Cyclic AMP but Not Calmodulin as a Potential Wasoconstrictor in Simulated Reperfusion.

The phenomena of ischemia and reperfusion are associated with the pathological background of cardiovascular diseases. Ischemia is initiated by ischemia reperfusion injury (IRI), which involves disruption of intracellular signaling pathways and causes cell death. The aim of this study was to assess the reactivity of vascular smooth muscle cells in the conditions of induced ischemia and reperfusion, and to determine the mechanisms leading to contractility disorders. This study was conducted using classical pharmacometric methods on an isolated model of the rat caudal artery. The experiment consisted of the analysis of the final and initial perfusate pressure measurements after induction of arterial contraction with phenylephrine in the presence of forskolin and A7 hydrochloride, two ligands modifying the contractility of vascular smooth muscle cells (VSMC). The pharmacometric analysis showed that in simulated reperfusion, cyclic nucleotides have a vasoconstrictive effect, and calmodulin has a vasodilating effect. The responsiveness of vascular smooth muscle cells to the vasopressor effects of α1-adrenomimetics during reperfusion may change uncontrollably, and the effects of secondary messengers may be counter physiological. Further studies are needed to evaluate the function of other second messengers on VSMCs in the process of ischemia and reperfusion.

Can Ashwagandha Benefit the Endocrine System?-A Review.

Withania somnifera, also known as Ashwagandha, has been used in traditional medicine for thousands of years. Due to the wide range of its activities, there has been interest in its possible beneficial effects on the human body. It is proved that, among others, Ashwagandha has anti-stress, anti-inflammatory, antimicrobial, anti-cancer, anti-diabetic, anti-obesity, cardioprotective, and hypolipidemic properties. Particularly interesting are its properties reported in the field of psychiatry and neurology: in Alzheimer's disease, Parkinson's disease, multiple sclerosis, depression, bipolar disorder, insomnia, anxiety disorders and many others. The aim of this review is to find and summarize the effect that Ashwagandha root extract has on the endocrine system and hormones. The multitude of active substances and the wide hormonal problems faced by modern society sparked our interest in the topic of Ashwagandha's impact on this system. In this work, we also attempted to draw conclusions as to whether W. somnifera can help normalize the functions of the human endocrine system in the future. The search mainly included research published in the years 2010-2023. The results of the research show that Ashwagandha can have a positive effect on the functioning of the endocrine system, including improving the secretory function of the thyroid gland, normalizing adrenal activity, and multidirectional improvement on functioning of the reproductive system. The main mechanism of action in the latter appears to be based on the hypothalamus-pituitary-adrenal (HPA) axis, as a decrease in cortisol levels and an increase in hormones such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in men were found, which results in stress level reduction and improvement in fertility. In turn, other studies prove that active substances from W. somnifera, acting on the body, cause an increase in the secretion of triiodothyronine (T3) and thyroxine (T4) by the thyroid gland and a subsequent decrease in the level of thyroid-stimulating hormone (TSH) in accordance with the hypothalamus-pituitary-thyroid (HPT) axis. In light of these findings, it is clear that Ashwagandha holds significant promise as a natural remedy for various health concerns, especially those related to the endocrine system. Future research may provide new insights into its mechanisms of action and expand its applications in both traditional and modern medicine. The safety and toxicity of Ashwagandha also remain important issues, which may affect its potential use in specific patient groups.

Synthesis, Electrochemical and Photochemical Properties of Sulfanyl Porphyrazine with Ferrocenyl Substituents.

Ferrocene is useful in modern organometallic chemistry due to its versatile applications in material sciences, catalysis, medicinal chemistry, and diagnostic applications. The ferrocene moiety can potentially serve many purposes in therapeutics and diagnostics. In the course of this study, (6-bromo-1-oxohexyl)ferrocene was combined with dimercaptomaleonitrile sodium salt to yield a novel maleonitrile derivative. Subsequently, this compound was subjected to an autocyclotetramerization reaction using the Linstead conditions in order to obtain an octaferrocenyl-substituted magnesium(II) sulfanyl porphyrazine. Following that, both compounds-the maleonitrile derivative and the porphyrazine derivative-were subjected to physicochemical characterization using UV-Vis, ES-TOF, MALDI-TOF, and one-dimensional and two-dimensional NMR spectroscopy. Moreover, the sulfanyl porphyrazine was subjected to various photophysical studies, including optical absorption and emission measurements, as well as the evaluation of its photochemical properties. Values of singlet oxygen generation quantum yields were obtained in different organic solvents. The electrochemical properties of the synthesized compounds were studied using cyclic voltammetry. According to the electrochemical results, the presence of electron-withdrawing oxohexyl groups attached to ferrocene afforded significantly more positive oxidation potentials of the ferrocene-based redox process up to 0.34 V vs. Fc+/Fc.

Impact of Vitamin D Supplementation on Inflammatory Markers' Levels in Obese Patients.

In view of research suggesting a possible beneficial impact of vitamin D on systemic inflammatory response, the authors decided to investigate an influence of vitamin D supplementation on serum levels of certain inflammatory markers in obese patients. The current study included such biomarkers as interleukin-6 (IL-6), pituitary adenylate cyclase-activating peptide (PACAP), advanced oxidation protein products (AOPP), C-X3-C Motif Chemokine Ligand 1 (CX3CL1), monocyte chemoattractant protein-1 (MCP-1), and nitric oxide (NO). The measurements were performed with the ELISA method before and after 3-month-long supplementation of 2000 IU of vitamin D orally. The results showed that the therapy did not induce any statistically significant changes in serum levels of MCP-1, IL-6, CX3CL1, and PACAP. The supplementation was related to a significant increase in measurements of NO and AOPP levels, although the correlation analysis between vitamin D concentration after its supplementation and the concentration of the molecular parameters did not show significant relation. In conclusion, our study seems to contradict certain aspects of findings available in the literature regarding the vitamin D's impact.

Cenobamate: Neuroprotective Potential of a New Antiepileptic Drug.

Central nervous system (CNS) injuries annually afflict approximately 2.7 million people in United States only, inflicting costs of nearly 100 billion US dollars. The gravity of this problem is a consequence of severe and prolonged disability of patients due to a scarce regeneration of CNS, along with the lack of efficient neuroprotective and neuroregenrative therapies. Therefore, the first and most important task in managing the CNS injury is reduction of the damaged area, and apoptosis of neurons occurs not only during the trauma, but in great extent within the following minutes and hours. This process, called secondary injury phase, is a result of trauma-induced metabolic changes in nervous tissue and neuron apoptosis. Cenobamate is a new antiepileptic drug approved by FDA on November 21, 2019. Regardless of its primary purpose, cenobamate, as a blocker of voltage-gated sodium channels and positive modulator of GABAa receptors, it appears to be a promising neuroprotective agent. Moreover, through activation of PI3K/Akt-CREB-BDNF pathway, it leads to the increase of anti-apoptotic factor levels and the decrease of pro-apoptotic factor levels, which induce inhibition of apoptosis and increase neuron survival. Similarly to riluzole, cenobamate could be an important part of a perioperative procedure in neurosurgery, decreasing the occurrence of neurological deficits. Provided that cenobamate will be effective in aforementioned conditions, it could improve treatment outcomes of millions of patients every year, thereby an extensive investigation of its efficacy as a neuroprotective treatment after central nervous system trauma should follow.

The Role of NF-κB in Uterine Spiral Arteries Remodeling, Insight into the Cornerstone of Preeclampsia.

Preeclampsia is one of the three leading causes of maternal morbidity and mortality worldwide. It afflicts 2-8% of pregnancies and is the most common cause of gestational hypertension. This article is focused on nuclear factor kappa B (NF-κB), its role in normal and pathological spiral arteries remodelling and development of preeclampsia, with evaluation if it is a promising therapeutic target. NF-κB is a key mediator of placentation. Since insemination, it stimulates production of proinflammatory cytokines by the uterine epithelium, which leads to activation of macrophages, uterine natural killer cells (uNKs), and other leukocytes. The trophoblast/uNK/macrophage crosstalk is crucial for implantation and spiral arteries remodeling, and NF-κB regulates that process through modification of cytokine expression, as well as cell phenotype and function. In the course of preeclampsia, the remodeling processes is disturbed by excessive inflammation and increased NF-κB activation. The pathological remodeling leads to uteroplacental dysfunction, release of proinflammatory cytokines into the maternal circulation, endothelial stress, and development of preeclampsia. The analysis of genetic and environmental inductors of NF-κB helps to distinguish preeclampsia risk groups. Furthermore, a selective inhibition of NF-κB or NF-κB activating pathways alleviates symptoms of preeclampsia in rat models; therefore, this could be an efficient therapeutic option.

Vasculoprotective Effects of Vildagliptin. Focus on Atherogenesis.

Vildagliptin is a representative of Dipeptidyl Peptidase-4 (DPP-4) inhibitors, antihyperglycemic drugs, approved for use as monotherapy and combination therapy in type 2 diabetes mellitus. By inhibiting enzymatic decomposition, DPP-4 inhibitors increase the half-life of incretins such as GLP-1 (Glucagon-like peptide-1) and GIP (Gastric inhibitors polypeptide) and prolong their action. Some studies present results suggesting the anti-sclerotic and vasculoprotective effects of vildagliptin reaching beyond glycemic control. Vildagliptin is able to limit inflammation by suppression of the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling pathway and proinflammatory agents such as TNF-α (tumor necrosis factor α), IL-1ß (Interleukin-1ß), and IL-8 (Interleukin 8). Moreover, vildagliptin regulates lipid metabolism; attenuates postprandial hypertriglyceridemia; and lowers serum triglycerides, apolipoprotein B, and blood total cholesterol levels. This DPP-4 inhibitor also reduces macrophage foam cell formation, which plays a key role in atheromatous plaque formation and stability. Vildagliptin reduces vascular stiffness via elevation of nitric oxide synthesis, improves vascular relaxation, and results in reduction in both systolic and diastolic blood pressure. Treatment with vildagliptin lowers the level of PAI-1 presenting possible antithrombotic effect. By affecting the endothelium, inflammation, and lipid metabolism, vildagliptin may affect the development of atherosclerosis at its various stages. The article presents a summary of the studies assessing vasculoprotective effects of vildagliptin with special emphasis on atherogenesis.

Neuroprotective Properties of Resveratrol and Its Derivatives-Influence on Potential Mechanisms Leading to the Development of Alzheimer's Disease.

The lack of effective Alzheimer's disease treatment is becoming a challenge for researchers and prompts numerous attempts to search for and develop better therapeutic solutions. Compounds that affect several routes of the neurodegeneration cascade leading to the development of disease are of particular interest. An example of such substances is resveratrol and its synthetic and natural derivatives, which have gained popularity in recent years and show promise as a possible new therapeutic option in the approach to Alzheimer's disease treatment. In this article, the state of the art evidence on the role of resveratrol (RSV) in neuroprotection is presented; research results are summarized and the importance of resveratrol and its derivatives in the treatment of Alzheimer's disease are underlined. It also focuses on various modifications of the resveratrol molecule that should be taken into account in the design of future research on drugs against Alzheimer's disease.

Effect of reperfusion on vascular smooth muscle reactivity in three contraction models.

BACKGROUND: Ischemia and reperfusion remain inseparable elements of numerous medical procedures such as by-pass surgery, organ transplantation or other cardiology and intervention radiology. The contraction of the smooth muscle of the vessel is considered to be one of the basic components leading to impaired perfusion, an increase in the oxygen deficit of the endothelium of the vessel, and subsequently also to tissues vascularized by the vessel. Main aim of this study was to evaluate the effect of ischemia and reperfusion on vascular smooth muscle cells stimulated pharmacologically with mastoparan-7 (direct G-protein activator) in comparison to stimulation of G-protein coupled receptor agonist - phenylephrine, and direct calcium channel activator - Bay K8644. MATERIAL AND METHODS: Experiments were performed on isolated and perfused tail artery of Wistar rats. Contraction force in our model was measured by increased level of perfusion pressure with a constant flow. RESULTS: Concentration-response curves obtained for phenylephrine, mastoparan-7 and Bay K8644 presented a sigmoidal relation. Ischemia induced hyporreactivity of vessels, whereas during reperfusion the significant time related hyperreactivity for phenylephrine and mastoparan-7 only but not for Bay K8644. These reactions were secondary to the modulation of calcium influx from intra- and extracellular calcium stores. CONCLUSIONS: Results of our experiments suggest that mastoparan-7 significantly induces contraction of vascular smooth muscle cells not only for controls but in the presence of ischemia and reperfusion too. Potential therapeutic applications of the observed reactions are important. They may include regenerative processes within the nervous system, studies on the improvement of blood flow within the microcirculation, or antimicrobial activity. Modulation of the G protein-phospholipase C response may also be an interesting point of action of future drugs modifying the response to stimulation during ischemia in particular, such activities could take place during the transport of organs for transplantation.

Neuroprotective Properties of Linagliptin: Focus on Biochemical Mechanisms in Cerebral Ischemia, Vascular Dysfunction and Certain Neurodegenerative Diseases.

Linagliptin is a representative of dipeptidyl peptidase 4 (DPP-4) inhibitors which are registered and used effectively in a treatment of diabetes mellitus type 2. They increase the levels of active forms of endogenous incretins such as GLP-1 and GIP by inhibiting their enzymatic decomposition. Scientific reports suggest beneficial effects of linagliptin administration via immunological and biochemical pathways involved in neuroprotective processes of CNS. Linagliptin's administration leads to a decrease in the concentration of proinflammatory factors such as: TNF-α, IL-6 and increases the number of anti-inflammatory patrolling monocytes CX3CR1bright. Significant reduction in Aß42 level has been associated with the use of linagliptin implying potential application in Alzheimer's disease. Linagliptin improved vascular functions by increasing production of nitric oxide (NO) and limiting concentration of apolipoprotein B. Linagliptin-induced decrease in macrophages infiltration may provide improvement in atheromatous plaque stabilization. Premedication with linagliptin increases neuron's survival after stroke and augments neuronal stem cells proliferation. It seems to be connected with SDF-1α/CXCR4 signaling pathway. Linagliptin prevented abnormal proliferation and migration of rat brain microvascular endothelial cells in a state of hypoperfusion via SIRT1/HIF-1α/VEGF pathway. The article presents a summary of the studies assessing neuroprotective properties of linagliptin with special emphasis on cerebral ischemia, vascular dysfunction and neurodegenerative diseases.

Liraglutide and its Neuroprotective Properties-Focus on Possible Biochemical Mechanisms in Alzheimer's Disease and Cerebral Ischemic Events.

Liraglutide is a GLP-1 analog (glucagon like peptide-1) used primarily in the treatment of diabetes mellitus type 2 (DM2) and obesity. The literature starts to suggest that liraglutide may reduce the effects of ischemic stroke by activating anti-apoptotic pathways, as well as limiting the harmful effects of free radicals. The GLP-1R expression has been reported in the cerebral cortex, especially occipital and frontal lobes, the hypothalamus, and the thalamus. Liraglutide reduced the area of ischemia caused by MCAO (middle cerebral artery occlusion), limited neurological deficits, decreased hyperglycemia caused by stress, and presented anti-apoptotic effects by increasing the expression of Bcl-2 and Bcl-xl proteins and reduction of Bax and Bad protein expression. The pharmaceutical managed to decrease concentrations of proapoptotic factors, such as NF-κB (Nuclear Factor-kappa ß), ICAM-1 (Intercellular Adhesion Molecule 1), caspase-3, and reduced the level of TUNEL-positive cells. Liraglutide was able to reduce the level of free radicals by decreasing the level of malondialdehyde (MDA), and increasing the superoxide dismutase level (SOD), glutathione (GSH), and catalase. Liraglutide may affect the neurovascular unit causing its remodeling, which seems to be crucial for recovery after stroke. Liraglutide may stabilize atherosclerotic plaque, as well as counteract its early formation and further development. Liraglutide, through its binding to GLP-1R (glucagon like peptide-1 receptor) and consequent activation of PI3K/MAPK (Phosphoinositide 3-kinase/mitogen associated protein kinase) dependent pathways, may have a positive impact on Aß (amyloid beta) trafficking and clearance by increasing the presence of Aß transporters in cerebrospinal fluid. Liraglutide seems to affect tau pathology. It is possible that liraglutide may have some stem cell stimulating properties. The effects may be connected with PKA (phosphorylase kinase A) activation. This paper presents potential mechanisms of liraglutide activity in conditions connected with neuronal damage, with special emphasis on Alzheimer's disease and cerebral ischemia.

Clozapine-induced agranulocytosis/granulocytopenia: mechanisms and monitoring.

PURPOSE OF REVIEW: Clozapine-induced agranulocytosis/granulocytopenia (CIAG) is an uncommon condition, but potentially fatal in consequences. The pathogenesis, despite multiple experiments, is not fully elucidated. The current theory suggests reactive oxygen species - nitrenium ion as the most important factor of CIAG. In this review, mechanism and monitoring of CIAG will be discussed. RECENT FINDINGS: The mechanism of CIAG seems to have an autoimmune background, rather than toxic. Clozapine has a high potential to undergo biochemical activation to nitrenium ion. The role of the primary metabolite of clozapine - N-desmethylclozapine - is in decline. Nitrenium ion is mainly synthesized by CYP3A4, CYP2D6, and myeloperoxidase system in leukocytes. An important component of CIAG pathogenesis is genetic aberration in human leukocyte antigen genes, and also genes associated with apoptosis and ubiquitination. Clozapine monitoring regimes differ between countries. US-derived clozapine Risk Evaluation and Mitigation Strategy is the most tolerant in the aspect of blood parameter thresholds. Therefore, it provides the opportunities for physician to continue the treatment and also to rechallenge the drug after the episode of CIAG. SUMMARY: Each patient with the episode of CIAG should be assessed individually, with special attention to risk factors and drug-drug interactions. Upon that, the decision about clozapine rechallenge or withdrawal should be made.

The role of Rho-kinase and calcium ions in constriction triggered by ET-1.

Endothelin-1 (ET-1) is one of the key factors regulating tension of smooth muscles in blood vessels. It is believed that ET-1 plays an important role in pathogenesis of hypertension, and cardiovascular diseases; therefore, research in order to limit ET-1-mediated action is still in progress. The main objective of this paper was to evaluate the role of Rho-kinase in the ET-1-induced constriction of arteries. The analysis also included significance of intra- and extracellular pool of calcium ions in constriction triggered by ET-1. The studies were performed on perfused Wistar rat tail arteries. Concentration response curve (CRC) was determined for ET-1 in the presence of increased concentrations of Rho-kinase inhibitor (Y-27632) and IP3-receptor antagonist (2APB), both in reference to constriction triggered by solely ET-1. Afterwards, the influence of calcium ions present in the perfusion fluid was evaluated in terms of the effect triggered by 2APB and occurring in arteries constricted by ET-1. ET-1, in concentration dependent manner, leads to increase in perfusion pressure. Y-27632 and 2APB lead to shift of the concentration response curve for ET-1 to the right with simultaneously lowered maximum effect. There was no difference in reaction of the artery constricted by ET-1 and treated with 2APB in solution containing calcium and in calcium-free solution. Vasoconstrictive action of endothelin is not significantly dependent on the inflow of extracellular calcium, but it is proportional to inflow of Ca2+ related to activation of IP3 receptors and to Rho-kinase activity.

Can Asiatic Acid from Centella asiatica Be a Potential Remedy in Cancer Therapy?-A Review.

Centella asiatica has been recognized for centuries in Eastern medicine for its pharmacological properties. Due to the increasing prevalence of oncological diseases worldwide, natural substances that could qualify as anticancer therapeutics are becoming increasingly important subjects of research. This review aims to find an innovative use for asiatic acid (AA) in the treatment or support of cancer therapy. It has been demonstrated that AA takes part in inhibiting phosphorylation, inducing cell death, and reducing tumor growth and metastasis by influencing important signaling pathways, such as PI3K, Akt, mTOR, p70S6K, and STAT3, in cancer cells. It is also worth mentioning the high importance of asiatic acid in reducing the expression of markers such as N-cadherin, ß-catenin, claudin-1, and vimentin. Some studies have indicated the potential of asiatic acid to induce autophagy in cancer cells through changes in the levels of specific proteins such as LC3 and p62. It can also act as an anti-tumor immunotherapeutic agent, thanks to its inductive effect on Smad7 in combination with naringenin (an Smad3 inhibitor). It seems that asiatic acid may be a potential anticancer drug or form of adjunctive therapy. Further studies should take into account safety and toxicity issues, as well as limitations related to the pharmacokinetics of AA and its low oral bioavailability.

Ashwagandha's Multifaceted Effects on Human Health: Impact on Vascular Endothelium, Inflammation, Lipid Metabolism, and Cardiovascular Outcomes-A Review.

Withania somnifera, commonly known as Ashwagandha, has been popular for many years. Numerous studies have shown that the extract of this plant, due to its wealth of active substances, can induce anti-inflammatory, neuroprotective, immunomodulatory, hepatoprotective, cardioprotective, anti-diabetic, adaptogenic, anti-arthritic, anti-stress, and antimicrobial effects. This review examines the impact of Ashwagandha extract on the vascular endothelium, inflammation, lipid metabolism, and cardiovascular outcomes. Studies have shown that Ashwagandha extracts exhibit an anti-angiogenic effect by inhibiting vascular endothelial growth factor (VEGF)-induced capillary sprouting and formation by lowering the mean density of microvessels. Furthermore, the results of numerous studies highlight the anti-inflammatory role of Ashwagandha extract, as the action of this plant causes a decrease in the expression of pro-inflammatory cytokines. Interestingly, withanolides, present in Ashwagandha root, have shown the ability to inhibit the differentiation of preadipocytes into adipocytes. Research results have also proved that W. somnifera demonstrates cardioprotective effects due to its antioxidant properties and reduces ischemia/reperfusion-induced apoptosis. It seems that this plant can be successfully used as a potential treatment for several conditions, mainly those with increased inflammation. More research is needed to elucidate the exact mechanisms by which the substances contained in W. somnifera extracts can act in the human body.

The Association of Tobacco Smoking and Level of Apoptosis in the Long Head of the Biceps Chronic Tendinopathy-An Immunohistochemical Study.

BACKGROUND: The substances present in cigarette smoke have a negative impact on cellular integrity and metabolism, can reduce blood flow to tissues, and can disrupt collagen synthesis. Ultimately this can lead to cell death, which clinically may result in impaired tendon healing and the onset of chronic tendinopathy. Within the shoulder, the exact association between the extent of apoptosis in the long head of the biceps (LHB) tendon and harmful factors like cigarette smoke remains unclear. OBJECTIVES: The purpose of this study was to investigate the connection between smoking, the degree of apoptosis in LHB tendinopathy, and the long-term outcomes of surgical treatment. DESIGN: Observational, retrospective study. METHODS: This study included 22 consecutive patients who had undergone arthroscopic biceps tenodesis or tenotomy for symptomatic LHB tendinopathy with or without concomitant rotator cuff tears (RCT). The intra-articular LHB tendon remnants were histologically examined by measuring the level of expression of apoptotic cell markers such as BCL2, cleaved caspase 3, and p53. Pre- and postoperative clinical outcomes were analyzed by collecting patient report outcome measures such as the American Shoulder and Elbow Surgeons (ASES) score and the Visual Analogue Scale (VAS) for pain. RESULTS: The smokers group had a mean pack-year history of 13.12 (SD = 9.94), mean number of cigarettes per day of 14.77 (SD = 4.64), and a mean smoking duration of 16.38 (SD = 10.1) years. Among the smoking indexes, the number of cigarettes per day showed a positive correlation with Snyder classification (p = 0.0459, rho = 0.3682). Non-smokers and smokers did not show a statistically significant difference in the expression indexes of BCL2, cleaved caspase 3, or p53 (p = 0.4216, p = 0.5449, p = 0.5613, respectively). However, the cleaved caspase 3 expression index showed a negative correlation with the severity of rotator cuff lesions in the total population (p = 0.0193, rho = -0.4651). CONCLUSIONS: While apoptotic processes in the LHB tendon were observed, no significant association was found between tobacco smoking, the extent of apoptosis, and clinical outcomes. However, the expression of the apoptotic marker cleaved caspase 3 correlated with the severity of rotator cuff pathology. Furthermore, active smoker status was associated with worse clinical outcomes in terms of pain following LHB tenodesis or tenotomy.

Augmentation Therapies as Treatments for Coexisting Somatic Problems in Schizophrenia-A Systematic Review.

The aim of this review is to appraise the data from available randomized clinical trials (RCT) regarding the possible combinations of neuroleptic and non-antipsychotic treatment which could enhance antipsychotic therapy efficacy whilst simultaneously addressing somatic symptoms in individuals with schizophrenia. A systematic search of the PubMed database up to February 2022 was conducted. Inclusion criteria: randomized controlled trials using augmentation therapy in chronic schizophrenia in adults, written in English, and only studies with psychometric assessments of schizophrenia were incorporated. Exclusion criteria: non-clinical, first episode of schizophrenia, patients on medication other than antipsychotics augmented, and not adjunctive therapy. Overall, 37 studies of 1931 patients with schizophrenia who received a combination of antipsychotic medication with other drugs were selected. A statistically significant reduction of negative and positive symptoms of schizophrenia, measured with the PANSS scale, when using a combination of antipsychotic treatment along with aspirin, simvastatin, N-acetylcysteine, or pioglitazone was found. A combination of antipsychotic medication with aspirin, simvastatin, N-acetylcysteine, or pioglitazone seems to be effective in the reduction of symptoms of schizophrenia in adults, but long-term studies are required to confirm this effect.

Current Treatment of Melanoma Brain Metastases.

Melanoma is a type of skin cancer in which there is a strong correlation between its occurrence and exposure to ultraviolet radiation. Although it is not the most common skin cancer, it has the highest mortality rate of all skin cancers. The prognosis of patients is significantly worsened by melanoma metastasis to the brain, which often occurs in patients with advanced disease. The formation and development of melanoma metastases to the brain involve a very complex process, and their mechanisms are not fully understood. One of the ways for metastatic melanoma cells to survive and develop cancer in the brain environment is the presence of oncogenic BRAF mutation, which occurs in up to 50% of metastatic melanoma cases. Before discovering new methods of treating metastases, the overall survival of patients with this disease was 6 months. Currently, research is being conducted on new drugs using immunotherapy (immune checkpoint inhibitors: anti-PD-1, anti-CTLA-4) and targeted therapy (BRAF and MEK inhibitors) to improve the prognosis of patients. In this article, we summarize the current state of knowledge about the results of treating brain metastases with new systemic therapies.

Natural Phytochemicals as SIRT Activators-Focus on Potential Biochemical Mechanisms.

Sirtuins are a family of proteins with enzymatic activity. There are seven mammalian sirtuins (SIRT1-SIRT7) that are found in different cellular compartments. They are a part of crucial cellular pathways and are regulated by many factors, such as chemicals, environmental stress, and phytochemicals. Several in vitro and in vivo studies have presented their involvement in anti-inflammatory, antioxidant, and antiapoptotic processes. Recent findings imply that phytochemicals such as resveratrol, curcumin, quercetin, fisetin, berberine, and kaempferol may regulate the activity of sirtuins. Resveratrol mainly activates SIRT1 and indirectly activates AMPK. Curcumin influences mainly SIRT1 and SIRT3, but its activity is broad, and many pathways in different cells are affected. Quercetin mainly modulates SIRT1, which triggers antioxidant and antiapoptotic responses. Fisetin, through SIRT1 regulation, modifies lipid metabolism and anti-inflammatory processes. Berberine has a wide spectrum of effects and a significant impact on SIRT1 signaling pathways. Finally, kaempferol triggers anti-inflammatory and antioxidant effects through SIRT1 induction. This review aims to summarize recent findings on the properties of phytochemicals in the modulation of sirtuin activity, with a particular focus on biochemical aspects.

Therapeutic Drug Monitoring of Direct Oral Anticoagulants in Patients with Extremely Low and High Body Weight-Pilot Study.

Phase III clinical trials for individual direct oral anticoagulants (DOACs) contained a limited representation of subjects with abnormal body weight, which were mostly limited to a BMI > 40 kg/m2, or body weight > 120 kg for obese subjects, and <50 kg for underweight subjects. Although low or high body weight is not a contraindication to DOACs therapy, it can significantly affect the safety and effectiveness of treatment. Due to the limited amount of clinical data on the use of DOACs in extremely abnormal weight ranges, optimal pharmacotherapy in this group of patients is a matter of controversy. The objective of this study was to evaluate the pharmacokinetics of DOAC properties in patients with abnormal body weight beyond the established cut-off points in the phase III studies for rivaroxaban, apixaban, and dabigatran. In total, 38 patients took DOACs for at least 12 months for non-valvular atrial fibrillation in 2019-2021. Blood samples were collected before the planned intake of the drug and 4 h after its administration. The determined concentrations of DOACs were statistically analyzed in relation to body weight, age, and eGFR (estimated Glomerular Filtration Rate). Among subjects taking apixaban, rivaroxaban, and dabigatran, the smallest representation of patients who achieved therapeutic concentrations were those treated with dabigatran. The population of people with abnormal body weight is a potential risk group of patients, in which some of them do not reach the therapeutic range of DOACs.