Protective actions of exercise-related FNDC5/Irisin in memory and Alzheimer's disease.

The proportion of elderly populations is rapidly booming, and human lifespan has considerably increased in the past century because of scientific and medical advances. However, the winds of change brought by the 21st century made sedentarism one of the factors that renders the brain vulnerable to age-related chronic diseases, such as Alzheimer's disease (AD). Conversely, physical exercise has been shown to stimulate molecular mechanisms beneficial to cognition. Here, we review evidence showing the positive effects of physical exercise in the brain. We further discuss recent evidence that irisin, a myokine stimulated by physical exercise derived from fibronectin type III domain-containing protein 5 (FNDC5) transmembrane protein, has neuroprotective actions in the brain. Lastly, we highlight the importance of the crosstalk between the periphery and the brain in cognition and the therapeutic potential of FNDC5/irisin in AD.

COVID-19: Rational discovery of the therapeutic potential of Melatonin as a SARS-CoV-2 main Protease Inhibitor.

The SARS-CoV-2 spread quickly across the globe. The World Health Organization (WHO) on March 11 declared COVID-19 a pandemic. The mortality rate, hospital disorders and incalculable economic and social damages, besides the unproven efficacy of the treatments evaluated against COVID-19, raised the need for immediate control of this disease. Therefore, the current study employed in silico tools to rationally identify new possible SARS-CoV-2 main protease (Mpro) inhibitors. That is an enzyme conserved among the coronavirus species; hence, the identification of an Mpro inhibitor is to make it a broad-spectrum drug. Molecular docking studies described the binding sites and the interaction energies of 74 Mpro-ligand complexes deposited in the Protein Data Bank (PDB). A structural similarity screening was carried out in order to identify possible Mpro ligands that show additional pharmacological properties against COVID-19. We identified 59 hit compounds and among them, melatonin stood out due to its prominent immunomodulatory and anti-inflammatory activities; it can reduce oxidative stress, defence cell mobility and efficiently combat the cytokine storm and sepsis. In addition, melatonin is an inhibitor of calmodulin, an essential intracellular component to maintain angiotensin-converting enzyme 2 (ACE-2) on the cell surface. Interestingly, one of the most promising hits in our docking study was melatonin. It revealed better interaction energy with Mpro compared to ligands in complexes from PDB. Consequently, melatonin can have response potential in early stages for its possible effects on ACE-2 and Mpro, although it is also promising in more severe stages of the disease for its action against hyper-inflammation. These results definitely do not confirm antiviral activity, but can rather be used as a basis for further preclinical and clinical trials.

The energetic brain - A review from students to students.

The past 20 years have resulted in unprecedented progress in understanding brain energy metabolism and its role in health and disease. In this review, which was initiated at the 14th International Society for Neurochemistry Advanced School, we address the basic concepts of brain energy metabolism and approach the question of why the brain has high energy expenditure. Our review illustrates that the vertebrate brain has a high need for energy because of the high number of neurons and the need to maintain a delicate interplay between energy metabolism, neurotransmission, and plasticity. Disturbances to the energetic balance, to mitochondria quality control or to glia-neuron metabolic interaction may lead to brain circuit malfunction or even severe disorders of the CNS. We cover neuronal energy consumption in neural transmission and basic ('housekeeping') cellular processes. Additionally, we describe the most common (glucose) and alternative sources of energy namely glutamate, lactate, ketone bodies, and medium chain fatty acids. We discuss the multifaceted role of non-neuronal cells in the transport of energy substrates from circulation (pericytes and astrocytes) and in the supply (astrocytes and microglia) and usage of different energy fuels. Finally, we address pathological consequences of disrupted energy homeostasis in the CNS.

Functional test of PCDHB11, the most human-specific neuronal surface protein.

BACKGROUND: Brain-expressed proteins that have undergone functional change during human evolution may contribute to human cognitive capacities, and may also leave us vulnerable to specifically human diseases, such as schizophrenia, autism or Alzheimer's disease. In order to search systematically for those proteins that have changed the most during human evolution and that might contribute to brain function and pathology, all proteins with orthologs in chimpanzee, orangutan and rhesus macaque and annotated as being expressed on the surface of cells in the human central nervous system were ordered by the number of human-specific amino acid differences that are fixed in modern populations. RESULTS: PCDHB11, a beta-protocadherin homologous to murine cell adhesion proteins, stood out with 12 substitutions and maintained its lead after normalizing for protein size and applying weights for amino acid exchange probabilities. Human PCDHB11 was found to cause homophilic cell adhesion, but at lower levels than shown for other clustered protocadherins. Homophilic adhesion caused by a PCDHB11 with reversion of human-specific changes was as low as for modern human PCDHB11; while neither human nor reverted PCDHB11 adhered to controls, they did adhere to each other. A loss of function in PCDHB11 is unlikely because intra-human variability did not increase relative to the other human beta-protocadherins. CONCLUSIONS: The brain-expressed protein with the highest number of human-specific substitutions is PCDHB11. In spite of its fast evolution and low intra-human variability, cell-based tests on the only proposed function for PCDHB11 did not indicate a functional change.

Effect of self-performed mechanical plaque control frequency on gingival inflammation revisited: a randomized clinical trial.

AIM: To evaluate the effect of self-performed mechanical plaque control (SPC) frequency on gingival health. METHODS: Thirty-nine subjects exhibiting limited gingival inflammation and minimal clinical attachment loss were enrolled in a single-blind, parallel group, randomized clinical trial. The subjects that were divided into three groups were tasked to perform SPC (using tooth brush and dental floss) at 12, 24 or 48 h intervals. Gingival index (GI), plaque index (PlI), and gingival crevicular fluid (GCF) volume were evaluated at baseline and 30 days follow-up. Groups were compared using anova and Tukey. RESULTS: No significant differences in mean GI change were observed between the 12 and 24 h SPC intervals from baseline to 30 days (-0.06 ± 0.13 versus 0.05 ± 0.09; p = 0.11). In contrast, the 48 h interval had significantly higher mean GI change than the 12 and 24 h intervals (0.33 ± 0.17; p = 0.001). Similarly, mean PlI change was not significantly different between the 12 and 24 h SPC intervals (0.11 versus 0.28; p = 0.15), whereas SPC at 48 h-intervals yielded a significantly increased PlI (0.39; p = 0.001). CONCLUSIONS: Self-performed mechanical plaque control performed at 12 h or 24 h intervals appears sufficient to maintain gingival health in subjects with no or limited clinical attachment loss.

Evaluation of an in vitro cell culture assay for the potency assessment of recombinant human erythropoietin.

Recombinant human erythropoietin is a sialoglycoprotein that stimulates erythropoiesis. To assess potency of human erythropoietin produced by recombinant technology, we investigated an in vitro TF-1 cell proliferation assay, which was applied in conjunction with a reversed-phase liquid chromatography method for the determination of the content of sialic acids. The results obtained, which were higher than 126.8ng/µg, were compared with those obtained with the in vivo normocythaemic mouse bioassay. The in vitro assay resulted in a non-significant lower mean difference of the estimated potencies (0.61% ± 0.026, p > 0.05). The use of this combination of methods represents an advance toward the establishment of alternative in vitro approaches, in the context of the Three Rs, for the potency assessment of biotechnology-derived medicines.

A service-based approach to cryoEM facility processing pipelines at eBIC.

Electron cryo-microscopy image-processing workflows are typically composed of elements that may, broadly speaking, be categorized as high-throughput workloads which transition to high-performance workloads as preprocessed data are aggregated. The high-throughput elements are of particular importance in the context of live processing, where an optimal response is highly coupled to the temporal profile of the data collection. In other words, each movie should be processed as quickly as possible at the earliest opportunity. The high level of disconnected parallelization in the high-throughput problem directly allows a completely scalable solution across a distributed computer system, with the only technical obstacle being an efficient and reliable implementation. The cloud computing frameworks primarily developed for the deployment of high-availability web applications provide an environment with a number of appealing features for such high-throughput processing tasks. Here, an implementation of an early-stage processing pipeline for electron cryotomography experiments using a service-based architecture deployed on a Kubernetes cluster is discussed in order to demonstrate the benefits of this approach and how it may be extended to scenarios of considerably increased complexity.

Peptide L13S Derived from the BRN2 POU Domain Reduces Metastasis In Vivo and Inhibits Cell Migration and Invasion In Vitro.

BACKGROUND/AIM: The Brain-Specific Homeobox/POU Domain Protein 2 (BRN2) transcription factor supports melanoma progression by regulating the expression of several genes involved in cell migration and invasion. We hypothesized that a peptide designed based on the POU domain of BRN2 could block the BRN2 transcription activity and, consequently, reduce metastasis. MATERIALS AND METHODS: Cell viability was accessed by Trypan Blue exclusion dye assay and xCelligence platform. Wound-healing scratch assay and transwell invasion with matrigel membrane assay were performed to analyze cell migration and invasion. The internalization mechanism of the L13S peptide was investigated using confocal microscopy and wound-healing scratch assay. The impact of L13S on cell protein expression was analyzed through western blotting. In vivo assays were conducted to evaluate the protective effect and toxicity of L13S in a metastatic model using murine melanoma cells. RESULTS: Here, we show that the peptide named L13S can inhibit the migration and invasion of murine melanoma cells (B16F10-Nex2) as well as the migration of human melanoma cells (SK-MEL-25 and A375) by regulating the expression of proteins involved in motility. Mechanistically, we found that L13S is internalized by murine melanoma cells via macropinocytosis and binds actin filaments and nuclei. More importantly, in vivo studies indicated that the peptide was able to significantly inhibit lung metastasis in syngeneic models without off-target effects and with virtually no cytotoxicity toward normal organs. CONCLUSION: L13S peptide is a strong candidate for further development as an anticancer agent for the treatment of melanoma metastasis.

Assessment of recombinant human parathyroid hormone: correlation of LC methods with bioassays.

Reversed-phase liquid chromatography (RP-LC) and size exclusion liquid chromatography (SE-LC) methods were validated for the assessment of recombinant human parathyroid hormone (rhPTH 1-34). The gradient RP-LC method was carried out on a Zorbax 300 SB C(18) column (150 mm × 4.6 mm i.d.), maintained at 40 °C. The mobile phase A consisted of 0.1 M sodium sulphate buffer, pH 2.3, and the mobile phase B was acetonitrile. The SE-LC method was carried out on a BioSep-SEC-S 2000 column (300 mm × 7.8 mm i.d.), maintained at 25 °C. The mobile phase consisted of 0.1 M phosphoric acid buffer, pH 2.5, run isocratically at a flow rate of 0.7 mL min(-1). Chromatographic separation was obtained with retention times of 12.2 min, and 13.2 min, and was linear over the concentration range of 1-250 µg mL(-1) (r(2) = 0.9997) and 2-300 µg mL(-1) (r(2) = 0.9993), respectively, for RP-LC and SE-LC, with photodiode array (PDA) detection at 214 nm. Specificity was established in degradation studies, which also showed that there was no interference of the excipients. Equally, the accuracy was 100.49% and 100.22%, with bias lower than 1.12% and 0.81% respectively. Moreover, the in vitro cytotoxicity test of related proteins and higher molecular weight forms showed significant differences (p < 0.05). Chromatographic methods were applied for the content/potency assessment of rhPTH and related proteins in biopharmaceutical injectable dosage forms, and the results were correlated with those of in vitro and in vivo bioassays. It is concluded that the employment of the methods in conjunction allows a great improvement in monitoring stability, contributing to evaluate alternatives which improve the quality control and thereby assure the therapeutic efficacy of the biotechnology-derived medicine.

Frequency of mechanical removal of plaque as it relates to gingival inflammation: a randomized clinical trial.

AIM: This single blind, randomized clinical trial evaluated the relationship between frequency of mechanical removal of plaque (MRP) and gingival inflammation. MATERIALS & METHODS: Fifty-two patients (maximum 5% of sites with gingival bleeding and no history of periodontitis) were randomized to different frequencies of MRP: 12, 24, 48 and 72 h. Plaque index (PlI) and gingival index (GI) were evaluated at baseline, 15 and 30 days. Intra- and inter-group differences were determined by repeated measures anova and mixed models anova, respectively, both followed by Tukey's test. RESULTS: The mean GI between baseline and 30 days remained statistically unchanged in the 12 h (0.51 ± 0.17 versus 0.63 ± 0.23, p = 0.137) and 24 h (0.43 ± 0.19 versus 0.59 ± 0.21, p = 0.052) groups, but increased significantly in the 48 h (0.48 ± 0.18 versus 0.84 ± 0.21, p = 0.001) and 72 h (0.55 ± 0.20 versus 0.94 ± 0.25, p = 0.000) groups. At 30 days, the average percentage of sites with GI scores of 1 and 2 was significantly higher in the 48 and 72 h than in the 12 and 24 h groups (p < 0.05). CONCLUSIONS: Frequencies of mechanical removal plaque up to 24 h may prevent an increase in the severity of gingival inflammation over a period of 30 days in patients with no history of periodontitis.

Effects of Palliative Chemotherapy in Unresectable or Metastatic Colorectal Cancer Patients With Poor Performance Status.

INTRODUCTION: Colorectal cancer is the second most common cancer in both genders and often presents as a metastatic, unresectable, or recurrent disease in early follow-up. It is uncertain the benefit of oxaliplatin-based palliative chemotherapy (CT) in the first line of treatment in patients with compromised performance status (PS), Eastern Cooperative Oncology Group (ECOG) 3 and 4. These patients are systematically excluded from clinical trials but may be treated in clinical practice. METHODS: We conducted a prospective observational cohort whose primary outcome was improving at least 2 points in the worst symptom in the Edmonton Symptom Assessment System Scale (ESAS-r), without grade 3 to 4 toxicity, comparing baseline and fourth week of treatment. Secondary endpoints included quality of life using the European Quality of Life-5 dimensions questionnaire, toxicity, response rate, clinical improvement of ECOG PS, and overall survival (OS). RESULTS: We included 28 patients, and 12 (42.8%) achieved the primary endpoint. Median overall survival was 86 days, 46% of patients did not respond to the fourth-week reevaluation due to clinical deterioration, and 17.8% presented toxicity grade ≥3, with 5 patients dying from toxicity. In addition, ECOG PS 4 or cholestasis had poorer overall survival. Finally, 25% and 53.6% of patients received these treatments in the last 14 and 30 days of life, respectively. CONCLUSION: In the present study, palliative multiagent chemotherapy in poor performance status patients with non-molecularly selected colorectal cancer tended to impact tumor symptoms control; however, there is no benefit in OS and a considerable risk of toxicity and treatment-related death.

Synaptic proteasome is inhibited in Alzheimer's disease models and associates with memory impairment in mice.

The proteasome plays key roles in synaptic plasticity and memory by regulating protein turnover, quality control, and elimination of oxidized/misfolded proteins. Here, we investigate proteasome function and localization at synapses in Alzheimer's disease (AD) post-mortem brain tissue and in experimental models. We found a marked increase in ubiquitinylated proteins in post-mortem AD hippocampi compared to controls. Using several experimental models, we show that amyloid-ß oligomers (AßOs) inhibit synaptic proteasome activity and trigger a reduction in synaptic proteasome content. We further show proteasome inhibition specifically in hippocampal synaptic fractions derived from APPswePS1ΔE9 mice. Reduced synaptic proteasome activity instigated by AßOs is corrected by treatment with rolipram, a phosphodiesterase-4 inhibitor, in mice. Results further show that dynein inhibition blocks AßO-induced reduction in dendritic proteasome content in hippocampal neurons. Finally, proteasome inhibition induces AD-like pathological features, including reactive oxygen species and dendritic spine loss in hippocampal neurons, inhibition of hippocampal mRNA translation, and memory impairment in mice. Results suggest that proteasome inhibition may contribute to synaptic and memory deficits in AD.

Irisin stimulates protective signaling pathways in rat hippocampal neurons.

Physical exercise stimulates neuroprotective pathways, has pro-cognitive actions, and alleviates memory impairment in Alzheimer's disease (AD). Irisin is an exercise-linked hormone produced by cleavage of fibronectin type III domain containing protein 5 (FNDC5) in skeletal muscle, brain and other tissues. Irisin was recently shown to mediate the brain benefits of exercise in AD mouse models. Here, we sought to obtain insight into the neuroprotective actions of irisin. We demonstrate that adenoviral-mediated expression of irisin promotes extracellular brain derived neurotrophic factor (BDNF) accumulation in hippocampal cultures. We further show that irisin stimulates transient activation of extracellular signal-regulated kinase 1/2 (ERK 1/2), and prevents amyloid-ß oligomer-induced oxidative stress in primary hippocampal neurons. Finally, analysis of RNA sequencing (RNAseq) datasets shows a trend of reduction of hippocampal FNDC5 mRNA with aging and tau pathology in humans. Results indicate that irisin activates protective pathways in hippocampal neurons and further support the notion that stimulation of irisin signaling in the brain may be beneficial in AD.

Isoflavones alter male and female fertility in different development windows.

Isoflavones are a group of secondary metabolites found in plants belonging to the class of phytoestrogens. These, because they have a chemical structure similar to the endogenous hormone 17ß-estradiol, act as endocrine disruptors over the different development window periods. This study aimed to evaluate male and female reproductive systems' responses when exposed to isoflavones during the development window. It is characterized as a bibliographic review, built after analyzing clinical and preclinical articles indexed in English, Portuguese, and Spanish published in the last ten years. The isoflavones, aglycone or glucosides, have essential therapeutic properties in the relief of postmenopausal symptoms in women, reduce the proliferation of cancers, in addition to being antioxidants. On the other hand, they can still behave in a similar way to 17ß-estradiol, binding to hormone receptors and acting as endocrine disruptors over the gestational period until pre-puberty, negatively affecting the development of the reproductive system. The effects on reproduction are not dose-response but are influenced by the type of isoflavone and period. There are variations in the serum concentration of hormones and action on their negative feedback on the hypothalamic-pituitary-testicular axis in males. Reproductive functions are also affected by spermatogenesis, such as decreased sperm count, lower reproductive performance, reduced litter size, low sperm production, and reduced seminal vesicle size. In females, puberty is reached later, irregular estrous cycle, reduced weight of the ovary, uterus, lower serum levels of estradiol and progesterone, reduced fertility, or interrupted fertility. At the end of the analysis of the selected publications, it can be concluded that despite the beneficial therapeutic effects in the face of pathologies, the unknown consumption of doses and types of isoflavones in food can damage the development and reproduction of individuals. Therefore, further studies must be carried out to elucidate the usual safe doses of the analyzed phytoestrogen. Greater control over insertion in foods targeted at pediatric consumers should be implemented until we have adequate safety.

Distance sampling surveys reveal 17 million vertebrates directly killed by the 2020's wildfires in the Pantanal, Brazil.

Anthropogenic factors have significantly influenced the frequency, duration, and intensity of meteorological drought in many regions of the globe, and the increased frequency of wildfires is among the most visible consequences of human-induced climate change. Despite the fire role in determining biodiversity outcomes in different ecosystems, wildfires can cause negative impacts on wildlife. We conducted ground surveys along line transects to estimate the first-order impact of the 2020 wildfires on vertebrates in the Pantanal wetland, Brazil. We adopted the distance sampling technique to estimate the densities and the number of dead vertebrates in the 39,030 square kilometers affected by fire. Our estimates indicate that at least 16.952 million vertebrates were killed immediately by the fires in the Pantanal, demonstrating the impact of such an event in wet savanna ecosystems. The Pantanal case also reminds us that the cumulative impact of widespread burning would be catastrophic, as fire recurrence may lead to the impoverishment of ecosystems and the disruption of their functioning. To overcome this unsustainable scenario, it is necessary to establish proper biomass fuel management to avoid cumulative impacts caused by fire over biodiversity and ecosystem services.

Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer's models.

Defective brain hormonal signaling has been associated with Alzheimer's disease (AD), a disorder characterized by synapse and memory failure. Irisin is an exercise-induced myokine released on cleavage of the membrane-bound precursor protein fibronectin type III domain-containing protein 5 (FNDC5), also expressed in the hippocampus. Here we show that FNDC5/irisin levels are reduced in AD hippocampi and cerebrospinal fluid, and in experimental AD models. Knockdown of brain FNDC5/irisin impairs long-term potentiation and novel object recognition memory in mice. Conversely, boosting brain levels of FNDC5/irisin rescues synaptic plasticity and memory in AD mouse models. Peripheral overexpression of FNDC5/irisin rescues memory impairment, whereas blockade of either peripheral or brain FNDC5/irisin attenuates the neuroprotective actions of physical exercise on synaptic plasticity and memory in AD mice. By showing that FNDC5/irisin is an important mediator of the beneficial effects of exercise in AD models, our findings place FNDC5/irisin as a novel agent capable of opposing synapse failure and memory impairment in AD.

Formulation, characterization, and in vitro/in vivo studies of capsaicin-loaded albumin nanoparticles.

Capsaicin (CAP) is a secondary metabolite with high therapeutic potential. It displays several bioactive properties including hypolipidemic, antioxidant, anti-inflammatory and analgesic effects. However, CAP presents toxicity to healthy cells and poor pharmacokinetic profile, which is characterized by toxic metabolites and short half-life. In this study, CAP-loaded albumin nanoparticles were obtained by the desolvation-coacervation method. The preparation process was optimized by the application of a factorial design. Nanoparticles presented diameter of about 200 nm, quasi-spherical morphology, encapsulation efficiency of 98.3 ±â€¯7.4%, and negative zeta potential. The in vitro release assay demonstrated a biphasic profile, characterized by a fast release over 12 h followed by a prolonged release rate. Nanoencapsulated CAP showed significant antioxidant activity in an in vitro assay which was concentration - and time-dependent. In addition, the in vivo study demonstrated for the first time that both free and nanoencapsulated drug reduced TNF-alpha concentrations in the absence of inflammatory stimuli model. These novel findings indicate that albumin nanoparticles are potential CAP carriers and that this new drug formulation may be useful in several conditions, including cancer, inflammation, and neuropathic pain.

The Relationship Between Copper, Iron, and Selenium Levels and Alzheimer Disease.

This study aimed to evaluate the concentrations of copper, iron, and selenium in elderly people with Alzheimer disease (AD), comparing the same parameters in a paired group of healthy people, in order to verify if the amount of these metals may influence the cognitive impairment progression. Patients' cognitive impairment was evaluated by Clinical Dementia Rating (CDR). The elementary quantification of erythrocytes was performed by inductively coupled plasma mass spectrometry technique. The statistical analyses were carried out by SPSS software 20.0 version, employing Shapiro-Wilk, Wilcoxon, Kruskall-Wallis, and Spearman correlation tests, considering significant results of p < 0.05. The sample was composed of 34% (n = 11) of women and 66% (n = 21) of men in each group. The AD group was characterized by a higher concentration of copper (p < 0.0001) and iron (p < 0.0001); however, there is no significant difference in selenium level. The analyses of the metal levels in different stages of AD were not significant in CDR-1, however in CDR-2 and CDR-3, elevated levels of copper and iron were observed; in CDR-3 patients, the level of selenium was lower (p < 0.008) compared to that of healthy controls. Patients with Alzheimer disease studied present increase in biometal blood levels, especially of copper and iron, and such increase can be different according to the disease stage and can cause more impairment cognitive functions in AD.

Stability-indicating capillary zone electrophoresis method for the assessment of recombinant human interleukin-11 and its correlation with reversed-phase liquid chromatography and biossay.

A stability-indicating capillary zone electrophoresis (CZE) method was validated for the analysis of recombinant human interleukin-11(rhIL-11) using rupatadine fumarate, as internal standard (IS). A fused-silica capillary, (50 µm i.d.; effective length, 40 cm) was used at 25°C; the applied voltage was 20 kV. The background electrolyte solution consisted of 50 mmol L(-1) sodium dihydrogen phosphate solution at pH 3.0. Injections were performed using a pressure mode at 50 mbar for 45 s, with detection by photodiode array detector set at 196 nm. Specificity and stability-indicating capability were established in degradation studies, which also showed that there was no interference of the excipients. The method was linear over the concentration range of 1.0-300 µg mL(-1) (r(2)=0.9992) and the limit of detection (LOD) and limit of quantitation (LOQ) were 0.2 µg mL(-1) and 1.0 µg mL(-1), respectively. The accuracy was 100.4% with bias lower than 1.1%. Moreover, the in vitro cytotoxicity test of the degraded products showed significant differences (p<0.05). The method was applied for the content/potency assessment of rhIL-11 in biopharmaceutical formulations, and the results were correlated to those of a validated reversed-phase LC method (RP-LC) and an TF-1 cell culture assay, showing non-significant differences (p>0.05). In addition the CZE and RP-LC methods were applied for the analysis of rhIL-11 in human plasma. Therefore, the proposed alternative method can be applied to monitor stability, to assure the batch-to-batch consistency and quality of the bulk and finished biotechnology-derived medicine.

CoMFA/CoMSIA 3D-QSAR of pyrimidine inhibitors of Pneumocystis carinii dihydrofolate reductase.

Pneumocystis carinii is typically a non-pathogenic fungus found in the respiratory tract of healthy humans. However, it may cause P. carinii pneumonia (PCP) in people with immune deficiency, affecting mainly premature babies, cancer patients and transplant recipients, and people with acquired immunodeficiency syndrome (AIDS). In the latter group, PCP occurs in approximately 80% of patients, a major cause of death. Currently, there are many available therapies to treat PCP patients, including P. carinii dihydrofolate reductase (PcDHFR) inhibitors, such as trimetrexate (TMX), piritrexim (PTX), trimethoprim (TMP), and pyrimethamine (PMT). Nevertheless, the high percentage of adverse side effects and the limited therapeutic success of the current drug therapy justify the search for new drugs rationally planned against PCP. This work focuses on the study of pyrimidine inhibitors of PcDHFR, using both CoMFA and CoMSIA 3D-QSAR methods.