Correction: Nasrullah et al. Omeprazole Prevents Colistin-Induced Nephrotoxicity in Rats: Emphasis on Oxidative Stress, Inflammation, Apoptosis and Colistin Accumulation in Kidneys. Pharmaceuticals 2022, 15, 782.

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LC-MS based metabolic profiling and wound healing activity of a chitosan nanoparticle-loaded formula of Teucrium polium in diabetic rats.

Healing of wounds is the most deteriorating diabetic experience. Felty germander (Teucrium polium) possesses antioxidant, anti-inflammatory and antimicrobial activities that could accelerate wound healing. Further, nanohydrogels help quicken healing and are ideal biomaterials for drug delivery. In the current study, the chemical profiling, and standardization of T. polium methanolic extract by LC-ESI/TOF/MS/MS and quantitative HPLC-DAD analyses were achieved. The wound healing enhancement in diabetic rats by T. polium nanopreparation (TP-NP) as chitosan nanogel (CS-NG) and investigating the potential mechanisms were investigated. The prepared hydrogel-based TP-NP were characterized with respect to particle size, zeta potential, pH, viscosity, and release of major components. LC-ESI/TOF/MS/MS metabolomic profiling of T. polium revealed the richness of the plant with phenolic compounds, particularly flavonoids. In addition, several terpenoids were detected. Kaempferol content of T. polium was estimated to be 7.85 ± 0.022 mg/ g of dry extract. The wound healing activity of TP-NP was explored in streptozotocin-induced diabetic rats. Diabetic animals were subjected to surgical wounding (1 cm diameter). Then they were divided in 5 groups (10 each). These included Group 1 (untreated control rats), Group 2 received the vehicle of CS-NG; Group 3 (0.5 g of TP prepared in hydrogel), Group 4 (0.5 g of TP-NP), Group 5 represented a positive control treated with 0.5 g of a commercial product. All treatments were applied topically for 21 days. Application of TP-NP on skin wounds of diabetic animals accelerated the healing process as evidenced by epithelium regeneration, formation of granulation tissue followed by epidermal proliferation, along with keratinization as verified by H&E. This was confirmed through enhanced collagen synthesis, as shown by raised hydroxyproline content and Col1A1 gene expression. Moreover, TP-NP significantly alleviated wound oxidative burst and diminished the expressions of inflammatory biomarkers. Meanwhile, TP-NP could enhance the expressions of transforming growth factor beta1 (TGF-ß1), in addition to the angiogenic markers; vascular endothelia growth factor A (VEGFA) and platelet-derived growth factor receptor alpha (PDGFRα). Collectively, chitosan nanogel of T. polium accelerates wound healing in diabetic rats, which could be explained - at least partly - through alleviating oxidative stress and inflammation coupled with pro-angiogenic capabilities.

Cordycepin- melittin nanoconjugate intensifies wound healing efficacy in diabetic rats.

The current study was designed to develop a nanoconjugate of cordycepin-melittin (COR-MEL) and assess its healing property in wounded diabetic rats. The prepared nanoconjugate has a particle size of 253.5 ± 17.4 nm with a polydispersity index (PDI) of 0.35 ± 0.04 and zeta potential of 17.2 ± 0.3 mV. To establish the wound healing property of the COR-MEL nanoconjugate, animal studies were pursued, where the animals with diabetes were exposed to excision and treated with COR hydrogel, MEL hydrogel, or COR-MEL nanoconjugate topically. The study demonstrated an accelerated wound contraction in COR-MEL nanoconjugate -treated diabetic rats, which was further validated by histological analysis. The nanoconjugate further exhibited antioxidant activities by inhibiting the accumulation of malondialdehyde (MDA) and exhaustion of superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzymatic activities. The nanoconjugate further demonstrated an enhanced anti-inflammatory activity by retarding the expression of interleukin (IL)-6 and tumor necrosis factor (TNF)-α. Additionally, the nanoconjugate exhibits a strong expression of transforming growth factor (TGF)-ß1, vascular endothelial growth factor (VEGF)-A, and platelet-derived growth factor (PDGFR)-ß, indicating enrichment of proliferation. Likewise, nanoconjugate increased the concentration of hydroxyproline as well as the mRNA expression of collagen, type I, alpha 1 (Col 1A1). Thus, it is concluded that the nanoconjugate possesses a potent wound-healing activity in diabetic rats via antioxidant, anti-inflammatory, and pro-angiogenetic mechanisms.

Andrographolide nanophytosomes exhibit enhanced cellular delivery and pro-apoptotic activities in HepG2 liver cancer cells.

Andrographolide (AG), a major active constituent of Andrographis paniculata, is known to hinder proliferation of several types of cancer cells. However, its poor solubility and cellular permeability restrict its use in clinical applications. In this study, AG-loaded phytosomes (AG-PTMs) were formulated and optimized with respect to particle size using l-α-phosphatidylcholine (PC):AG ratio and sonication time (ST) as independent variables. The optimized formula was prepared at 1:2.7 for AG:PC molar ratio and 4.9 min for ST and exhibited a particle size of 243.7 ± 7.3 nm, polydispersity index (PDI) of 0.310 and entrapment efficiency of 72.20 ± 4.53. Also, the prepared formula showed a slow release of AG over 24-h period. The antiproliferative activity of AG-PTMs was investigated against the liver cancer cell line HepG2. AG-PTMs significantly repressed the growth of HepG2 cells with an IC50 value of 4.02 ± 0.14 µM. AG uptake by HepG2 cells was significantly enhanced in incubations containing the optimized formula. AG-PTMs also caused G2-M cell cycle phase arrest and increased the fraction of apoptotic cells in pre-G1 phase. These effects were associated with induction of oxidative stress and mitochondrial dysfunction. In addition, AG-PTMs significantly upregulated mRNA expression of BAX and downregulated that of BCL2. Furthermore, AG-PTMs significantly enhanced the concentration of caspase-3 in comparison to raw AG. These data indicate that the phytosomal delivery of AG significantly inhibited HepG2 cell proliferation through enhanced cellular uptake, arresting cell cycle at the G2-M phase and inducing mitochondrial-dependent apoptosis.

Electrospun Nanofiber Composites for Drug Delivery: A Review on Current Progresses.

A medication's approximate release profile should be sustained in order to generate the desired therapeutic effect. The drug's release site, duration, and rate must all be adjusted to the drug's therapeutic aim. However, when designing drug delivery systems, this may be a considerable hurdle. Electrospinning is a promising method of creating a nanofibrous membrane since it enables drugs to be placed in the nanofiber composite and released over time. Nanofiber composites designed through electrospinning for drug release purposes are commonly constructed of simple structures. This nanofiber composite produces matrices with nanoscale fiber structure, large surface area to volume ratio, and a high porosity with small pore size. The nanofiber composite's large surface area to volume ratio can aid with cell binding and multiplication, drug loading, and mass transfer processes. The nanofiber composite acts as a container for drugs that can be customized to a wide range of drug release kinetics. Drugs may be electrospun after being dissolved or dispersed in the polymer solution, or they can be physically or chemically bound to the nanofiber surface. The composition and internal structure of the nanofibers are crucial for medicine release patterns.

Omeprazole Prevents Colistin-Induced Nephrotoxicity in Rats: Emphasis on Oxidative Stress, Inflammation, Apoptosis and Colistin Accumulation in Kidneys.

The clinical value of colistin, a polymyxin antibiotic, is limited by its nephrotoxicity. Omeprazole is a commonly prescribed proton pump inhibitor. The current study aimed to evaluate the effects of the concomitant administration of omeprazole on colistin-induced nephrotoxicity in rats. Omeprazole significantly ameliorated colistin nephrotoxicity as evidenced by prevention in the rise in the serum level of creatinine, urea and cystactin C as well as urinary N-acetylglucosamine activity. This was confirmed by histological studies that indicated a decreased incidence of interstitial nephritis, degenerative cortical changes and collagen deposition. This was accompanied by the prevention of oxidative stress as omeprazole significantly inhibited the lipid peroxidation, glutathione depletion and enzymatic exhaustion of superoxide dismutase as well as catalase. Additionally, omeprazole inhibited the expression of interleukin-6 and tumor necrosis factor-α. Further, omeprazole inhibited the colistin-induced rise in Bax and the down-regulation of Bcl2 mRNA expression. An assessment of the serum levels of colistin revealed that omeprazole had no significant impact. However, it was observed that omeprazole significantly inhibited the accumulation of colistin in kidney tissues. In conclusion, omeprazole protects against colistin-induced nephrotoxicity. This can be attributed to, at least partly, omeprazole's anti-oxidant, anti-inflammatory and anti-apoptotic activities in addition to its ability to prevent the toxic accumulation of colistin in kidneys.

Thioctamer: a novel thioctic acid-glatiramer acetate nanoconjugate expedites wound healing in diabetic rats.

The current work aims to design thioctic acid (TA) and glatiramer acetate (GA) nanoconjugate (thioctamer) loaded hydrogel formula as well as evaluation of thioctamer preclinical efficacy in expediting wound healing in a rat model of the diabetic wound. Thioctamer was prepared by conjugation of GA and TA in a 1:1 molar ratio. Particle size, zeta potential, and thermodynamic stability of the prepared thioctamer were assessed. Thioctamer was loaded in hydroxypropyl methylcellulose-based hydrogel and in vitro release study was investigated. The ability of thioctamer to enhance the process of wound healing in diabetic rats was investigated by assessing wound contraction and immunohistochemical assessment of the inflammation markers IL-6 and TNF-α. The results demonstrated that thioctamer showed particle size of 137 ± 21.4 nm, polydispersity index (PDI) of 0.235, and positive zeta potential value of 7.43 ± 4.95 mV. On day 7 of making a skin excision, diabetic rat wounds administered thioctamer preparation showed almost complete healing (95.6 ± 8.6%). Meanwhile, % of wound contraction in animals treated with TA or GA groups exhibited values amounting to 56.5 ± 5.8% and 62.6 ± 7.1%, respectively. Histological investigation showed that the highest healing rate was noted in the thioctamer group animals, as the surface of the wound was nearly fully protected by regenerated epithelium with keratinization, with few inflammatory cells noticed. Thioctamer significantly (p<.05) inhibited IL-6 and TNF-α expression as compared with sections obtained from the negative control, TA, GA, or positive control group animals on day 7. The evidence of the ability of thioctamer to significantly expedite wound healing in the diabetic rats is presented.

MXene (Ti3C2Tx)-Embedded Nanocomposite Hydrogels for Biomedical Applications: A Review.

Polymeric nanocomposites have been outstanding functional materials and have garnered immense attention as sustainable materials to address multi-disciplinary problems. MXenes have emerged as a newer class of 2D materials that produce metallic conductivity upon interaction with hydrophilic species, and their delamination affords monolayer nanoplatelets of a thickness of about one nm and a side size in the micrometer range. Delaminated MXene has a high aspect ratio, making it an alluring nanofiller for multifunctional polymer nanocomposites. Herein, we have classified and discussed the structure, properties and application of major polysaccharide-based electroactive hydrogels (hyaluronic acid (HA), alginate sodium (SA), chitosan (CS) and cellulose) in biomedical applications, starting with the brief historical account of MXene's development followed by successive discussions on the synthesis methods, structures and properties of nanocomposites encompassing polysaccharides and MXenes, including their biomedical applications, cytotoxicity and biocompatibility aspects. Finally, the MXenes and their utility in the biomedical arena is deliberated with an eye on potential opportunities and challenges anticipated for them in the future, thus promoting their multifaceted applications.

Microneedle-Based Natural Polysaccharide for Drug Delivery Systems (DDS): Progress and Challenges.

In this focused progress review, the most widely accepted methods of transdermal drug delivery are hypodermic needles, transdermal patches and topical creams. However, microneedles (MNs) (or microneedle arrays) are low-invasive 3D biomedical constructs that bypass the skin barrier and produce systemic and localized pharmacological effects. In the past, biomaterials such as carbohydrates, due to their physicochemical properties, have been extensively used to manufacture microneedles (MNs). Due to their wide range of functional groups, carbohydrates enable the design and development of tunable properties and functionalities. In recent years, numerous microneedle products have emerged on the market, although much research needs to be undertaken to overcome the various challenges before the successful introduction of microneedles into the market. As a result, carbohydrate-based microarrays have a high potential to achieve a future step in sensing, drug delivery, and biologics restitution. In this review, a comprehensive overview of carbohydrates such as hyaluronic acid, chitin, chitosan, chondroitin sulfate, cellulose and starch is discussed systematically. It also discusses the various drug delivery strategies and mechanical properties of biomaterial-based MNs, the progress made so far in the clinical translation of carbohydrate-based MNs, and the promotional opportunities for their commercialization. In conclusion, the article summarizes the future perspectives of carbohydrate-based MNs, which are considered as the new class of topical drug delivery systems.

Icariin ameliorates metabolic syndrome-induced benign prostatic hyperplasia in rats.

Metabolic syndrome (MetS) is an immense health issue that causes serious complications in aging males including BPH. Icariin (ICA) is a flavonol glycoside that exerts a plethora of pharmacological effects. The present investigation tested the potential of ICA to ameliorate benign prostatic hyperplasia (BPH) induced by MetS in rats. Animals were allocated to 5 groups in which the first and second groups were kept on water and regular food pellets. MetS was induced in the third, fourth, and fifth groups by keeping the animals on high fructose and salt diets for twelve consecutive weeks. These groups were given vehicle, ICA (25 mg/kg), and ICA (50 mg/kg), respectively. MetS was confirmed by an increase in rats' weight, accumulation of visceral fat, insulin resistance, and dyslipidemia. This was accompanied by manifestation of BPH including increased prostate weight, prostate index, and histopathological alterations. Treating the animals with both doses of ICA significantly ameliorated the increase in weight and index of the prostate as well as altered prostate histopathology. In addition, ICA significantly decreased cyclin D1 expression, upregulated Bax, and downregulated Bcl2 mRNA expression. ICA prevented lipid peroxidation, reduced glutathione depletion, and catalase exhaustion, which further lowered markers of prostate inflammation such as interleukin-6 and tumor necrosis factor-α. Moreover, ICA prevented the decrease in prostate content of phosphorylated 5'-adenosine monophosphate (AMP)-activated protein kinase (pAMPK). In conclusion, ICA protects against MetS-induced BPH. This is due to its antiproliferative, proapoptotic, antioxidant, and anti-inflammatory activities as well as the activation of AMPK.

Formulation, Optimization and Evaluation of Cytarabine-Loaded Iron Oxide Nanoparticles: From In Vitro to In Vivo Evaluation of Anticancer Activity.

Innovative drug delivery systems based on iron oxide nanoparticles (INPs) has generated a lot of interest worldwide and have prime biomedical benefits in anticancer therapy. There are still issues reported regarding the stability, absorption, and toxicity of iron oxide nanoparticles (INPs) when administered due to its rapid surface oxidation and agglomeration with blood proteins. To solve this problem, we have synthesized trehalose-coated stabilized iron oxide nanoparticles (TINPs) by a co-precipitation technique. The surface coating of INPs with trehalose helps to improve the stability, prevents protein binding, and increase absorption uptake inside the body. Developed TINPs was then loaded with anticancer drug cytarabine by chemical crosslinking encapsulation method using suitable solvent. Engineered cytarabine-loaded trehalose-coated stabilized iron oxide nanoparticles (CY-TINPs) were optimized for particle size, zeta potential (-13.03 mV), and solid-state characterization such as differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), and transmission electron microscope (TEM) studies. The particle size of 50 nm was achieved for developed CY-TINPs. The developed CY-TINPs was further evaluated for in vitro cell line investigations which confirmed potential cytotoxic activity. Developed CY-TINPs show remarkable enhancement in in vivo pharmacokinetic parameters Cmax as 425.26 ± 2.11 and AUC0-72 as 11,546.64 ± 139.82 as compared to pure drug. Compared to traditional drug delivery, the CY-TINPs formulation can effectively delay release, improve bioavailability, and boost cytotoxic activity against tumors.

Caffeic Acid Phenethyl Ester Loaded PEG-PLGA Nanoparticles Enhance Wound Healing in Diabetic Rats.

Delayed wound healing is a serious complication of diabetes and a main reason for foot amputation. Caffeic acid phenethyl ester (CAPE) is a main active constituent of honeybee propolis with reported appealing pharmacological activities. In the current study, CAPE was loaded onto PEG-PLGA nanoparticles and showed a particle size of 198 ± 7.3 nm and polydispersity index of 0.43 ± 0.04. An in vivo study was performed to appraise the wound-healing activity of CAPE-loaded PEG-PLGA nanoparticles (CAPE-NPs) in diabetic rats. Wound closure was significantly accelerated in rats treated with CAPE-NPs. This was confirmed via histological examinations of skin tissues that indicated expedited healing and enhanced collagen deposition. This was accompanied by observed antioxidant activity as evidenced by the prevention of lipid peroxidation and the exhaustion of superoxide dismutase (SOD) and catalase (CAT) activities. In addition, CAPE-NPs showed superior anti-inflammatory activity as compared with the regular formula of CAPE, as they prevented the expression of interleukin-6 (IL-6) as well as tumor necrosis-alpha (TNF-α). The pro-collagen actions of CAPE-NPs were highlighted by the enhanced hyroxyproline content and up-regulation of Col 1A1 mRNA expression. Furthermore, the immunohistochemial assessment of skin tissues indicated that CAPE-NPs enhance proliferation and angiogenesis, as shown by the increased expression of transforming growth factor ß1 (TGF-ß1) and platelet-derived growth factor subunit B (PDGF-B). In conclusion, CAPE-loaded PEG-PLGA nanoparticles possess potent healing effects in diabetic wounds. This is mediated, at least partially, by its antioxidant, anti-inflammatory, and pro-collagen as well as angiogenic activities.

The Multifaceted Role of Curcumin in Advanced Nanocurcumin Form in the Treatment and Management of Chronic Disorders.

Curcumin is the primary polyphenol in turmeric's curcuminoid class. It has a wide range of therapeutic applications, such as anti-inflammatory, antioxidant, antidiabetic, hepatoprotective, antibacterial, and anticancer effects against various cancers, but has poor solubility and low bioavailability. Objective: To improve curcumin's bioavailability, plasma concentration, and cellular permeability processes. The nanocurcumin approach over curcumin has been proven appropriate for encapsulating or loading curcumin (nanocurcumin) to increase its therapeutic potential. Conclusion: Though incorporating curcumin into nanocurcumin form may be a viable method for overcoming its intrinsic limitations, and there are reasonable concerns regarding its toxicological safety once it enters biological pathways. This review article mainly highlights the therapeutic benefits of nanocurcumin over curcumin.

Wound Healing Activity of Opuntia ficus-indica Fixed Oil Formulated in a Self-Nanoemulsifying Formulation.

INTRODUCTION: Delayed wound healing represents a common health hazard. Traditional herbal products have been often utilized to promote wound contraction. The current study aimed at assessing the wound healing activity of Opuntia ficus-indica seed oil (OFI) and its self-nanoemulsifying drug delivery system (OFI-SNEDDS) formula in a rat model of full-thickness skin excision. METHODS: Based on droplet size, an optimized OFI-SNEDDS formula was prepared and used for subsequent evaluation. Wound healing activity of OFI and OFI-SNEDDS was studied in vivo. RESULTS: The optimized OFI-SNEDDS formula droplet size was 50.02 nm. The formula exhibited superior healing activities as compared to regular OFI seed oil-treated rats at day 14 of wounding. This effect was further confirmed by histopathological examinations of H&E and Masson's Trichrome-stained skin sections. Moreover, OFI-SNEDDS showed the highest antioxidant and anti-inflammatory activities as compared to OFI seed oil-treated animals. Both OFI and OFI-SNEDDS significantly enhanced hydroxyproline skin content and upregulated Col1A1 mRNA expression, accompanied by enhanced expression of transforming factor-beta (TGF-ß). Further, OFI-SNEDDS improved angiogenesis as evidenced by increased expression of vascular endothelial growth factor (VEGF). CONCLUSION: OFI possesses wound healing properties that are enhanced by self-emulsification of the oil into nano-droplets. The observed activity can be attributed, at least partly, to its anti-inflammatory, pro-collagen and angiogenic properties.

Euryops arabicus Promotes Healing of Excised Wounds in Rat Skin: Emphasis on Its Collagen-Enhancing, Antioxidant, and Anti-Inflammatory Activities.

Euryops arabicus Steud (E. arabicus) belongs to the family Asteraceae. It has several uses in folk medicine in the Arabian Peninsula. The current study aimed at evaluating the wound healing properties of the E. arabicus extract in rats. Primarily, E. arabicus successfully accelerated cell migration in vitro and it also showed no signs of dermal toxicity. Topical application of E. arabicus extract (5% or 20%) expedited healing of excised skin in rats. Histological examinations indicated that E. arabicus shortened epithelization period, stimulated fibroblast activity, and increased collagen deposition in wound tissues. The plant extract exerted antioxidant activity as evidenced by inhibition of GSH depletion and MDA accumulation and enhanced mRNA expression of Sod1 in wound tissues collected at the end of the experiment. Further, E. arabicus inhibited the rise of TNF-α and IL-1ß in the skin wound region. The anti-inflammatory was confirmed by the observed down regulation of Ptgs2, Nos2, IL-6, and NF-κB mRNA expression. In addition, the extract enhanced the expression of TGF-ß1 and HIF-1α in wounded skin tissues as indicated immunohistochemically. Conclusively, E. arabicus expedites excision wound healing in rats. Collagen-enhancing, anti-inflammatory, and antioxidant properties mediate the observed wound healing activity. These findings might contribute to our understanding of the ethnobotanical use of E. arabicus in wounds.

Osteoprotective Activity and Metabolite Fingerprint via UPLC/MS and GC/MS of Lepidium sativum in Ovariectomized Rats.

Lepidium sativum seeds are used traditionally to accelerate healing of bone fracture in addition to its culinary uses. This study aimed to characterize the osteoprotective effect of L. sativum in an ovariectomized rat model at two dose levels (50 and 100 mg/kg) using 17ß-estradiol as a positive reference standard. Moreover, a complete metabolite profile of L. sativum via UHPLC/PDA/ESI-MS, as well as headspace solid-phase microextraction (SPME)-GC/MS is presented. Results revealed that L. sativum extract exhibited significant anti-osteoporotic actions as evidenced by mitigating the decrease in relative bone weight concurrent with improved longitudinal and perpendicular femur compression strength. Further, the extract enhanced the serum bone formation biomarkers lactate dehydrogenase (LDH) activity and osteocalcin levels. The extract also inhibited exhaustion of superoxide dismutase (SOD) as well as glutathione peroxidase (GPx) activities and accumulation of lipid peroxides in bone tissues. This is in addition to ameliorating the rise in the markers of bone resorption carboxyterminal telopeptide, type I (CTXI) and tartrate-resistant acid phosphatase (TRAP) and modulating receptor activator of nuclear factor kappa-Β ligand (RANKL)/ osteoprotegerin (OPG) expression. Metabolite characterization suggests that glucosinolates, lignans, coumarins, phenolic acids, and alkaloids mediate these anti-osteoporotic effects in a synergistic manner.