Role of the AMP-Activated Protein Kinase in the Pathogenesis of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a complex disorder characterized by elevated androgen levels, menstrual irregularities, and polycystic morphology of the ovaries. Affecting 6-10% of women in childbearing age, PCOS is a leading cause of infertility worldwide. In recent years, there has been a growing acknowledgment of the involvement of adenosine monophosphate-activated protein kinase (AMPK) in the development of polycystic ovary syndrome (PCOS). The expression of AMPK is diminished in polycystic ovaries, and when AMPK is silenced in human granulosa cells, there is a rise in the expression of steroidogenic enzymes, resulting in increased production of estradiol and progesterone. Additionally, in mouse models, the inhibiting AMPK intensifies the polycystic appearance of ovaries and impairs the process of ovulation. Moreover, it has been shown that AMPK activators like metformin and resveratrol ameliorate PCOS associated signs and symptoms in experimental and clinical studies. These findings, collectively, indicate the key role of AMPK in the pathogenesis of PCOS. Understanding the role of AMPK in PCOS will offer rewarding information on details of PCOS pathogenesis and will provide novel more specific therapeutic approaches. The present review summarizes the latest findings regarding the role of AMPK in PCOS obtained in experimental and clinical studies.

TiO2/PEG as smart anticorrosion and drug-eluting platforms in inflammatory conditions.

The failure of a titanium implant is often attributed to inflammatory reactions following implantation. This study focuses on the synthesis of a polyethylene glycol (PEG) layer on porous titanium dioxide (TiO2) coatings using plasma electrolytic oxidation (PEO). This PEG layer serves as a foundation for a drug-eluting platform designed to respond to pH stimuli during inflammation. Betamethasone (BET), a widely used anti-inflammatory drug, was loaded onto the pH-responsive functional PEG layers. The application of the PEG-BET layer onto TiO2 coatings through the vacuum dip coating method resulted in a pH-sensitive sustained release of BET over a 30-day period. Notably, the release rates were 81% at pH 5.0 and 55% at pH 7.2. Electrochemical corrosion tests conducted in both normal and acidic inflammatory solutions demonstrated that duplex composite coatings offer superior protection compared to simple oxide coatings. In a pH 5.0 solution, corrosion current density measurements revealed values of 1.75 µA cm-2 (PEO/PEG-BET), 8.87 µA cm-2 (PEO), and 49.17 µA cm-2 (bare titanium). These results highlight the effectiveness of the PEO/PEG-BET layer in sealing pores within PEO coatings, subsequently reducing the infiltration of corrosive ions in inflammatory environments.

The use of combination therapy for the improvement of colistin activity against bacterial biofilm.

Colistin is used as a last resort for the management of infections caused by multi-drug resistant (MDR) bacteria. However, the use of this antibiotic could lead to different side effects, such as nephrotoxicity, in most patients, and the high prevalence of colistin-resistant strains restricts the use of colistin in the clinical setting. Additionally, colistin could induce resistance through the increased formation of biofilm; biofilm-embedded cells are highly resistant to antibiotics, and as with other antibiotics, colistin is impaired by bacteria in the biofilm community. In this regard, the researchers used combination therapy for the enhancement of colistin activity against bacterial biofilm, especially MDR bacteria. Different antibacterial agents, such as antimicrobial peptides, bacteriophages, natural compounds, antibiotics from different families, N-acetylcysteine, and quorum-sensing inhibitors, showed promising results when combined with colistin. Additionally, the use of different drug platforms could also boost the efficacy of this antibiotic against biofilm. The mentioned colistin-based combination therapy not only could suppress the formation of biofilm but also could destroy the established biofilm. These kinds of treatments also avoided the emergence of colistin-resistant subpopulations, reduced the required dosage of colistin for inhibition of biofilm, and finally enhanced the dosage of this antibiotic at the site of infection. However, the exact interaction of colistin with other antibacterial agents has not been elucidated yet; therefore, further studies are required to identify the precise mechanism underlying the efficient removal of biofilms by colistin-based combination therapy.

Dishevelled: An emerging therapeutic oncogene in human cancers.

Cancer is a multifaceted and complex disorder characterized by uncontrolled rates of cell proliferation and its ability to spread and attack other organs. Emerging data indicated several pathways and molecular targets are engaged in cancer progression. Among them, the Wnt signaling pathway was shown to have a crucial role in cancer onset and progression. Dishevelled (DVL) acts in a branch point of canonical and non-canonical Wnt pathway. DVL not only acts in the cytoplasm to inactivate the destruction complex of ß-catenin but is also transported into the nucleus to affect the transcription of target genes. Available data revealed that the expression levels of DVL increased in cell and clinical specimens of various cancers, proposing that it may have an oncogenic role. DVL promoted cell invasion, migration, cell cycle, survival, proliferation, 3D-spheroid formation, stemness, and epithelial mesenchymal transition (EMT) and it suppressed cell apoptosis. The higher levels of DVL is associated with the clinicopathological characteristic of cancer-affected patients, including lymph node metastasis, tumor grade, histological type, and age. In addition, the higher levels of DVL could be a promising diagnostic and prognostic biomarker in cancer as well as it could be a mediator in cancer chemoresistance to Methotrexate, paclitaxel, and 5-fluorouracil. This study aimed to investigate the underlying molecular mechanism of DVL in cancer pathogenesis as well as to explore its importance in cancer diagnosis and prognosis as well as its role as a mediator in cancer chemotherapy.

Lung protective effect of Ticagrelor in endotoxemia.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. This study aimed to investigate the potential protective effect of the lungs in sepsis by modulating inflammatory and oxidative stress markers. Twenty-four adult male Swiss-albino mice, aged 8-12 weeks and weighing 20-30 g, were divided into four equal groups (n=6): sham (laparotomy only), CLP (laparotomy plus cecal ligation and puncture), vehicle (DMSO administered one hour before CLP), and Ticagrelor (50 mg/kg IP administered one hour before CLP). Tissue levels of pro-inflammatory and oxidative stress markers in the lung were assessed using ELISA. F2 isoprostane levels were significantly higher in the sepsis group (p<0.05) compared to the sham group, while Ticagrelor significantly decreased the inflammatory and oxidative stress markers compared to the sepsis group. All mice in the sepsis group had considerable (p=0.05) lung tissue damage, but Ticagrelor considerably decreased lung tissue injury (p=0.05). Furthermore, Ticagrelor was found to reduce tissue cytokine levels of the lung (IL-1, TNF a, IL-6, F2 isoprostane, GPR 17, MIF) in male mice during CLP-induced polymicrobial sepsis by modulation of pro-inflammatory and oxidative stress cascade signaling pathways.

Peptide-Based Therapeutics in Cancer Therapy.

A monster called cancer is still one of the most challenging human problems and one of the leading causes of death in the world. Different types of treatment methods are used for cancer therapy; however, there are challenges such as high cost and harmful side effects in using these methods. Recent years have witnessed a surge in the development of therapeutic peptides for a wide range of diseases, notably cancer. Peptides are preferred over antibiotics, radiation therapy, and chemotherapy in the treatment of cancer due to a number of aspects, including flexibility, easy modification, low immunogenicity, and inexpensive cost of production. The use of therapeutic peptides in cancer treatment is a novel and intriguing strategy. These peptides provide excellent prospects for targeted drug delivery because of their high selectivity, specificity, small dimensions, good biocompatibility, and simplicity of modification. Target specificity and minimal toxicity are benefits of therapeutic peptides. Additionally, peptides can be used to design antigens or adjuvants for vaccine development. Here, types of therapeutic peptides for cancer therapy will be discussed, such as peptide-based cancer vaccines and tumor-targeting peptides (TTP) and cell-penetrating peptides (CPP).

A thorough and current study of miR-214-related targets in cancer.

Cancer is a complex genetic anomaly involving coding and non-coding transcript structural and expressive irregularities. A class of tiny non-coding RNAs known as microRNAs (miRNAs) regulates gene expression at the post-transcriptional level by binding only to messenger RNAs (mRNAs). Due to their capacity to target numerous genes, miRNAs have the potential to play a significant role in the development of tumors by controlling several biological processes, including angiogenesis, drug resistance, metastasis, apoptosis, proliferation, and drug resistance. According to several recent studies, miRNA-214 has been linked to the emergence and spread of tumors. The human genome's q24.3 arm contains the DNM3 gene, which is about 6 kb away and includes the microRNA-214. Its primary purpose was the induction of apoptosis in cancerous cells. The multifaceted and complex functions of miR-214 as a modulator in neoplastic conditions have been outlined in the current review.

STAT3 Signaling Axis and Tamoxifen in Breast Cancer: A Promising Target for Treatment Resistance.

Signal transducers and activators of transcription 3 (STAT 3) have been proposed to be responsible for breast cancer development. Moreover, evidence depicted that upregulation of STAT3 is responsible for angiogenesis, metastasis, and chemo-resistance of breast cancer. Tamoxifen (TAM) resistance is a major concern in breast cancer management which is mediated by numerous signaling pathways such as STAT3. Therefore, STAT3 targeting inhibitors would be beneficial in breast cancer treatment. The information on the topic in this review was gathered from scientific databases such as PubMed, Scopus, Google Scholar, and ScienceDirect. The present review highlights STAT3 signaling axis discoveries and TAM targeting STAT3 in breast cancer. Based on the results of this study, we found that following prolonged TAM treatment, STAT3 showed overexpression and resulted in drug resistance. Moreover, it was concluded that STAT3 plays an important role in breast cancer stem cells, which correlated with TAM resistance.

Correction: Immobilized Ni on TMEDA@ßSiO2@αSiO2@Fe3O4: as a novel magnetic nanocatalyst for preparation of pyrido[2,3-d:6,5-d']dipyrimidines.

[This corrects the article DOI: 10.1039/D3RA01720F.].

Targeting Nrf2 signaling pathway by quercetin in the prevention and treatment of neurological disorders: An overview and update on new developments.

BACKGROUND: Neurological disorders (NLDs) are widely acknowledged as a significant public health concern worldwide. Stroke, Alzheimer's disease (AD), and traumatic brain injury (TBI) are three of these disorders that have sparked major study attention. Neurological dysfunction, protein buildup, oxidation and neuronal injury, and aberrant mitochondria are all prevalent neuropathological hallmarks of these disorders. The signaling cascade of nuclear factor erythroid 2 related factor 2 (Nrf2) shares all of them as a common target. Several studies have found that overexpression of Nrf2 is a promising treatment method in NLDs. Effective treatment of these disorders continues to be a universal concern regardless of various medicines. In order to treat a variety of neurological problems, organic remedies may provide an alternative treatment. It has been demonstrated that polyphenols like quercetin (Que) offer considerable capabilities for treating NLDs. One of Que's greatest key targets, Nrf2, has the capacity to control the production of a number of cytoprotective enzymes that exhibit neuroprotective, detoxifying, and antioxidative effects. Additionally, Que enhanced the expression of Nrf2 and inhibited alterations in the shape and death of neurons in the hippocampus. OBJECTIVE: In this review, we have focused on Que's medicinal prospects as a neuroprotective drug. METHODS: PubMed, Scopus, Science Direct, and Google Scholar were used to search articles for this study. RESULTS: The findings of this research demonstrate that (1) Que protected the blood-brain barrier via stimulating Nrf2 in animal stroke, which alleviated ischemic reperfusion and motor dysfunction. (2) By triggering the Nrf2 pathway, Que reduced the neuroinflammation and oxidative damage brought on by TBI in the cortex. (3) In an experimental model of AD, Que enhanced cognitive function by decreasing A1-4, antioxidant activity, and Nrf2 levels in the brain. CONCLUSION: We discuss recent research on Que-mediated Nrf2 expression in the management of several NLDs in this paper.

Immobilized Ni on TMEDA@ßSiO2@αSiO2@Fe3O4: as a novel magnetic nanocatalyst for preparation of pyrido[2,3-d:6,5-d']dipyrimidines.

In the current body of research, a very quick and effectual procedure for the synthesis of pyrido[2,3-d:6,5-d']dipyrimidines has been developed. This method is accomplished through the one-pot multi-component reaction of 2-thiobarbituric acid, NH4OAc and aldehydes utilizing Ni-TMEDA@ßSiO2@αSiO2@Fe3O4 as a novel mesoporous nanomagnetic catalyst at room temperature. This protocol is one of the few reports of the preparation of these derivatives without the use of conventional heating as well as energies such as microwave and ultrasound radiation. The characterization of the prepared catalyst was well accomplished by different techniques such as FT-IR, ICP-OES, SEM, TEM, BET, XRD, VSM, TGA, EDX and Elemental mapping. This organometallic catalyst was reusable for seven times with negligible decrement in its catalytic performance. In addition, all of the products were produced with high TON and TOF values, which demonstrates that our catalyst has a very high level of activity in the preparation of pyrido[2,3-d:6,5-d']dipyrimidines.

Investigating the effect of pregabalin on postoperative pain in non-emergency craniotomy.

BACKGROUND: Surgical procedures performed in the suboccipital and subtemporal regions are associated with severe pain. The present study was designed to determine pregabalin's effect on postoperative pain in elective craniotomy. METHOD: This double-blind prospective randomized clinical trial was conducted on 50 patients aged 20-60 with ASA classifications I and II. The patients who qualified for elective craniotomies were split into intervention (two capsules =300 mg pregabalin) and control groups (two capsule starch). Patients were also assessed at recovery, 2, 6, 12, and 24 h after surgery for their pain and level of sedation. Data were analyzed by SPSS software version 23, and a P-value ≤ 0.05 was considered significant. RESULTS: The mean pain score in the intervention group was lower than the control group at recovery (p = 0.224), 2 h (p = 0.001), 6 h (p = 0.011), and 12 h (p = 0.032) after surgery. The methadone consumption in the control group was significantly higher than the intervention group (p < 0.05). There was no significant difference between the two groups regarding the level of sedation (p > 0.05). The mean heart rate at induction (p = 0.01), 15 min (p = 0.01), 30 min (p = 0.025), recovery (p = 0.031), and 2 h (p = 0.021) after surgery and the MAP at recovery, 2 h, and 6 h after surgery was significantly lower than the control group (p = 0.029), (p = 0.013), and (p = 0.038), respectively. CONCLUSION: Our investigation demonstrated the effectiveness of pregabalin two hours before surgery on decreasing postoperative pain and analgesic consumption without disturbance in neurological examinations and any specific adverse effects.

Cardiac Injury Following Chemo/Radiation Therapy: An Updated Review on Mechanisms and Therapeutic Approaches.

Cardiovascular disorders are among the critical side effects of cancer therapy. Damage to the function and normal structure of the heart can cause serious threats to patients that are being treated for cancer. Cardiovascular complications may be induced by various types of chemotherapy drugs and also radiation therapy. The severity of cardiovascular toxicity depends on several factors, such as types of drugs, tumor location for radiotherapy, the presence of cardiac disease history, the dose of drugs or ionizing radiation, etc. Radiotherapy and chemotherapy can cause heart diseases through various mechanisms, such as oxidative stress, inflammation, cell death, fibrosis, endothelial to mesenchymal transition (EndMT), etc. Chronic inflammation following damage to a huge number of cells can trigger more accumulation of inflammatory cells and chronic release of reactive oxygen species (ROS) and nitric oxide (NO). Oxidative stress can induce more cell death and cardiac remodeling through damage to vessels and valvular and disruption of the normal structure of the extracellular matrix. These changes may lead to cardiomyopathy, myocarditis, pericarditis, and vascular disorders that may lead to heart attack and death. This review provides basic information on cellular and molecular mechanisms of different types of cardiovascular disorders following cancer therapy by radiation or chemotherapy. We also recommend some adjuvants and targets to reduce the risk of heart toxicity by radiation/chemotherapy.

Recent progressions in biomedical and pharmaceutical applications of chitosan nanoparticles: A comprehensive review.

Nowadays, the most common approaches in the prognosis, diagnosis, and treatment of diseases are along with undeniable limitations. Thus, the ever-increasing need for using biocompatible natural materials and novel practical modalities is required. Applying biomaterials, such as chitosan nanoparticles (CS NPs: FDA-approved long-chain polymer of N-acetyl-glucosamine and D-glucosamine for some pharmaceutical applications), can serve as an appropriate alternative to overcome these limitations. Recently, the biomedical applications of CS NPs have extensively been investigated. These NPs and their derivatives can not only prepare through different physical and chemical approaches but also modify with various molecules and bioactive materials. The potential properties of CS NPs, such as biocompatibility, biodegradability, serum stability, solubility, non-immunogenicity, anti-inflammatory properties, appropriate pharmacokinetics and pharmacodynamics, and so forth, have made them excellent candidates for biomedical applications. Therefore, CS NPs have efficiently applied for various biomedical applications, like regenerative medicine and tissue engineering, biosensors for the detection of microorganisms, and drug delivery systems (DDS) for the suppression of diseases. These NPs possess a high level of biosafety. In summary, CS NPs have the potential ability for biomedical and clinical applications, and it would be remarkably beneficial to develop new generations of CS-based material for the future of medicine.

A green chemistry approach for oxidation of alcohols using novel bioactive cobalt composite immobilized on polysulfone fibrous network nanoparticles as a catalyst.

In this study, cobalt composite immobilized on polysulfone fibrous network nanoparticles (CCPSF NPs) were synthesized in a controllable and one-step way under microwave-assisted conditions. The structure of CCPSF NPs was characterized by SEM images (for morphology and size distribution), TGA (for thermal stability), BET technique (for the specific surface area), FT-IR spectroscopy (for relation group characterization), and XRD patterns (for crystal size). The oxidation of the primary and secondary alcohols to aldehyde and ketone was investigated using synthesized CCPSF NPs under solvent-free microwave-assisted conditions, and high oxidizing activity was observed. In addition to oxidation properties, the anticancer activity of the synthesized CCPSF NPs in breast cancer was evaluated by the MTT method , and significant results were obtained.

Berberine Protests the Heart from Ischemic Reperfusion Injury via Interference with Oxidative and Inflammatory Pathways.

BACKGROUND: Ischemia and reperfusion (I/R) is a pathological condition characterized by an initial restriction of blood supply to an organ followed by the subsequent restoration of perfusion and concomitant reoxygenation. OBJECTIVE: The aim of the study is to assess the possible cardioprotective potential effect of berberine in myocardial ischemia reperfusion injury induced by ligation of coronary artery in a male rat model. METHODS: Total amount of 28 adult male albino rats were randomized into 4 equal groups: 1) Sham group, rats underwent the same anesthetic and surgical procedure as the control group except for LAD ligation; 2), Active control group, rats subjected to regional ischemia for 30 min by ligation of LAD coronary artery and reperfusion for 2 hours, 3), Control vehicle group, rats received dimethyl sulphoxide (DMSO) (vehicle of berberine) via IP route and subjected to ischemia for 30 minutes before ligation of LAD coronary artery & reperfusion for 2 hr; 4), Berberine treated group, rats pretreated with berberine10 mg/kg via IP injection 30minutes before ligation of LAD coronary artery & then subjected to reperfusion for 2 hr. RESULTS: In the control group, as compared with sham, tissue TNF-α, IL-6, IL-10, caspase-3 and BAX, plasma cTn-T and serum MDA significantly increased (P<0.05), while serum GSH significantly decreased (P<0.05). The histopathological control group showed a significant cardiac injury (P<0.05) compared with the sham group. Berberine significantly counteracted (P<0.05) the increase of TNF-α, IL-6, caspase-3 and BAX and counteracted the increase in plasma cTn-T and serum MDA. Berberine produces a significant elevation (P<0.05) in cardiac IL-10 and serum GSH with a significant reduction in (P<0.05) cardiac injury. CONCLUSION: Berberine attenuates myocardial I/R injury in male rats via interfering with inflammatory reactions and apoptosis which were induced by I/R injury.

Combinación de bardoxolona y DMF Mejora la isquemia cerebral/reperfusión Lesión en ratas macho / Combination of Bardoxolone and DMF Ameliorates Cerebral Ischemia / Reperfusion Injury in Male Rats

Background: Ischemic stroke has been ranked as the second cause of death in patients worldwide. Inflammation which is activated during cerebral ischemia/reperfusion (I/R) is an important mechanism leading to brain injury. The present study aimed to investigate the effect of Berberine on cerebral I/R injury and the role of inflammation in this process. Material and Methods: The study was carried out on 36 Wistar-albino rats, divided into four groups including: Sham group, I/R group, I/R+ (control-vehicle DMSO) and I/R+ Berberine 5 mg/kg injected intraperitoneally 1 hour before induction of ischemia. Measurement of brain tissue IL-1ß, ICAM1, caspase-3, Notch 1 and Jagged 1 was done after one hour of reperfusion in addition to assessment of the brain infracted area and histopathological analysis. Results: Berberine attenuates cerebral I/R injury induced increase in inflammatory cytokine (IL-1ß), adhesion molecule (ICAM-1) and proapoptotic enzyme (caspase-3). Additionally, it reduces the size of infracted area and histopathological damage; such protective effect could be mediated by Notch 1 signaling pathway since Berberine further unregulated the increased levels of Notch 1 and Jagged 1 seen in brain with I/R injury. Conclusions: Berberine has a neurocytoprotective outcome against cerebral I/R injury which is manifested as anti-inflammatory anti-apoptotic effect that preserved cell structure and viability, in the meantime this effect could be mediated by Notch 1 signaling pathway.