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The RAS-RAF-ERK1/2 pathway is a crucial target for anticancer drug development because of the high prevalence of ERK activation in human cancers. Mitogen-activated protein kinases (MAPKs) are pivotal intracellular cascade molecules critical in all eukaryotic cells for the recognition of and response to external stimuli. RAS plays an important role with respect to cell proliferation. MDA-MB-231 is a triple-negative breast cancer (TNBC) cell line carrying a G13D KRAS mutant; hence, it is resistant to drugs. Herein, the authors evaluated a synthetic cell-penetrating peptide that binds to RAS with high affinity (termed RAS-binding peptide, RBP) for the treatment of MDA-MB-231 cancer. In this study, MDA-MB-231 cells exhibited reduced proliferation since RBP inhibited the interaction between RAS and RAF. Moreover, a decrease in RBP-treated MDA-MB-231 cell migration and invasion were observed. The expression of phosphorylatedERK1/2 and RAF-bound RAS was reduced by RBP treatment. In chicken egg xenografts, RBP inhibited tumor growth and metastatic invasion. Infiltration of immune cells was evaluated via histopathological analysis, and reduction in the level of Ki-67, a proliferation marker in human tumor cells, was evident through immunohistochemical (IHC). Taken together, the peptide RBP was suggested to be a new therapeutic target in RAS-mutated cancer.

Health care and medicine were revolutionized in recent years by the development of biomaterials, such as stents, implants, personalized drug delivery systems, engineered grafts, cell sheets, and other transplantable materials. These materials not only support the growth of cells before transplantation but also serve as replacements for damaged tissues in vivo. Among the various biomaterials available, those made from natural biological sources such as extracellular proteins (collagen, fibronectin, laminin) have shown significant benefits, and thus are widely used. However, routine biomaterial-based research requires copious quantities of proteins and the use of pure and intact extracellular proteins could be highly cost ineffective. Gelatin is a molecular derivative of collagen obtained through the irreversible denaturation of collagen proteins. Gelatin shares a very close molecular structure and function with collagen and thus is often used in cell and tissue culture to replace collagen for biomaterial purposes. Recent technological advancements such as additive manufacturing, rapid prototyping, and three-dimensional printing, in general, have resulted in great strides toward the generation of functional gelatin-based materials for medical purposes. In this review, the structural and molecular similarities of gelatin to other extracellular matrix proteins are compared and analyzed. Current strategies for gelatin crosslinking and production are described and recent applications of gelatin-based biomaterials in cell culture and tissue regeneration are discussed. Finally, recent improvements in gelatin-based biomaterials for medical applications and future directions are elaborated. Impact statement In this study, we described gelatin's biochemical properties and compared its advantages and drawbacks over other extracellular matrix proteins and polymers used for biomaterial application. We also described how gelatin can be used with other polymers in creating gelatin composite materials that have enhanced mechanical properties, increased biocompatibility, and boosted bioactivity, maximizing its benefits for biomedical purposes. The article is relevant, as it discussed not only the chemistry of gelatin, but also listed the current techniques in gelatin/biomaterial manufacturing and described the most recent trends in gelatin-based biomaterials for biomedical applications.

Under Inflammatory bowel disease (IBD), impaired intestinal barrier from lumen is highly associated with ongoing IBD symptoms and it also contributes as a precursor for IBD. Current IBD therapeutics lack on mucosal regeneration, which the unmet needs could be the next first in class therapeutics for IBD. Here, we propose NIPEP-IBD, a synthetically modified peptide that promotes adhesion, migration, and differentiation of intestinal epithelial cells via interaction of integrin beta 1. From NIBEC’s specialized peptide discovery platform screening, specifically sequenced peptide has been selected for regenerative functional peptide, termed NIPEP-IBD. NIPEP-IBD selectively targeted and bound to integrin beta 1 protein, and its interaction was also verified in vitro, using immunoprecipitation and immunofluorescence assays on epithelial cells. Consequently, NIPEP-IBD increased integrin beta 1 expression, followed by phosphorylated FAK and RhoA proteins. As FAK-RhoA signaling pathway is known to modulate cytoskeletal rearrangement and maturation of epithelial cells, tight junction markers and rapid wound closure of epithelial cells was accelerated by NIPEP-IBD induction. The effect of NIPEP-IBD was further analyzed in vivo IBD model. DSS-induced colitis mouse model was used to analyze therapeutic effect of NIPEP-IBD in each IP and PO administration, and impaired mucosa layer by DSS was recovered by NIPEP-IBD, verified with H&E staining. Moreover, NIPEP-IBD treated mice showed reduced immune cell infiltration in colon tissue and reduced pro-inflammatory cytokines in plasma. In vivo fluorescence imaging system was further used to track distribution of NIPEP-IBD, and NIPEP-IBD specifically binds to impaired epithelium, co-localized with integrin beta 1 protein. The following GLP toxicity studies, ADME studies, and PK studies demonstrated that safety of NIPEP-IBD was verified as a therapeutic agent. Therefore, NIPEP-IBD is a safe and effective therapeutic peptide on IBD patients by restituting epithelial layer of colon and maintain its remission.

Under Inflammatory bowel disease (IBD), autoantibody-type VII collagen complex can induce autoimmune reaction and continue with the inflammation. Here, we introduced synthetic 19 amino acid sequenced peptide termed as NIPEP-IM-0127 that inhibits autoantibody-type VII collagen complex formation. The NIPEP-IM-0127 was further formulated for oral administration. Primary function of NIPEP-IM-0127 selectively localizes to wound gut barrier and masks exposed type VII collagen, which is the starting of autoimmune reaction. Disrupted type VII collagen by the disease was bound to the applied peptide, which interfere autoimmune complex formation by competitive binding inhibition between antibody and peptide. NIPEP-IM-0127 thus recovered inflammatory cytokine level by the inhibition of immune complex creation. The orally applied NIPEP-IM-0127 peptide was primarily detected at the surface of colon tissue after 9 hours of administration, while no distributions were shown in other organs. Most importantly, significant mucosal regeneration and healing has been achieved by NIPEP-IM-0127. The following GLP toxicity studies, including safety pharmacology, genotoxicity, single and repeated dose toxicity, demonstrated that NIPEP-IM-0127 showed no significant toxic effect in in mouse and monkey. Taken together, the NIPEP-IM-0127 is suggested to be a novel therapeutic candidate for IBD treatment by the dual effects combining immune modulation and intestine barrier healing.

Stem cells proliferate by undergoing self-renewal and differentiate into multiple cell lineages in response to biochemical and biophysical stimuli. Various biochemical cues such as growth factors, nucleic acids, chemical reagents, and small molecules have been used to induce stem cell differentiation or reprogramming or to maintain their pluripotency. Moreover, biophysical cues such as matrix stiffness, substrate topography, and external stress and strain play a major role in modulating stem cell behavior. In this chapter, we have summarized microenvironmental regulation of stem cell behavior through biochemical and biophysical stimulation.

Stem cells proliferate by undergoing self-renewal and differentiate into multiple cell lineages in response to biochemical and biophysical stimuli. Various biochemical cues such as growth factors, nucleic acids, chemical reagents, and small molecules have been used to induce stem cell differentiation or reprogramming or to maintain their pluripotency. Moreover, biophysical cues such as matrix stiffness, substrate topography, and external stress and strain play a major role in modulating stem cell behavior. In this chapter, we have summarized microenvironmental regulation of stem cell behavior through biochemical and biophysical stimulation.