a sample from a human subject developing T1D using said recombinant antigen molecules. According to the invention, the presence, absence, or amount of one or more autoantibody molecules against said self-antigens is determined with a luciferase immune precipitation system (LIPS) assay or a modified version of a LIPS assay, i.e., a solid phase capture LIPS (scLIPS) assay.

The invention discloses a stem cell medicine for pancreas islet repair and application, and belongs to the technical field of stem cell biology, and the stem cell medicine for pancreas islet repair is prepared by compounding a carrier, pancreatic progenitor cells and pancreas islet-like cells in proportion. The problems that in the prior art, due to the fact that stem cells are unstable in differentiation efficiency, poor in synergistic effect and poor in biocompatibility, islet injury cannot be repaired, and diabetes cannot be treated are solved. According to the present invention, the dual mechanisms of endogenous beta cell repair and exogenous beta cell supplement are adopted, and the beta cell function recovery and the group structure reconstruction are synchronously achieved through the reasonable ratio, such that the in-vivo blood glucose of the mouse is significantly reduced, the beta cell number and the glucose tolerance dose of the mouse are increased, and the low immunogenicity and the high anti-inflammatory property are simultaneously provided. The compound can be used for treating type I and type II diabetes mellitus, improving the insulin secretion function and relieving local inflammatory response of pancreas by promoting pancreas islet beta cell proliferation, and has application potential in treatment of type I and type II diabetes mellitus and pancreas islet repair.

This invention discloses a sulfated arabinoglycoside, its preparation method, and its applications, belonging to the field of biomedical technology. The technical solution includes a sulfated arabinoglycoside derived from *Streptococcus linearis* polysaccharide; a degree of polymerization of 2-5; arabinose as the main monosaccharide, and containing galactose; the molar percentage of arabinose is not less than 80%, and the molar percentage of galactose is not more than 20%; the main chain is composed of (1→4)-β-L-pyranose arabinose groups, with the sulfate groups of the arabinose mainly substituted at the C-3 position. This invention is applied to inhibiting the abnormal aggregation of human pancreatic islet amyloid peptide (hIAPP), solving the problem of the lack of safe and effective intervention methods for the abnormal aggregation of human pancreatic islet amyloid peptide in existing technologies. It features stable raw material sources, high safety, a simple and mild preparation method suitable for large-scale preparation, and the ability to inhibit the abnormal aggregation of human pancreatic islet amyloid peptide and reduce pancreatic β-cell damage.

The invention belongs to the technical field of biological medicine, and provides a human umbilical cord mesenchymal stem cell preparation and application thereof, the preparation comprises human umbilical cord mesenchymal stem cells, ginsenoside Rg3 and a medicinal carrier; the medicinal carrier is a phosphate buffer solution; according to the application, 1 * 10 < 6 > HUCMSCs pretreated by Rg3 are subjected to caudal vein injection on a T2DM mouse model induced by high fat diet combined with STZ, the curative effect and mechanism are verified by combining OGTT, IPITT, serum biochemical detection, HE / PAS tissue staining, q-PCR and other technologies, and finally the purposes of improving glycometabolism of the T2DM mouse, repairing liver / kidney / pancreas target organ injuries, protecting pancreas islet beta cell functions, reducing pancreas islet beta cell functions, reducing pancreas islet beta cell functions, reducing pancreas islet beta cell functions, reducing pancreas islet beta cell functions and the like are achieved. And a theoretical basis is provided for accurate intervention of T2DM by activating an IGF-1R / PI3K-AKT signal channel and regulating and controlling the expression of a glycometabolism-related gene.

The invention belongs to the technical field of polypeptide preparation and biological medicine, and particularly relates to a preparation method of Jingzhaotoxin polypeptide XI (JZTX-XI) and application of Jingzhaotoxin polypeptide XI (JZTX-XI) in treatment of diabetes mellitus. A Jingzhaotoxin polypeptide XI coding gene, a nucleotide sequence of a 6 * His tag, a nucleotide sequence of a thrombin restriction enzyme cutting site and a nucleotide sequence of an MBP hydrotropy tag are connected to a prokaryotic expression vector for prokaryotic expression, and a target polypeptide which is high in purity, complete in disulfide bond folding and uniform in conformation is obtained through purification. The purity and the biological activity are relatively high. Meanwhile, the treatment activity of the JZTX-XI in the aspect of diabetes is verified, and it is found that the JZTX-XI can remarkably reduce fasting blood glucose of mice with type II diabetes, remarkably up-regulate a glucose transport regulation gene Glut2, improve glucose tolerance and insulin sensitivity, relieve polydipsia and polyuria symptoms and promote insulin secretion and islet cell proliferation.