PEGylated Pemetrexed and PolyNIPAM Decorated Gold Nanoparticles: A Biocompatible and Highly Stable CT Contrast Agent for Cancer Imaging.

This study describes a multifunctional nanoparticle platform for targeted CT imaging and therapy of cancers. Pemetrexed (conjugated with polyethylene glycol, MW 2000 Da) and polyNIPAM (PEGylated) were designed for targeted delivery to folate receptors and thermally ablated tumors, respectively. These moieties were coated on gold nanoparticles (7 and 30 nm), and the prepared compounds were characterized using 1H NMR, FT-IR, CHNS, DLS, TEM, TGA, and UV-vis. The resulting agents exhibited 2-4 times higher X-ray attenuation compared to Visipaque and demonstrated specific accumulation in tumor tissue (4T1 xenograft model) 90 min after injection in mice. The nanoparticles displayed anticancer activity against 4T1 and MDA-MB-231 breast cancer cells (IC50: 182.87 and 206.18 µg/mL) and good biocompatibility. Importantly, the platform showed excellent stability over a year and at pH 2-12 and temperature range of -78 to 40 °C, and a water-dichloromethane extraction method was optimized for efficient purification, facilitating large-scale production.

Dynamic Adaptation in Extant Porins Facilitates Antibiotic Tolerance in Energetic Escherichia coli.

Bacteria can tolerate antibiotics despite lacking the genetic components for resistance. The prevailing notion is that tolerance results from depleted cellular energy or cell dormancy. In contrast to this view, many cells in the tolerant population of Escherichia coli can exhibit motility - a phenomenon that requires cellular energy, specifically, the proton-motive force (PMF). As these motile-tolerant cells are challenging to isolate from the heterogeneous tolerant population, their survival mechanism is unknown. Here, we discovered that motile bacteria segregate themselves from the tolerant population under micro-confinement, owing to their unique ability to penetrate micron-sized channels. Single-cell measurements on the motile-tolerant population showed that the cells retained a high PMF, but they did not survive through active efflux alone. By utilizing growth assays, single-cell fluorescence studies, and chemotaxis assays, we showed that the cells survived by dynamically inhibiting the function of existing porins in the outer membrane. A drug transport model for porin-mediated intake and efflux pump-mediated expulsion suggested that energetic tolerant cells withstand antibiotics by constricting their porins. The novel porin adaptation we have uncovered is independent of gene expression changes and may involve electrostatic modifications within individual porins to prevent extracellular ligand entry.

One-Step Preparation of Luteolin Nanoemulsion and Evaluation of its Anti-inflammatory Effect in Animal Models.

BACKGROUND: Nanoemulsions are promising drug delivery systems for topical application owing to the high transdermal penetration. OBJECTIVE: Due to the side effects of existing anti-inflammatory drugs, much attention has been paid to natural products such as flavonoids. The aim of this work was to formulate luteolin nanoemulsion (LNE) and to evaluate its anti-inflammatory effect. METHODS: LNE was prepared using the low-energy spontaneous emulsion method and characterized by transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy and dynamic light scattering (DLS). The anti-inflammatory effect of LNE was assessed in formalin and acetic acid-induced inflammation methods (Whittle test). Treatment with LNE (i.p, 4 consecutive days, 40 mg/kg) was compared with diclofenac 25 mg/kg and normal saline. In the formalin test, data were recorded at 1, 2 and 4 hours after formalin injection and in the Wittle test, the extent of Evans blue leakage in the peritoneal cavity was considered as vascular permeability. RESULTS: Formalin-induced edema decreased in the LNE group, but this reduction was not significant (p > 0.05), however, in Whittle test, both LNE and diclofenac significantly reduced Evans blue leakage compared with the group treated with acetic acid alone (p < 0.05). CONCLUSION: Our results confirm the anti-inflammatory effect of LNE and give up a new platform for the design and development of bio-based carriers for more successful drug delivery.

The role of glycans in the mechanobiology of cancer.

Although cancer is a genetic disease, physical changes such as stiffening of the extracellular matrix also commonly occur in cancer. Cancer cells sense and respond to extracellular matrix stiffening through the process of mechanotransduction. Cancer cell mechanotransduction can enhance cancer-promoting cell behaviors such as survival signaling, proliferation, and migration. Glycans, carbohydrate-based polymers, have recently emerged as important mediators and/or modulators of cancer cell mechanotransduction. Stiffer tumors are characterized by increased glycan content on cancer cells and their associated extracellular matrix. Here we review the role of cancer-associated glycans in coupled mechanical and biochemical alterations during cancer progression. We discuss the recent evidence on how increased expression of different glycans, in the form of glycoproteins and proteoglycans, contributes to both mechanical changes in tumors and corresponding cancer cell responses. We conclude with a summary of emerging tools that can be used to modify glycans for future studies in cancer mechanobiology.

A review on in vitro/in vivo response of additively manufactured Ti-6Al-4V alloy.

Bone replacement using porous and solid metallic implants, such as Ti-alloy implants, is regarded as one of the most practical therapeutic approaches in biomedical engineering. The bone is a complex tissue with various mechanical properties based on the site of action. Patient-specific Ti-6Al-4V constructs may address the key needs in bone treatment for having customized implants that mimic the complex structure of the natural tissue and diminish the risk of implant failure. This review focuses on the most promising methods of fabricating such patient-specific Ti-6Al-4V implants using additive manufacturing (AM) with a specific emphasis on the popular subcategory, which is powder bed fusion (PBF). Characteristics of the ideal implant to promote optimized tissue-implant interactions, as well as physical, mechanical/chemical treatments and modifications will be discussed. Accordingly, such investigations will be classified into 3B-based approaches (Biofunctionality, Bioactivity, and Biostability), which mainly govern native body response and ultimately the success in implantation.

Mercury Exposure and Risk of Type 2 Diabetes: A Systematic Review and Meta-Analysis.

Methods: Scopus and PubMed databases were systematically searched from their inception to November 2021 to obtain pertinent studies. Standardized mean differences (SMDs) with corresponding 95% confidence intervals (CIs) were calculated to evaluate the difference in Hg levels between people with and without T2DM. The association of the Hg exposure with T2DM was assessed using a random-effects model by pooling the odds ratios (ORs) and 95% CIs. Results: A total of 17 studies, with 42,917 participants, aged ≥18 years, were analyzed. Overall, Hg levels were significantly higher in T2DM patients compared with non-T2DM controls (SMD = 1.07; 95%CI = 0.59 to 1.55, P ≤ 0.001), with significant heterogeneity across studies (I2 = 96.1%; P=≤0.001). No significant association was found between Hg exposure and risk of T2DM in the overall analysis and subgroup analysis based on the source of sample and study design. However, higher exposure to Hg was related to reduced risk of T2DM in men (OR = 0.71; 95%CI = 0.57 to 0.88), but not in women. No significant evidence for publication bias was detected. Conclusions: Although the Hg level in T2DM is significantly higher than that of nondiabetics, there was no association between Hg exposure and the overall risk of T2DM. Nevertheless, our study shows that higher exposure to Hg might reduce the risk of T2DM in men.

Diosgenin: Mechanistic Insights on its Anti-inflammatory Effects.

Diosgenin (DG), a well-known steroid saponin, has shown anti-inflammatory effects. This review was aimed to discuss all published literature concerning the anti-inflammatory effects of diosgenin. Based on the modulatory impact of DG on the NF-κB pathway, its supplementation is associated with downregulation of the NF-κB pathway and TGF-ß, resulting in inhibition of inflammation. It appears that upstream modulators of NF-κB signaling pathways such as Tlrs and downstream mediators include iNOS and COX-2, leading to the inhibition of the inflammatory response and development of pathological conditions. Due to the low toxicity of the herbal compounds, the risk of the side effects of DG use for the management of inflammatory disorders such as asthma, rheumatism, rhinitis, and arthritis is lower than that of synthetic glucocorticoids. It has been shown that regulation of NF-κB and oxidative stress signaling pathways by DG is beneficial against cardiotoxicity induced by chemotherapeutic agents such as doxorubicin.

Cell encapsulation in alginate-based microgels using droplet microfluidics; a review on gelation methods and applications.

Cell encapsulation within the microspheres using a semi-permeable polymer allows the two-way transfer of molecules such as oxygen, nutrients, and growth factors. The main advantages of cell encapsulation technology include controlling the problems involved in transplanting rejection in tissue engineering applications and reducing the long-term need for immunosuppressive drugs following organ transplantation to eliminate the side effects. Cell-laden microgels can also be used in 3D cell cultures, wound healing, and cancerous clusters for drug testing. Since cell encapsulation is used for different purposes, several techniques have been developed to encapsulate cells. Droplet-based microfluidics is one of the most valuable techniques in cell encapsulating. This study aimed to review the geometries and the mechanisms proposed in microfluidic systems to precisely control cell-laden microgels production with different biopolymers. We also focused on alginate gelation techniques due to their essential role in cell encapsulation applications. Finally, some applications of these microgels and researches will be explored.

Investigating the protective role of metformin on lithium-induced hypothyroidism.

Induction of oxidative stress events has been shown to be associated with lithium (Li) hypothyroidism induction. Metformin (MET) is a commonly used antidiabetic drug with multiple properties including antiproliferative activity, antioxidant potency, and is used in polycystic ovarian syndrome treatment. Here, in this study, we aimed to investigate the effect of different doses of MET on Li-induced hypothyroidism for elucidating its mechanism of action. The obtained results demonstrated the oxidative stress reduction in thyroid tissues upon MET treatment. Besides this, the biochemical analysis revealed a significant reduction in T3 and TSH levels (down to 2 ng/ml and 0.05 µU/ml, respectively) in coordination with an observable reduction in T4 level (up to 2.1 ng/ml). Also, a significant reduction in Li-related tissue damages including changes in the morphology and the size of follicles, rate of vascularity, detachment of follicular cells, inflammatory cells infiltration, and follicular cells hypertrophy and disruption was observed. Ultimately, regarding the significant improvement in thyroid tissues and valuable antioxidant activity determined in tissues treated with MET, it is concluded that MET co-administration with Li can significantly reduce the negative effects of Li and enhance the efficacy of Li therapy.

Carbon-based Nanomaterials and Curcumin: A Review of Biosensing Applications.

Curcumin, the main active constituent of turmeric (Curcuma longa L.), is a naturally occurring phenolic compound with a wide variety of pharmacological activities. Although it has multiple pharmaceutical properties, its bioavailability and industrial usage are hindered due to rapid hydrolysis and low water solubility. Due to the growing market of curcumin, exact determination of curcumin in trade and human biological samples is important for monitoring therapeutic actions. Different nanomaterials have been suggested for sensing curcumin; and in this case, carbon-based nanomaterials (CNMs) are one of the most outstanding developments in nanomedicine, biosensing, and regenerative medicine. There are a considerable number of reports which have shown interesting potential of CNMs-based biosensors in the sensitive and selective detection of curcumin. Therefore, this review aims to increase understanding the interaction of curcumin with CNMs in the context of biosensing.

The Diagnosis and Treatment of a Rare Maxillary Plasmacytoma: a Case Report.

The jaw plasmacytoma is a very rare condition, which its diagnosis is difficult in clinical routine. Up to now, less than 60 cases of jaw plasmacytoma have been reported in the literature. In the present case report, we reported a rare case of jaw plasmacytoma in a 42-year-old female, which was misdiagnosed with dental granuloma and abscess. The diagnosis of plasmacytoma was done by immunohistochemistry (IHC) evaluation following a cone beam computed tomography (CBCT) assessment. The patient was treated with radiotherapy and is disease free after 2 years.

Sol-Gel Synthesis, Physico-Chemical and Biological Characterization of Cerium Oxide/Polyallylamine Nanoparticles.

Cerium oxide nanoparticles (CeO2-NPs) have great applications in different industries, including nanomedicine. However, some studies report CeO2-NPs-related toxicity issues that limit their usage and efficiency. In this study, the sol-gel method was applied to the synthesis of CeO2-NPs using poly(allylamine) (PAA) as a capping and/or stabilizing agent. The different molecular weights of PAA (15,000, 17,000, and 65,000 g/mol) were used to investigate the physico-chemical and biological properties of the NPs. In order to understand their performance as an anticancer agent, three cell lines (MCF7, HeLa, and erythrocyte) were analyzed by MTT assay and RBC hemolysis assay. The results showed that the CeO2-NPs had anticancer effects on the viability of MCF7 cells with half-maximal inhibitory concentration (IC50) values of 17.44 ± 7.32, 6.17 ± 1.68, and 0.12 ± 0.03 µg/mL for PAA15000, PAA17000, PAA65000, respectively. As for HeLa cells, IC50 values reduced considerably to 8.09 ± 1.55, 2.11 ± 0.33, and 0.20 ± 0.01 µg/mL, in order. A decrease in the viability of cancer cells was associated with the 50% hemolytic concentration (HC50) of 0.022 ± 0.001 mg/mL for PAA15000, 3.74 ± 0.58 mg/mL for PAA17000, and 7.35 ± 1.32 mg/mL for PAA65000. Ultraviolet-Visible (UV-vis) spectroscopy indicated that an increase in the PAA molecular weight led to a blue shift in the bandgap and high amounts of Ce3+ on the surface of the nanoceria. Thus, PAA65000 could be considered as a biocompatible nanoengineered biomaterial for potential applications in cancer nanomedicine.

Curcumin: a phytochemical modulator of estrogens and androgens in tumors of the reproductive system.

Curcumin (Cur) is an active derivative extracted from turmeric which exerts a wide range of interactions with biomolecules through complex signaling pathways. Cur has been extensively shown to possess potential antitumor properties. In addition, there is growing body of evidence suggesting that Cur may exert potential anti-estrogen and anti-androgen activity. In vitro and in vivo studies suggest that anticancer properties of Cur against tumors affecting the reproductive system in females and males may be underlied by the Cur-mediated inhibition of androgen and estrogen signaling pathways. In this review we examine various studies assessing the crosstalk between Cur and both androgen and estrogen hormonal activity. Also, we discuss the potential chemopreventive and antitumor role of Cur in the most prevalent cancers affecting the reproductive system in females and males.

Clinical and Radiographic Assessments of Tooth Socket Preservation Using Leukocyte Platelet-Rich Fibrin.

Leukocyte platelet-rich fibrin (L-PRF) has the potential to accelerate wound healing. Here, we assess clinical and radiographic outcomes of socket preservation using L-PRF. For this single-blind, randomized, split-mouth clinical trial, we selected 22 patients (15 males and seven females), who required extraction of single-rooted teeth. Subjects were randomly assigned to two groups. We used L-PRF in the extraction socket on one side and no material on the contralateral side. We obtained cone-beam computed tomographic images and diagnostic casts from tooth extraction sockets before surgery and 3 mo after the procedure. Changes in buccolingual diameter and height of bone at 3 mo after tooth extraction (compared to baseline) were determined and digitized data statistically analyzed using Statistical Package for the Social Sciences software, ver. 25.0 (IBM, Armonk, NY) via the paired t-test. In tooth sockets with/without L-PRF application 3 mo after extraction, bone buccolingual diameter significantly decreased at socket center to 0, 1, and 3 mm from the ridge crest, compared to baseline. A significant reduction occurred in sockets with/without L-PRF application in buccal and lingual bone height at the bony socket midbuccal portion of and mesial and distal septa (p < 0.0001). However, the Mann-Whitney U test showed changes to be significantly greater in controls than the case group (p < 0.0001). Taking into account study limitations, application of L-PRF in tooth extraction sockets significantly decreased reductions in bone height and buccolingual diameter compared to control sockets.

Clinical Features, Treatment, Prognosis, and Mortality in Paraquat Poisonings: A Hospital-Based Study in Iran.

OBJECTIVE: The aim of the present study was to evaluate the demographics, clinical characteristics, fatal dose, the efficacy of treatments, and prognosis in paraquat (PQ) poisoning in the Kerman Province of Iran. METHODS: This analytical cross-sectional study was conducted on 126 PQ poisoned patients who were referred to Afzalipour Hospital during 2006-2015. Demographic variables such as age and gender, signs and symptoms of poisoning, the estimated ingested dosage of PQ, and clinical outcome were extracted from medical records. Patients were compared and categorized into two groups considering the outcome: survivors and nonsurvivors. Patients with nonoral exposures, combined drug exposures, PQ exposures more than 24 h before the presentation, and critical underlying diseases were not included in the study. FINDINGS: Our results indicated that the mean dose of PQ used by all patients was 2358 mg, which was reported as 1846 and 2812 mg in females and males, respectively. Moreover, the results showed that the highest mortality rate was in patients with respiratory distress, followed by oral ulceration and excess salivation. In all PQ-poisoned patients, the dose of greater than approximately 2250 mg predicted death with 86.2% specificity and 75.7% sensitivity. CONCLUSION: Based on the results of the present study, the mortality rate in PQ-poisoned patients depended on the dose of poison, blood sugar level, and aspartate transaminase levels. Our results suggest that these parameters have excellent prognostic value for the prediction of mortality.

Antiproliferative Effects of Free and Encapsulated Hypericum Perforatum L. Extract and Its Potential Interaction with Doxorubicin for Esophageal Squamous Cell Carcinoma.

OBJECTIVES: Esophageal squamous cell carcinoma (ESCC) is considered as a deadly medical condition that affects a growing number of people worldwide. Targeted therapy of ESCC has been suggested recently and required extensive research. With cyclin D1 as a therapeutic target, the present study aimed at evaluating the anticancer effects of doxorubicin (Dox) or Hypericum perforatum L. (HP) extract encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles on the ESCC cell line KYSE30. METHODS: Nanoparticles were prepared using double emulsion method. Cytotoxicity assay was carried out to measure the anti-proliferation activity of Dox-loaded (Dox NPs) and HP-loaded nanoparticles (HP NPs) against both cancer and normal cell lines. The mRNA gene expression of cyclin D1 was evaluated to validate the cytotoxicity studies at molecular level. RESULTS: Free drugs and nanoparticles significantly inhibited KYSE30 cells by 55-73% and slightly affected normal cells up to 29%. The IC50 of Dox NPs and HP NPs was ~ 0.04-0.06 mg/mL and ~ 0.6-0.7 mg/mL, respectively. Significant decrease occurred in cyclin D1 expression by Dox NPs and HP NPs (P < 0.05). Exposure of KYSE-30 cells to combined treatments including both Dox and HP extract significantly increased the level of cyclin D1 expression as compared to those with individual treatments (P < 0.05). CONCLUSION: Dox NPs and HP NPs can successfully and specifically target ESCC cells through downregulation of cyclin D1. The simultaneous use of Dox and HP extract should be avoided for the treatment of ESCC.

Carbon nanomaterials and amyloid-beta interactions: potentials for the detection and treatment of Alzheimer's disease?

Carbon-based nanomaterials have unique physicochemical properties relevant to the diagnosis and treatment of various diseases. There have been many reports indicating that carbon nanomaterials (CNMs) can interact and perturb biomolecules such as proteins and amyloid structures. This review is an attempt to reflect the role of CNMs in the treatment and detection of Alzheimer's disease (AD). The potential of CNMs in the field of neuroscience has also been reviewed. The exposure to CNMs ends up with effective radical and peptide scavenging structures, which, in turn, inhibit further formation and progression of amyloid fibrils. However, the effect of CNMs on initial nucleation and lag phase in this process may promote fibrillation. We have discussed the controversy that whether CNMs promote or inhibit the formation of amyloid beta (Aß) fibrils to help preventing their toxicity or enhancing their therapeutic effects.

Effects of estrogens and androgens on mitochondria under normal and pathological conditions.

Several lines of evidence have suggested that mitochondrial dysfunction plays a key role in neurodegeneration. The mitochondrial function is a potential target for steroid hormones, which could exert protective activities in the brain and other tissues. The decrease of some sex steroids with aging has been associated with deleterious effects on brain function and progression to neurodegenerative diseases. Recent in vitro and in vivo evidence provides the basis for this review on the interplay of sex steroids and mitochondrial defects in preventing or improving pathological events in the central nervous system (CNS). In this article, the role of mitochondria under normal and pathological states will be discussed. In addition, we will review studies conducted on steroidal compounds, which have neuroprotective effects targeting mitochondria. It has been shown that these compounds could exert both direct and indirect effects on mitochondria that promote or preserve mitochondrial function under pathological circumstances, such as acute brain injury and chronic neurodegeneration.

Mast cell tryptase - Marker and maker of cardiovascular diseases.

Mast cells are tissue-resident cells, which have been proposed to participate in various inflammatory diseases, among them the cardiovascular diseases (CVDs). For mast cells to be able to contribute to an inflammatory process, they need to be activated to exocytose their cytoplasmic secretory granules. The granules contain a vast array of highly bioactive effector molecules, the neutral protease tryptase being the most abundant protein among them. The released tryptase may act locally in the inflamed cardiac or vascular tissue, so contributing directly to the pathogenesis of CVDs. Moreover, a fraction of the released tryptase reaches the systemic circulation, thereby serving as a biomarker of mast cell activation. Actually, increased levels of circulating tryptase have been found to associate with CVDs. Here we review the biological relevance of the circulating tryptase as a biomarker of mast cell activity in CVDs, with special emphasis on the relationship between activation of mast cells in their tissue microenvironments and the pathophysiological pathways of CVDs. Based on the available in vitro and in vivo studies, we highlight the potential molecular mechanisms by which tryptase may contribute to the pathogenesis of CVDs. Finally, the synthetic and natural inhibitors of tryptase are reviewed for their potential utility as therapeutic agents in CVDs.

Curcumin: A naturally occurring autophagy modulator.

Autophagy is a self-degradative process that plays a pivotal role in several medical conditions associated with infection, cancer, neurodegeneration, aging, and metabolic disorders. Its interplay with cancer development and treatment resistance is complicated and paramount for drug design since an autophagic response can lead to tumor suppression by enhancing cellular integrity and tumorigenesis by improving tumor cell survival. In addition, autophagy denotes the cellular ability of adapting to stress though it may end up in apoptosis activation when cells are exposed to a very powerful stress. Induction of autophagy is a therapeutic option in cancer and many anticancer drugs have been developed to this aim. Curcumin as a hydrophobic polyphenol compound extracted from the known spice turmeric has different pharmacological effects in both in vitro and in vivo models. Many reports exist reporting that curcumin is capable of triggering autophagy in several cancer cells. In this review, we will focus on how curcumin can target autophagy in different cellular settings that may extend our understanding of new pharmacological agents to overcome relevant diseases.