Revolutionizing Treatment Strategies for Autoimmune and Inflammatory Disorders: The Impact of Dipeptidyl-Peptidase 4 Inhibitors

Kashif Rahim,1 Muhammad Shan,2 Ihtisham Ul Haq,3– 5 Muhammad Naveed Nawaz,2 Sajida Maryam,3,4 Mansour S Alturki,6 Abdulaziz H Al Khzem,6 Kamel Metwally,7 Simona Cavalu,8 Saleh F Alqifari,9 Galal Yahya10 1School of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, People’s Republic of China; 2Department of Microbiology, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Punjab, Pakistan; 3Department of Physical Chemistry and Technology of Polymers, Silesian University of Technology, Gliwice, Poland; 4Joint Doctoral School, Silesian University of Technology, Gliwice, 44-100, Poland; 5Programa de Pós-graduação em Inovação Tecnológica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil; 6Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam, 34212, Saudi Arabia; 7Department of Medicinal Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, 71491, Saudi Arabia; 8Faculty of Medicine and Pharmacy, University of Oradea, Oradea, 410073, Romania; 9Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk, 71491, Saudi Arabia; 10Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Al Sharqia, 44519, EgyptCorrespondence: Kashif Rahim, School of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, People’s Republic of China, Email [email protected] Saleh F Alqifari, Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk, 71491, Saudi Arabia, Email [email protected]: DPP4 (Dipeptidyl-peptidase 4) a versatile protease, emerges as a prominent player in soluble and membrane-bound forms. Its heightened expression has been intimately linked to the initiation and severity of diverse autoimmune diseases, spanning rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis (SSc), inflammatory bowel disease, autoimmune diabetes, and even SARS-CoV-2 infection. Operating as a co-stimulator of T cell activity, DPP4 propels T cell proliferation by binding adenosine deaminase (ADA), thereby augmenting the breakdown of adenosine—an influential inhibitor of T cell proliferation. However, the discovery of a wide range of DPP4 inhibitors has shown promise in alleviating these diseases’ signs, symptoms, and severity. The available DPP4 inhibitors have demonstrated significant effectiveness in blocking DPP4 activity. Based on the characterization of their binding mechanisms, three distinct groups of DPP4 inhibitors have been identified: saxagliptin, alogliptin, and sitagliptin, each representing a different class. Elevated levels of angiotensin-converting enzyme 2 (ACE2) expression are associated with producing various coronavirus peptidases. With its anti-inflammatory properties, Sitagliptin may assist COVID-19 patients in preventing and managing cytokine storms. This comprehensive review delves into the burgeoning realm of DPP4 inhibitors as therapeutic interventions for diverse autoimmune diseases. With a discerning focus on their efficacy, the investigation sheds light on their remarkable capacity to alleviate the burdensome signs and symptoms intricately linked to these conditions.Keywords: autoimmune diseases, DPP4 inhibitors, inflammatory disorders, MERS-CoV, diabetes mellitus, COVID-1

Phytochemical profile, antioxidant capacity and wound healing potential of Viscum album L. growing on Robinia pseudoacacia L.

Mistletoe (Viscum album L.), a semi-parasitic medicinal plant, continues to be of interest, due to its phytochemical composition. The leaves of mistletoe contain phenols, which have a variety of biological effects. The main goal was to characterize the mistletoe that parasitized Robinia pseudoacacia L., (called VAR) in terms of phenolic compounds and to assess the wound healing potential in vitro using the scratch method. Furthermore, the antioxidant capacity was evaluated both by spectrophotometric techniques (DPPH, FRAP, TEAC), as well as by the ability of the mistletoe extract to synthesize green selenium nanoparticles. Among the phenolic acids, dihydroxybenzoic acid is in high level (2.86±0.03 mg/g dw), whereas isorhamnetin-glucuronides dominate the flavonol class (0.593±0.03 mg/g dw). The presence of phenolic compounds in the VAR leaves provides antioxidant capacity. The reducing capacity of VAR extract was demonstrated for the first time by the biosynthesis of nanoselenium particles (NSePs) with a regular, spherical shape and a diameter of around 130 nm. The VAR concentrations of 25-200 µg/mL showed no toxic effect on normal human dermal fibroblasts (NHDF), and the concentration of 100 µg/mL exhibited the best percentage of wound surface closure in vitro (94.08%). The results show that mistletoe is a promising plant because of its phytochemical composition and antioxidant capacity, which can modulate the wound repair process in vitro

Orexins in apoptosis: a dual regulatory role

The orexins, also referred to as hypocretins, are neuropeptides that originate from the lateral hypothalamus (LH) region of the brain. They are composed of two small peptides, orexin-A, and orexin-B, which are broadly distributed throughout the central and peripheral nervous systems. Orexins are recognized to regulate diverse functions, involving energy homeostasis, the sleep-wake cycle, stress responses, and reward-seeking behaviors. Additionally, it is suggested that orexin-A deficiency is linked to sleepiness and narcolepsy. The orexins bind to their respective receptors, the orexin receptor type 1 (OX1R) and type 2 (OX2R), and activate different signaling pathways, which results in the mediation of various physiological functions. Orexin receptors are widely expressed in different parts of the body, including the skin, muscles, lungs, and bone marrow. The expression levels of orexins and their receptors play a crucial role in apoptosis, which makes them a potential target for clinical treatment of various disorders. This article delves into the significance of orexins and orexin receptors in the process of apoptosis, highlighting their expression levels and their potential contributions to different diseases. The article offers an overview of the existing understanding of the orexin/receptor system and how it influences the regulation of apoptosis

Biocompatibility and Bone Formation of Flexible, Cotton Wool-like PLGA/Calcium Phosphate Nanocomposites in Sheep

BACKGROUND: The purpose of this preliminary study was to assess the in vivo performance of synthetic, cotton wool-like nanocomposites consisting of a biodegradable poly(lactide-co-glycolide) fibrous matrix and containing either calcium phosphate nanoparticles (PLGA/CaP 60:40) or silver doped CaP nanoparticles (PLGA/Ag-CaP 60:40). Besides its extraordinary in vitro bioactivity the latter biomaterial (0.4 wt% total silver concentration) provides additional antimicrobial properties for treating bone defects exposed to microorganisms. MATERIALS AND METHODS: Both flexible artificial bone substitutes were implanted into totally 16 epiphyseal and metaphyseal drill hole defects of long bone in sheep and followed for 8 weeks. Histological and histomorphological analyses were conducted to evaluate the biocompatibility and bone formation applying a score system. The influence of silver on the in vivo performance was further investigated. RESULTS: Semi-quantitative evaluation of histology sections showed for both implant materials an excellent biocompatibility and bone healing with no resorption in the adjacent bone. No signs of inflammation were detectable, either macroscopically or microscopically, as was evident in 5 µm plastic sections by the minimal amount of inflammatory cells. The fibrous biomaterials enabled bone formation directly in the centre of the former defect. The area fraction of new bone formation as determined histomorphometrically after 8 weeks implantation was very similar with 20.5 ± 11.2 % and 22.5 ± 9.2 % for PLGA/CaP and PLGA/Ag-CaP, respectively. CONCLUSIONS: The cotton wool-like bone substitute material is easily applicable, biocompatible and might be beneficial in minimal invasive surgery for treating bone defects

Adherence Properties of Acrylic Bone Cement to Alumina Ceramics Designed for Clinical Applications

The aim of this study is to investigate the adherence properties of acrylic cement based on PMMA to alumina ceramics. These ceramics are suitable for orthopedic and dental applications, as bioinert components in prosthetic surgery. The surface of alumina specimens were subjected to a special treatment based on acid etched followed by two different fluoride treatments: $SnF_2$ and $NaBF_4$, respectively. The structural properties of $Al_2O_3$ specimens were investigated before any treatments by X-ray diffraction, Fourier transform infrared spectroscopy and scanning electron microscopy. The modification occurred after the chemical treatment was investigated by X-ray photoelectron spectroscopy. The adherence of commercial acrylic cement to both treated alumina specimens was evaluated by scanning electron microscopy upon transversal cutting of the specimens. The results demonstrated that $SnF_2$ is more favorable with respect to adhesion of PMMA based orthopedic cements

A Comparative Study of Quercetin-Loaded Nanocochleates and Liposomes: Formulation, Characterization, Assessment of Degradation and In Vitro Anticancer Potential

Quercetin, a flavonoid, has antioxidant and anti-inflammatory properties and the potential to inhibit the proliferation of cancer, but its therapeutic efficacy is lowered due to poor solubility and bioavailability. Quercetin-loaded nanocochleates (QN) were developed using a trapping method by the addition of calcium ions into preformed negatively charged liposomes (QL) prepared by a thin-film hydration method. Liposomes were optimized by varying the concentration of Dimyristoyl phosphatidyl glycerol and quercetin by applying D-optimal factorial design using Design-Expert® software. Stable rods were observed using TEM with an average particle size, zeta potential and encapsulation efficiency of 502 nm, −18.52 mV and 88.62%, respectively, for QN which were developed from spherical QL showing 111.06 nm, −40.33 mV and 74.2%, respectively. In vitro release of quercetin from QN and QL was extended to 24 h. Poor bioavailability of quercetin is due to its degradation in the liver, so to mimic in vivo conditions, the degradation of quercetin released from QL and QN was studied in the presence of rat liver homogenate (S9G) and results revealed that QN, due to its unique structure, i.e., series of rolled up solid layers, shielded quercetin from the external environment and protected it. The safety and biocompatibility of QL and QN were provenby performing cytotoxicity studies on fibroblast L929 cell lines. QN showed superior anticancer activity compared to QL, as seen for human mouth cancerKB cell lines. Stability studies proved that nanocochleates were more stable than liposomal formulations. Thus, nanocochleates might serve as pharmaceutical nanocarriers for the improved efficacy of drugs with low aqueous solubility, poor bioavailability, poor targeting ability and stability

Emerging Approach for the Application of <i>Hibiscus sabdariffa</i> Extract Ointment in the Superficial Burn Care

Wound healing comprises organized events involving tissue repair and regeneration. The discovery of toll-like receptors (TLRs) sheds recent light on the mechanisms involved in initiating inflammatory responses throughout the healing cascades. Hibiscus sabdariffa (HS) components may exhibit a wound healing action, owing to their antioxidant and anti-inflammatory activities. This study was designed to investigate the early effects of HS loaded in an ointment base on wound healing, antioxidant, antimicrobial effects, burning intensity, and histopathological features on the rat burn model in comparison to the standard treatment, Iruxol® ointment. A burn injury model was used to evaluate the wound healing potency of the preparation. Rats were treated with ointments three times on the day of the induction of the burn. Findings revealed that the strong antioxidant properties of the HS-loaded ointment augmented the skin healing potential by stimulating biomarkers required for skin regeneration. HS repressed the burning-induced inflammation by the effective reduction in the levels of tumor necrosis factor α (TNF-α) and IL-6 through TLR4 protein inhibition. Topical HS downregulates transforming growth factor-beta (TGF-β) levels. HS extract possesses a potential bactericidal activity against highly resistant clinical isolates of Pseudomonas aeruginosa. Overall, this study proclaims that HS-loaded topical preparations could be a valuable product that serves as adjuvants to accelerate burn wound healing through inactivating the TLR4 pathway