Applications of honeybee-derived products in bone tissue engineering.

Nowadays, there is an increasing prevalence of bone diseases and defects caused by trauma, cancers, infections, and degenerative and inflammatory conditions. The restoration of bone tissue lost due to trauma, fractures, or surgical removal resulting from locally invasive pathologies requires bone regeneration. As an alternative to conventional treatments, sustainable materials based on natural products, such as honeybee-derived products (honey, propolis, royal jelly, bee pollen, beeswax, and bee venom), could be considered. Honeybee-derived products, particularly honey, have long been recognized for their healing properties. There are a mixture of phytochemicals that offer bone protection through their antimicrobial, antioxidant, and anti-inflammatory properties. This review aims to summarize the current evidence regarding the effects of honeybee-derived products on bone regeneration. In conclusion, honey, propolis, royal jelly, beeswax, and bee venom can potentially serve as natural products for promoting bone health.

The Combined Effect of Curcumin and Crocin on the Reduction of Inflammatory Responses in Arthritic Rats.

The present study evaluated the anti-arthritic impact of combined crocin and curcumin on Adjuvant Induced Arthritis (AIA) in rats. Arthritis model was induced in rats by injecting Complete Freund's adjuvant (CFA) into the right hind paw and was subsequently treated with crocin and curcumin. Evaluation of anti-arthritic activity was carried out using paw swelling, hematological parameters, biochemical parameters, inflammatory cytokines, and histopathology of rats. The results showed increased paw swelling, increased serum markers levels, including CRP, RF, ALP, ALT, and AST, and inflammatory cytokines (ILlß and TNFα) along with histology changes (cartilage and bone degradation) in arthritic rats when compared to the normal group. Crocin, curcumin and crocin + curcumin administration at different doses (especially combination at 40 mg/kg and 30 mg/kg respectively), as well as MTX revealed suitable therapeutic effect on AIA rats. Moreover, both phytochemicals and their combination at different doses showed effective anti-arthritic effects owing to their anti-inflammatory effects. Therefore, crocin and curcumin, either alone or in combination, can be a suitable treatment modality for rheumatoid arthritis .

Evaluation of Antimicrobial and Wound Healing Effects of Gold Nanoparticles Containing Abelmoschus esculentus (L.) Aqueous Extract.

Background. Wound healing is a complex process of replacing devitalized cellular structures and tissues with healthy cells and tissue. Nanotechnology has been increasingly proposed as a novel platform to treat wounds and skin regeneration. The aim of this study was to evaluate the antibacterial, antioxidant, cytotoxic, and cutaneous wound healing activities of phytosynthesized Au NPs using Abelmoschus esculentus (okra) and synthesized Au NPs by using the citrate synthesis method. The Ok Au NPs were characterized using various techniques like UV-Vis absorption spectroscopy, FTIR, X-ray diffraction (XRD), and transmission electron microscopy (TEM). Cutaneous wounds were created on 30 rats and randomized into three groups: untreated and two groups treated with Ch Au NPs and Ok Au NPs. The treatment was carried out daily for 12 days. A peak characterized the Ok Au NPs at 538 nm in the UV-Vis spectrum. Based on the results of FTIR spectroscopy, various functional oxygenated groups such as hydroxyl, carboxyl, and nitrogenous groups were observed. XRD confirmed the crystalline nature of the nanoparticles. TEM images of Ok Au NPs showed a spherical shape and size range of 75 nm. DPPH test showed similar antioxidant potentials for Au NPs. The Au NPs showed cell viability in a dose-dependent manner, and this technique was found to be nontoxic. Agar well diffusion, which is the method to determine antibacterial characteristics of Au NPs, showed a significant beneficial effect against a variety of bacterial species. In addition, histopathological results showed that Au NPs could accelerate wound closure. Therefore, Au NPs could be suitable for wound healing applications.

Bortezomib: a proteasome inhibitor for the treatment of autoimmune diseases.

Autoimmune diseases (ADs) are conditions in which the immune system cannot distinguish self from non-self and, as a result, tissue injury occurs primarily due to the action of various inflammatory mediators. Different immunosuppressive agents are used for the treatment of patients with ADs, but some clinical cases develop resistance to currently available therapies. The proteasome inhibitor bortezomib (BTZ) is an approved agent for first-line therapy of people with multiple myeloma. BTZ has been shown to improve the symptoms of different ADs in animal models and ameliorated symptoms in patients with systemic lupus erythematous, rheumatoid arthritis, myasthenia gravis, neuromyelitis optica spectrum disorder, Chronic inflammatory demyelinating polyneuropathy, and autoimmune hematologic diseases that were nonresponsive to conventional therapies. Proteasome inhibition provides a potent strategy for treating ADs. BTZ represents a proteasome inhibitor that can potentially be used to treat AD patients resistant to conventional therapies.

Utilization of Lipid-based Nanoparticles to Improve the Therapeutic Benefits of Bortezomib.

Cancer is a condition where there is an uncontrolled growth of cells resulting in high mortality. It is the second most frequent cause of death worldwide. Bortezomib (BTZ) is a Proteasome Inhibitor (PI) that is used for the treatment of a variety of cancers. It is the first PI that has received the approval of the US Food and Drug Administration (FDA) to treat mantle cell lymphoma and multiple myeloma. High incidence of sideeffects, limited dose, low water solubility, fast clearance, and drug resistance are the significant limitations of BTZ. Therefore, various drug delivery systems have been tried to overcome these limitations of BTZ in cancer therapy. Nanotechnology can potentially enhance the aqueous solubility of BTZ, increase its bioavailability, and control the release of BTZ at the site of administration. The lipid-based nanocarriers, such as liposomes, solid lipid NPs, and microemulsions, are some of the developments in nanotechnology, which could potentially enhance the therapeutic benefits of BTZ.

The Effect of Phase Transition Temperature on Therapeutic Efficacy of Liposomal Bortezomib.

AIMS: Here, three liposomal formulations of DPPC/DPPG/Chol/DSPE-mPEG2000 (F1), DPPC/DPPG/Chol (F2) and HSPC/DPPG/Chol/DSPE-mPEG2000 (F3) encapsulating BTZ were prepared and characterized in terms of their size, surface charge, drug loading, and release profile. Mannitol was used as a trapping agent to entrap the BTZ inside the liposomal core. The cytotoxicity and anti-tumor activity of formulations were investigated in vitro and in vivo in mice bearing tumor. BACKGROUND: Bortezomib (BTZ) is an FDA approved proteasome inhibitor for the treatment of mantle cell lymphoma and multiple myeloma. The low solubility of BTZ has been responsible for the several side effects and low therapeutic efficacy of the drug. Encapsulating BTZ in a nano drug delivery system; helps overcome such issues. Among NDDSs, liposomes are promising diagnostic and therapeutic delivery vehicles in cancer treatment. OBJECTIVE: Evaluating anti-tumor activity of bortezomib liposomal formulations. METHODS: Data prompted us to design and develop three different liposomal formulations of BTZ based on Tm parameter, which determines liposomal stiffness. DPPC (Tm 41°C) and HSPC (Tm 55°C) lipids were chosen as variables associated with liposome rigidity. In vitro cytotoxicity assay was then carried out for the three designed liposomal formulations on C26 and B16F0, which are the colon and melanoma cancer mouse-cell lines, respectively. NIH 3T3 mouse embryonic fibroblast cell line was also used as a normal cell line. The therapeutic efficacy of these formulations was further assessed in mice tumor models. RESULT: MBTZ were successfully encapsulated into all the three liposomal formulations with a high entrapment efficacy of 60, 64, and 84% for F1, F2, and F3, respectively. The findings showed that liposomes mean particle diameter ranged from 103.4 to 146.8nm. In vitro cytotoxicity studies showed that liposomal-BTZ formulations had higher IC50 value in comparison to free BTZ. F2-liposomes with DPPC, having lower Tm of 41°C, showed much higher anti-tumor efficacy in mice models of C26 and B16F0 tumors compared to F3-HSPC liposomes with a Tm of 55°C. F2 formulation also enhanced mice survival compared with untreated groups, either in BALB/c or in C57BL/6 mice. CONCLUSION: Our findings indicated that F2-DPPC-liposomal formulations prepared with Tm close to body temperature seem to be effective in reducing the side effects and increasing the therapeutic efficacy of BTZ and merits further investigation.

Enhancing the Therapeutic Efficacy of Bortezomib in Cancer Therapy Using Polymeric Nanostructures.

Bortezomib (VELCADE®) is a boronate peptide and first-in-class proteasome inhibitor serving an important role in degenerating several intracellular proteins. It is a reversible inhibitor of the 26S proteasome, with antitumor activity and antiproliferative properties. This agent principally exerts its antineoplastic effects by inhibiting key players in the nuclear factor κB (NFκB) pathway involved in cell proliferation, apoptosis, and angiogenesis. This medication is used in the management of multiple myeloma. However, more recently, it has been used as a therapeutic option for mantle cell lymphoma. While promising, bortezomib has limited clinical applications due to its adverse effects (e.g., hematotoxicity and peripheral neuropathy) and low effectiveness in solid tumors resulting from its poor penetration into such masses and suboptimal pharmacokinetic parameters. Other limitations to bortezomib include its low chemical stability and bioavailability, which can be overcome by using nanoparticles for its delivery. Nanoparticle delivery systems can facilitate the targeted delivery of chemotherapeutic agents in high doses to the target site, while sparing healthy tissues. Therefore, this drug delivery system has provided a solution to circumvent the limitations faced with the delivery of traditional cancer chemotherapeutic agents. Our aim in this review was to describe polymer-based nanocarriers that can be used for the delivery of bortezomib in cancer chemotherapy.

Parenteral systems for statin delivery: a review.

The oral route of drug administration is the most common and convenient route for dosing statin drugs, and, in fact, most medications, because of ease of drug delivery, patient compliance, and cost-effectiveness. However, the oral administration of statin drugs has disadvantages such as hepatic first-pass metabolism and degradation within the gastrointestinal tract that limit their overall bioavailability. This review introduces several diverse non-oral delivery methods for the administration of statins. These alternative delivery systems and routes of administration are varied and are capable of improving the bioavailability and therapeutic efficacy of statin drugs.

Therapeutic effects of Crocin in autoimmune diseases: A review.

The immune system when acts against selfmolecules results in an imbalance in immunologic tolerance leading to the development of several autoimmune diseases (ADs) such as rheumatoid arthritis, asthma, ulcerative colitis, type 1 diabetes, and multiple sclerosis. Improved recognition of the mechanisms of ADs has led to the advancement of the management of these diseases. The principal mediators of ADs are inflammatory molecules. The herbal medicines due to their antioxidant and antiinflammatory properties have an important role in the management of ADs. Crocin is the principal chemical component extracted from saffron, which is a medicinal plant. This review focuses on the therapeutic effects of Crocin in various ADs.

Preparation and characterization of nanoliposomal bortezomib formulations and evaluation of their anti-cancer efficacy in mice bearing C26 colon carcinoma and B16F0 melanoma.

Three Bortezomib (BTZ) liposomal formulations including of HSPC/Cholesterol/DSPE-mPEG2000 (F1), HSPC/DSPG/Cholesterol (F2), and HSPC/DSPG/Cholesterol/DSPE-mPEG2000 (F3) were prepared and characterized. Results demonstrated that the size of formulations ranged 72-92 nm. The DSPE-mPEG2000 containing formulations (F1 and F3) had higher BTZ encapsulation compared to F2 formulation. The size of the liposomal formulations increased slightly when stored at 4 °C for 6 months; the zeta potential of formulations remained constant. There were no significant differences in the release properties BTZ from liposomal formulations in pH 7.0; however, in acidic pH of 5.5 the release of BTZ from F1 and F3 was higher than F2. Three formulations cytotoxicity studies demonstrated IC50 values more than free BTZ on all cell lines examined. Evaluation of antitumor activity in mice bearing C26 colon carcinoma and B16F0 melanoma tumors showed that all the designed liposomal formulations have higher efficacy compared to free BTZ. In tumor models, F2 was more effective than the F1 and F3. Our findings indicated that F2 considerably increased the therapeutic efficacy of BTZ, which promises new formulation with the potential use in clinic and merits further investigation.

The molecular mechanisms of curcumin's inhibitory effects on cancer stem cells.

Curcumin is a dietary polyphenol and a bioactive phytochemical that possesses anti-inflammatory, antioxidant, anticancer, and chemopreventive properties, which make it capable of affecting multiple sites along the stem cell pathways to induce apoptosis in these cells. Curcumin's function is through suppression of cytokine release, especially the secretion of interleukins. Some of the predominant activities of stem cells include regeneration of identical cells and the ability to maintain the proliferation and multipotentiality. However, these cells could be stimulated to differentiate into specific cell types, leading to the development of tumors. Cancer stem cells (CSC) are capable of sustaining tumor formation and differentiation, and are normally characterized by self-renewal mechanisms. Furthermore, these cells might be responsible for tumor relapse and resistance to therapy. Several studies have focused on the mechanisms of curcumin action in manipulating transcription factors, signaling pathways, CSC markers, microRNAs related to CSCs functions and apoptosis induction in various human cancer cells. In the present review, we aimed to summarize the reported molecular mechanisms of curcumin's effects on CSCs.

Application of nanotechnology to improve the therapeutic benefits of statins.

Hyperlipidemia is defined as an elevated level of lipids and lipoproteins in the blood and is considered to be a significant risk factor for accelerating the process of atherosclerosis and, consequently, cardiovascular disease. The level of cholesterol, especially low-density lipoprotein cholesterol (LDL-C), is commonly elevated in hyperlipidemia and represents the primary therapeutic target. Statins are a group of drugs that function by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and are extremely efficacious in reducing elevated LDL-C in the serum and preventing atherosclerotic cardiovascular disease. However, statins have some limitations, such as poor aqueous solubility, low oral absorption, and, consequently, limited bioavailability when administered by the oral route. The field of nanotechnology is now well developed and some of these newer nanotechnology strategies offer systems with enhanced aqueous solubility of the statin, increased absorption, bioavailability, and controlled release of the statin at the site of administration. Here, we discuss nano-sized drug delivery systems to enhance the therapeutic potential of statins.

Genetics and rheumatoid arthritis susceptibility in Iran.

Rheumatoid arthritis (RA) is an autoimmune disorder with a number of risk factors, including both genetic and environmental. A number of RA risk associated genomic loci has been identified. In this review, we summarize the association of genetic factors with RA reported in population studies in Iran. No significant association was found between the majority of genetic factors identified in other populations and risk for RA in the Iranian subjects. This conflicting result could be due to the ethnic differences and diversity that are present in Iran. We conclude that there is a need to investigate larger groups of Iranian subjects, encompassing different regions of Iran, to either prove or refute these initial findings.

Sub-chronic Dermal Toxicity of Silver Nanoparticles in Guinea Pig: Special Emphasis to Heart, Bone and Kidney Toxicities.

Silver nanoparticles (Ag NPs) have been widely used as new potent antimicrobial agents in cosmetic and hygienic products. Present study compares the tissue levels of Ag NPs in different organs of Guiana Pigs quantitatively after dermal application and analysis the morphological changes and pathological abnormalities on the basis of the Ag NPs tissue levels. Before toxicological assessments,the size of colloidal nanosilver was recorded by X-Ray Diffraction and Transmission Electron Microscope tests and the sizes of samples were recorded in sizes less than 100 nm. For toxicological evaluation, male guinea pigs were exposed to three concentrations of Ag NPs (100, 1000 and 10000 ppm) according to acute pretests for further assessments in subchronic model in a period of 13 weeks . A close correlation between dermal exposure and tissue levels of Ag NPs was found (p < 0.05) and tissue uptakes happened in dose dependent manner with the following ranking: ki dney>muscle>bone>skin>liver>heart >spleen. In histopathological studies, severe proximal convoluted tubule degeneration and distal convoluted tubule were seen in the kidneys of the middle and high-dose animals. Separated lines and marrow space narrow were determined as two major signs of bone toxicities which observed in three different dose levels of Ag NPs. Increased dermal dose of Ag NPs caused cardiocyte deformity, congestion and inflammation. The three different Ag NPs concentration gave comparable results for several endpoints measured in heart, bone and kidney, but differed in tissue concentrations and the extent of histopathological changes. It seems that Ag ions could be detected in different organs after dermal exposure ,which has the potential to provide target organ toxicities in a time and dose dependent manner.

Toxicity assessment of nanosilver wound dressing in Wistar rat.

Antibiotic resistance to microorganisms is one of the major problems faced in the field of wound care in burns patients. Silver nanoparticles have come up as potent antimicrobial agent and are being evaluated in diverse medical applications ranging from silver based dressings to silver coated medical devices. We aimed in present study to test the release of nanosilver from nanosilver wound dressing and compare the dermal and systemic toxicity of nanosilver dressings in a repeated dose (21 days) model. Under general anesthesia, a limited standard 2nd degree burns were provided on the back of each rat in all treatment, negative control (simple dressing) and 5% silver nitrate groups, each contained 5 male wistar rats. According to the analysis made by atomic absorption spectrometry, the wound dressings released 0.599 ± 0.083 ppm of nanosilver during first 24 hrs of study. Daily observations were recoded and wounds were covered with new dressings each 24 hrs. Burn healing was observed in nanosilver wound dressing group in shorter time periods than the control groups. In toxicity assessment, this dressing didn't cause any hematological and histopathological abnormalities in treatment group but biochemical studies showed significant rise of plasma transaminase (ALT) at the endpoint (21 days) of the study (P=0.027). Portal mononuclear lymphoid and polymorphonuclear leukocyte infiltrations in three to four adjacent foci were recognized around the central hepatic vein in treatment group. Mild hepatotoxic effects of nanosilver wound dressing in wistar rat emphasize the necessity of more studies on toxicity potentials of low dose nanosilver by dermal applications.

Association between glycodelin and aryl hydrocarbon receptor in Iranian breast cancer patients: impact of environmental endocrine disrupting chemicals.

Breast cancer affects Iranian women one decade younger than their counterparts in other countries and the underlying risk factors have remained controversial. The aryl hydrocarbon receptor (AhR) mediates the effects of many environmental endocrine disruptors and contributes to the many other genes and Gd is an endocrine-regulated glycoprotein which may induce by AhR ligands in endometrium. This study has aimed to compare the interactions between Gd and AhR and other fundamental genes (p53, K-Ras, ER, PgR, AR) between pre and post menopausal Iranian breast cancer patients. To conduct immunohistochemical studies with appropriate monoclonal antibodies, 25 premenopausal invasive ductal carcinomas and 29 postmenopausal invasive ductal carcinomas were selected retrospectively in 2008-2010 from the pathology department of Imam Khomeini hospital complex of Tehran. Higher levels of AhR in epithelial cells of premenopausal patients and breast fibroadenoma emphasized the susceptibility of these cells to environmental induced tumors. Current study demonstrated a significant association between tumoral levels of Gd and AhR (p=0.002) in breast cancers which confirms the preliminary hypothesis about the role of TCDD exposure on Gd biosynthesis and secretion in TCDD-treated endometrial epithelial cells. In summary this study showed the dual prognostic role of Gd especially in premenopausal breast cancer which could be induced by AhR overexpression. Further studies are necessary to find the direct role of breast carcinogens as well as endocrine disrupting chemicals on the differential levels of Gd in breast tumors.