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Alzheimer's disease (AD) urgently needs innovative treatments due to the increasing aging population and lack of effective drugs and therapies. The amyloid fibrosis of AD-associated β-amyloid (Aβ) that could induce a series of cascades, such as oxidative stress and inflammation, is a critical factor in the progression of AD. Recently, peptide-based therapies for AD are expected to be great potential strategies for the high specificity to the targets, low toxicity, fast blood clearance, rapid cell and tissue permeability, and superior biochemical characteristics. Specifically, various chiral amino acids or peptide-modified interfaces draw much attention as effective manners to inhibit Aβ fibrillation. On the other hand, peptide-based inhibitors could be obtained through affinity screening such as phage display or by rational design based on the core sequence of Aβ fibrosis or by computer aided drug design based on the structure of Aβ. These peptide-based therapies can inhibit Aβ fibrillation and reduce cytotoxicity induced by Aβ aggregation and some have been shown to relieve cognition in AD model mice and reduce Aβ plaques in mice brains. This review summarizes the design method and characteristics of peptide inhibitors and their effect on the amyloid fibrosis of Aβ. We further describe some analysis methods for evaluating the inhibitory effect and point out the challenges in these areas, and possible directions for the design of AD drugs based on peptides, which lay the foundation for the development of new effective drugs in the future. [ABSTRACT FROM AUTHOR]

Mechanism of the Au@CeO 2 -CK2.1 yolk-shell nanozymes in alleviating inflammation and enhancing chondrogenic drug response to combat osteoarthritis by combining the antioxidant, mitochondrial regulation, and chondrogenic effects. [Display omitted] • Dysregulated mitochondrial homeostasis contributes to decreased drug response in OA. • Au@CeO 2 -CK2.1 yolk-shell nanozyme is developed as a novel therapeutic nanomaterial. • Au@CeO 2 -CK2.1 restores mitochondrial dynamics and rescues drug response of OA chondrocytes. • Photothermal, antioxidant, and peptide therapy demonstrate synergistic effects. • Au@CeO 2 -CK2.1 effectively promotes OA cartilage regeneration in vivo. In osteoarthritic chondrocytes, dysregulation of mitochondrial dynamics due to excessive intracellular reactive oxygen species (ROS) under inflammatory conditions is a significant contributory factor to poor treatment outcomes, because it leads to a reduced cell response to chondrogenic drugs during this state. The aim of this study was to develop a multifunctional Au@CeO 2 yolk-shell nanozyme (YSN) as a novel therapeutic nanomaterial and drug delivery system. Under photothermal conditions, Au@CeO 2 nanozymes neutralized excessive ROS, enhanced antioxidant capacity, and maintained mitochondrial homeostasis of osteoarthritic chondrocytes, thereby restoring cellular responsiveness to external stimuli. Furthermore, bioactive peptide CK2.1 loaded in YSNs (Au@CeO 2 -CK2.1) achieved ordered release under photothermal conditions, effectively promoting chondrocyte anabolic activity. In a mice osteoarthritis (OA) model, local Au@CeO 2 -CK2.1 photothermal therapy effectively enhanced cartilage repair and regeneration in vivo. Mechanically, our research uncovers that decreased chondrogenic drug response is associated with activation of extracellular regulated kinase-1 and -2 (ERK1/2) pathway, and Au@CeO 2 -CK2.1 YSNs regulates mitochondrial dynamics through inhibiting ERK1/2 and dynamin-1-like protein (DRP1) phosphorylation. The results of this study demonstrated an effective therapeutic strategy that rescued chondrogenic drug response in osteoarthritic chondrocytes, achieving anti-inflammation and cartilage regeneration. [ABSTRACT FROM AUTHOR]

Huntington's disease is a neurodegenerative disease caused by CAG repeat in the first exon of HTT (Huntingtin) gene, leading to abnormal form of Htt protein containing enlarged polyglutamine strands of variable length that stick together to form aggregates and is toxic to brain causing brain damage. Complete reversal of brain damage is not possible till date but recovery may be possible by peptide therapy. The peptide-based therapy for Huntington's disease includes both poly Q peptide as well as non poly Q peptides like (QBP1)2, p42, Exendin 4, ED11, CaM, BiP, Leuprorelin peptide. The novel approach that is currently being tested in this article is the peptide-based therapy to target the mutated protein. This approach is based on the principle of preventing the aggregation of mutant Htt by blocking the potential sites responsible for protein aggregation and thereby ameliorating the disease symptoms. Herein, we have screened a variety of potential peptides that were known to prevent the protein aggregation, comparatively analyzed their binding affinity with homology modeled Htt protein, designed novel peptides based upon conservation analysis among screened potential peptides as a therapeutic agent, comparatively analyzed the therapeutic potential of novel peptides against modeled Htt protein for investigating the therapeutic prospects of Huntington's disease. We have designed a peptide for the therapy of Huntington's disease by comparing several peptides, which are already in use for Huntington's disease.

Diffuse astrocytomas are the most aggressive and lethal glial tumors of the central nervous system (CNS). Their high cellular heterogeneity and the presence of specific barriers, i.e., blood−brain barrier (BBB) and tumor barrier, make these cancers poorly responsive to all kinds of currently available therapies. Standard therapeutic approaches developed to prevent astrocytoma progression, such as chemotherapy and radiotherapy, do not improve the average survival of patients. However, the recent identification of key genetic alterations and molecular signatures specific for astrocytomas has allowed the advent of novel targeted therapies, potentially more efficient and characterized by fewer side effects. Among others, peptides have emerged as promising therapeutic agents, due to their numerous advantages when compared to standard chemotherapeutics. They can be employed as (i) pharmacologically active agents, which promote the reduction of tumor growth; or (ii) carriers, either to facilitate the translocation of drugs through brain, tumor, and cellular barriers, or to target tumor-specific receptors. Since several pathways are normally altered in malignant gliomas, better outcomes may result from combining multi-target strategies rather than targeting a single effector. In the last years, several preclinical studies with different types of peptides moved in this direction, providing promising results in murine models of disease and opening new perspectives for peptide applications in the treatment of high-grade brain tumors.

Background and Aims Triggering receptor expressed on myeloid cells-1 [TREM-1] is known to amplify inflammation in several diseases. Autophagy and endoplasmic reticulum [ER] stress, which activate the unfolded protein response [UPR], are closely linked and defects in these pathways contribute to the pathogenesis of inflammatory bowel disease [IBD]. Both autophagy and UPR are deeply involved in host-microbiota interactions for the clearance of intracellular pathogens, thus contributing to dysbiosis. We investigated whether inhibition of TREM-1 would prevent aberrant inflammation by modulating autophagy and ER stress and preventing dysbiosis. Methods An experimental mouse model of colitis was established by dextran sulphate sodium treatment. TREM-1 was inhibited, either pharmacologically by LR12 peptide or genetically with Trem-1 knock-out [KO] mice. Colon tissues and faecal pellets of control and colitic mice were used. Levels of macroautophagy, chaperone-mediated autophagy [CMA], and UPR proteins were evaluated by western blotting. The composition of the intestinal microbiota was assessed by MiSeq sequencing in both LR12-treated and KO animals. Results We confirmed that inhibition of TREM-1 attenuates the severity of colitis clinically, endoscopically and histologically. We observed an increase in macroautophagy [ATG1/ULK-1, ATG13, ATG5, ATG16L1, and MAP1LC3-I/II] and in CMA [HSPA8 and HSP90AA1], whereas there was a decrease in the UPR [PERK, IRE-1α, and ATF-6α] protein expression levels in TREM-1 inhibited colitic mice. TREM-1 inhibition prevented dysbiosis. Conclusions TREM-1 may represent a novel drug target for the treatment of IBD, by modulating autophagy activity and ER stress. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a progressive neurodegenerative hereditary disease clinically characterised by the presence of involuntary movements, behavioural problems and cognitive decline. The disease-onset is usually between 30 and 50 years of age. HD is a rare disorder affecting approximately 1.3 in 10,000 people in the European Union. It is caused by an expanded CAG repeat in the first exon of the Huntingtin (HTT) gene, leading to an abnormal form of the Huntingtin protein (Htt) (polyQHtt), containing N-terminus, enlarged polyglutamine strands of variable length that stick together to form aggregates and nuclear inclusions in the damaged brain cells. Treatments currently used for Huntington's disease are symptomatic and aimed at temporally relieving the symptoms of the disease; although some promising therapies are on study, there is no drug capable of stopping disease progression either in the form of delaying onset or slowing disability progression. The utilization of peptides interacting with polyQ stretches or with Htt protein to prevent misfolding and aggregation of the expanded polyQ protein is a fascinating idea, because of low potential toxicity and ability to target very initial steps in the pathophysiological cascade of the disease, such as aggregation or cleavage process. Indeed, several therapeutic peptides have been developed and were found to significantly slow down the progression of symptoms in experimental models of Huntington's disease. This review is essentially focusing on the latest development concerning peptide strategy. In particular, we focused on a 23aa peptide P42, which is a part of the Htt protein. It is expected to work principally by preventing the abnormal Htt protein from sticking together, thereby preventing pathological consequences of aggregation and improving the symptoms of the disease. In the meantime, as P42 is part of the Htt protein, some therapeutic properties might be linked to the physiological actions of the peptide itself, considered as a functional domain of the Htt protein. [ABSTRACT FROM AUTHOR]

Abstract: The transcription factor nuclear factor E2-related factor 2 (Nrf2) regulates the expression of multiple cytoprotective genes that have been shown to offer protection in response to a number of insults. The present study describes a novel strategy to increase expression of Nrf2-responsive genes in brain injured mice. Under normal conditions, the adapter protein Kelch-like ECH-associated protein 1 (Keap1) binds to Nrf2 and promotes its proteosomal degradation in the cytoplasm. The amino acid sequence DEETGE, located at amino acid 77–82 of Nrf2, is critical for Nrf2–Keap1 interaction, and synthetic peptides containing this sequence can be used to disrupt the complex in vitro. We observed that intracerebroventricular (i.c.v.) infusion of a peptide containing the DEETGE sequence along with the cell transduction domain of the HIV-TAT protein (TAT–DEETGE) into brain-injured mice did not increase the mRNA levels for Nrf2-driven genes. However, when a calpain cleavage sequence was introduced between the TAT sequence and the DEETGE sequence, the new peptide (TAT–CAL–DEETGE) increased the mRNA levels of these genes. Increased gene expression was not observed when the TAT–CAL–DEETGE peptide was injected into uninjured animals. Furthermore, injection of TAT–CAL–DEETGE peptides before or after brain injury reduced blood–brain barrier compromise, a prominent secondary pathology that negatively influences outcome. The present strategy to increase Nrf2-responsive gene expression can be adapted to treat other insults or diseases based on their underlying mechanism(s) of cellular damage. [Copyright &y& Elsevier]

Abstract: Interferon-γ (IFN-γ) plays a pathogenic role in systemic lupus erythematosus (SLE). Uncontrolled IFN-γ signaling may result from a deficiency in the negative regulator, namely, suppressor of cytokine signaling-1 (SOCS-1). We investigated the activation status of IFN-γ signaling pathway in SLE-afflicted (New-Zealand-Black×New-Zealand-White)F1 mice and determined its responsiveness when treating with a tolerogenic peptide, hCDR1, which ameliorates SLE. SOCS-1 was suppressed and pSTAT1 was enhanced in spleen-derived cells from SLE-affected mice as compared with healthy controls. Treatment with hCDR1 reversed the expression of these two molecules in association with clinical amelioration. In vitro stimulation with IFN-γ resulted in elevated levels of SOCS-1 in cells from both vehicle and hCDR1-treated mice but this effect reached significance only in cells of the latter group, which also exhibited reduced levels of pSTAT1. Thus, SOCS-1 is diminished in SLE-affected mice, and treatment with hCDR1 results in its up-regulation thereby restoring control of IFN-γ signaling pathway. [Copyright &y& Elsevier]

Over the past few decades, the field of cancer therapy has seen a significant change in the way in which formulations are designed and developed, resulting in more efficient products that allow us to ultimately achieve improved drug bioavailability, efficacy, and safety. However, although many formulations have entered the market, many others have fallen by the wayside leaving the scientific community with several lessons to learn. The successes (and failures) achieved with formulations that have been approved in Europe and/or by the FDA for the three major types of cancer therapy (peptide-based therapy, chemotherapy, and radiotherapy) are reviewed herein, covering the period from the approval of the first prolonged-release system for hormonal therapy to the appearance of the first biodegradable microspheres intended for chemoembolization in 2020. In addition, those products that have entered phase III clinical trials that have been active over the last five years are summarized in order to outline future research trends and possibilities that lie ahead to develop clinically translatable formulations for cancer treatment. [ABSTRACT FROM AUTHOR]

Diffuse astrocytomas are the most aggressive and lethal glial tumors of the central nervous system (CNS). Their high cellular heterogeneity and the presence of specific barriers, i.e., blood–brain barrier (BBB) and tumor barrier, make these cancers poorly responsive to all kinds of currently available therapies. Standard therapeutic approaches developed to prevent astrocytoma progression, such as chemotherapy and radiotherapy, do not improve the average survival of patients. However, the recent identification of key genetic alterations and molecular signatures specific for astrocytomas has allowed the advent of novel targeted therapies, potentially more efficient and characterized by fewer side effects. Among others, peptides have emerged as promising therapeutic agents, due to their numerous advantages when compared to standard chemotherapeutics. They can be employed as (i) pharmacologically active agents, which promote the reduction of tumor growth; or (ii) carriers, either to facilitate the translocation of drugs through brain, tumor, and cellular barriers, or to target tumor-specific receptors. Since several pathways are normally altered in malignant gliomas, better outcomes may result from combining multi-target strategies rather than targeting a single effector. In the last years, several preclinical studies with different types of peptides moved in this direction, providing promising results in murine models of disease and opening new perspectives for peptide applications in the treatment of high-grade brain tumors. [ABSTRACT FROM AUTHOR]

Introduction : The apelinergic system is regarded as a novel therapeutic target for cardiovascular health, fluid homeostasis, the hypothalamic-pituitary-adrenal (HPA) axis as well as carbohydrate and fat metabolism. Two endogenous peptide ligands, namely apelin and elabela, have been demonstrated to moderate its various metabolic and neurological functions. Both bind with high (sub)-nanomolar affinity to APJR but get degraded rapidly in circulation. In addition, various diseases have been associated with the depletion of these regulatory peptides. Besides blocking the degrading proteases, a common strategy in targeting drugs to APJR is the development of metabolically stable peptide analogs or small molecule modulators. Supporting this trend, patent literature has evolved from 121 patents in 2014 to a total of almost 1000 patents today. Areas covered : This review includes WIPO-listed small molecule and peptide-based agonists, antagonists and allosteric modulators of APJR published between 2014 and 2019. Expert opinion : Both apelin peptide analogues and small molecule modulators are emerging, only recently including one example of an elabela-based analogue. Patent activity is predominantly on agonistic modulators since they show higher affinity and fewer off-target effects. Although several low nanomolar binders with half-lives exceeding 24 h have been confirmed in animal models, clinical validation of these drug-targets is sparse.

Berylliosis is driven by the accumulation in the lung of beryllium-specific T helper type 1 (Th1) cells recognizing beryllium as antigen when presented principally by human leucocyte antigen DP molecules carrying a glutamate at position β69 (HLA-DPGlu69). This study was designed to clarify the precise role of peptides in beryllium binding to the HLA-DP groove’s pocket 4 and to identify peptides with higher affinity for pocket 4 that might prevent beryllium presentation and T-cell stimulation. Beryllium/HLA-DP interactions were analysed by the ability of beryllium to compete with CLIP and CLIP-derived peptides to HLA-DPGlu69 soluble molecule. The CLIP-derived low-affinity peptide CLIP-AA, could not outcompete beryllium; while the CLIP-derived high-affinity peptides CLIP-YY, CLIP-QY and CLIP-RF were only marginally influenced by the presence of beryllium in the competition assay. The effect of these CLIP-derived high-affinity peptides on beryllium presentation was determined by measuring interferon-γ (IFN-γ) release upon beryllium stimulation of peripheral blood mononuclear cells obtained from beryllium-hypersensitive subjects. CLIP-YY did inhibit beryllium presentation and T-cell activation, while CLIP-QY and CLIP-RF markedly enhanced the IFN-γ response to beryllium. Anti-HLA-DP monoclonal antibody blocked the beryllium-induced IFN-γ release in the presence of CLIP-QY (88%) and CLIP-RF (76%). A similar effect was observed for CLIP-YY capability to block IFN-γ release by beryllium stimulation in the presence of CLIP-QY (79%) and CLIP-RF (76%). Overall, these data support the proposal that HLA-DP high-affinity peptides might be used as a model for specific berylliosis therapy. [ABSTRACT FROM AUTHOR]