Ancient Plasmodium genomes shed light on the history of human malaria.

Malaria-causing protozoa of the genus Plasmodium have exerted one of the strongest selective pressures on the human genome, and resistance alleles provide biomolecular footprints that outline the historical reach of these species1. Nevertheless, debate persists over when and how malaria parasites emerged as human pathogens and spread around the globe1,2. To address these questions, we generated high-coverage ancient mitochondrial and nuclear genome-wide data from P. falciparum, P. vivax and P. malariae from 16 countries spanning around 5,500 years of human history. We identified P. vivax and P. falciparum across geographically disparate regions of Eurasia from as early as the fourth and first millennia BCE, respectively; for P. vivax, this evidence pre-dates textual references by several millennia3. Genomic analysis supports distinct disease histories for P. falciparum and P. vivax in the Americas: similarities between now-eliminated European and peri-contact South American strains indicate that European colonizers were the source of American P. vivax, whereas the trans-Atlantic slave trade probably introduced P. falciparum into the Americas. Our data underscore the role of cross-cultural contacts in the dissemination of malaria, laying the biomolecular foundation for future palaeo-epidemiological research into the impact of Plasmodium parasites on human history. Finally, our unexpected discovery of P. falciparum in the high-altitude Himalayas provides a rare case study in which individual mobility can be inferred from infection status, adding to our knowledge of cross-cultural connectivity in the region nearly three millennia ago.

The Genetic Origin of the Indo-Europeans.

The Yamnaya archaeological complex appeared around 3300BCE across the steppes north of the Black and Caspian Seas, and by 3000BCE reached its maximal extent from Hungary in the west to Kazakhstan in the east. To localize the ancestral and geographical origins of the Yamnaya among the diverse Eneolithic people that preceded them, we studied ancient DNA data from 428 individuals of which 299 are reported for the first time, demonstrating three previously unknown Eneolithic genetic clines. First, a "Caucasus-Lower Volga" (CLV) Cline suffused with Caucasus hunter-gatherer (CHG) ancestry extended between a Caucasus Neolithic southern end in Neolithic Armenia, and a steppe northern end in Berezhnovka in the Lower Volga. Bidirectional gene flow across the CLV cline created admixed intermediate populations in both the north Caucasus, such as the Maikop people, and on the steppe, such as those at the site of Remontnoye north of the Manych depression. CLV people also helped form two major riverine clines by admixing with distinct groups of European hunter-gatherers. A "Volga Cline" was formed as Lower Volga people mixed with upriver populations that had more Eastern hunter-gatherer (EHG) ancestry, creating genetically hyper-variable populations as at Khvalynsk in the Middle Volga. A "Dnipro Cline" was formed as CLV people bearing both Caucasus Neolithic and Lower Volga ancestry moved west and acquired Ukraine Neolithic hunter-gatherer (UNHG) ancestry to establish the population of the Serednii Stih culture from which the direct ancestors of the Yamnaya themselves were formed around 4000BCE. This population grew rapidly after 3750-3350BCE, precipitating the expansion of people of the Yamnaya culture who totally displaced previous groups on the Volga and further east, while admixing with more sedentary groups in the west. CLV cline people with Lower Volga ancestry contributed four fifths of the ancestry of the Yamnaya, but also, entering Anatolia from the east, contributed at least a tenth of the ancestry of Bronze Age Central Anatolians, where the Hittite language, related to the Indo-European languages spread by the Yamnaya, was spoken. We thus propose that the final unity of the speakers of the "Proto-Indo-Anatolian" ancestral language of both Anatolian and Indo-European languages can be traced to CLV cline people sometime between 4400-4000 BCE.

Differential fibril morphologies and thermostability determine functional roles of Staphylococcus aureus PSMα1 and PSMα3.

Phenol-soluble modulins (PSMs) are virulent peptides secreted by staphylococci that undergo self-assembly into amyloid fibrils. This study focuses on Staphylococcus aureus PSMα1 and PSMα3, which share homologous sequences but exhibit distinct amyloid fibril structures. Upon subjecting PSMα1 to an 80°C heat shock, it fibrillates into cross-ß structures, resulting in the loss of cytotoxic activity. Conversely, PSMα3 cross-α fibrils undergo reversible disaggregation upon heat shock, leading to the recovery of cytotoxicity. The differential thermostability probably arises from the presence of hydrogen bonds along the ß-strands within the ß-sheets of the cross-ß fibrils. We propose that the breakdown of PSMα3 fibrils into soluble species, potentially co-aggregating with membrane lipids, is crucial for its toxic process and enables the reversible modulation of its biological activity under stress conditions. In contrast, the formation of robust and irreversible cross-ß fibrils by PSMα1 corresponds to its role in biofilm stability. These findings emphasize how the unique fibril morphologies and thermostability of PSMα1 and PSMα3 shape their functional roles in various environments of S. aureus.

Contribution of TRPC3-mediated Ca2+ entry to taste transduction.

The current concept of taste transduction implicates the TASR/PLCß2/IP3R3/TRPM5 axis in mediating chemo-electrical coupling in taste cells of the type II. While generation of IP3 has been verified as an obligatory step, DAG appears to be a byproduct of PIP2 cleavage by PLCß2. Here, we provide evidence that DAG-signaling could play a significant and not yet recognized role in taste transduction. In particular, we found that DAG-gated channels are functional in type II cells but not in type I and type III cells. The DAG-gated current presumably constitutes a fraction of the generator current triggered by taste stimulation in type II cells. Bitter stimuli and DAG analogs produced Ca2+ transients in type II cells, which were greatly decreased at low bath Ca2+, indicating their dependence on Ca2+ influx. Among DAG-gated channels, transcripts solely for TRPC3 were detected in the taste tissue, thus implicating this channel in mediating DAG-regulated Ca2+ entry. Release of the afferent neurotransmitter ATP from CV papillae was monitored online by using the luciferin/luciferase method and Ussing-like chamber. It was shown that ATP secretion initiated by bitter stimuli and DAG analogs strongly depended on mucosal Ca2+. Based on the overall findings, we speculate that in taste transduction, IP3-driven Ca2+ release is transient and mainly responsible for rapid activation of Ca2+-gated TRPM5 channels, thus forming the initial phase of receptor potential. DAG-regulated Ca2+ entry through apically situated TRPC3 channels extends the primary Ca2+ signal and preserves TRPM5 activity, providing a needful prolongation of the receptor potential.

Twisted Few-Mode Optical Fiber with Improved Height of Quasi-Step Refractive Index Profile.

This work presents designed and fabricated silica few-mode optical fiber (FMF) with induced twisting 10 and 66 revolutions per meter, core diameter 11 µm, typical "telecommunication" cladding diameter 125 µm, improved height of quasi-step refractive index profile and numerical aperture 0.22. Proposed FMF supports 4 guided modes over "C"-band. We discussed selection of specified optical fiber parameters to provide desired limited mode number over mentioned wavelength range. Some results of tests, performed with pilot samples of manufactured FMF, are represented, including experimentally measured spectral responses of laser-excited optical signals, that comprise researches and analysis of few-mode effects, occurring after fiber Bragg grating writing.

Modeling of Pharmacokinetic Profiles of Insulin Aspart and Biphasic Insulin Aspart 30/70.

This study includes modeling and simulation of insulin aspart pharmacokinetics (PK). The authors used PK data of biosimilar insulins-insulin aspart and biphasic insulin aspart 30/70-to develop a predictive population PK model for the insulins. The model was built via Monolix software, taking into account the weight-based dosing and the dose and body-weight effects on the parameters. The model-based simulations were performed using the R package mlxR for various administered doses and various ratios of insulin aspart forms for a better understanding of the insulin behavior. The optimal model was a 1-compartment model with a combination of zero- and first-order absorptions, with absorption lag for the soluble form of insulin aspart and first-order absorption for the insulin aspart protamine suspension. The assumption of identical behavior of 2 insulins at the distribution and elimination phases was made. The developed PK model was fitted successfully to the experimental data, and all fitted parameters displayed a moderate coefficient of variation. The PK model allows us to predict PK profiles for various doses and formulations of insulin aspart and can be used to improve the accuracy, safety, and ethics of novel clinical trials of insulin.

Effect of Caloric Restriction on Aging: Fixing the Problems of Nutrient Sensing in Postmitotic Cells?

The review discusses the role of metabolic disorders (in particular, insulin resistance) in the development of age-related diseases and normal aging with special emphasis on the changes in postmitotic cells of higher organisms. Caloric restriction helps to prevent such metabolic disorders, which could probably explain its ability to prolong the lifespan of laboratory animals. Maintaining metabolic homeostasis is especially important for the highly differentiated long-lived body cells, whose lifespan is comparable to the lifespan of the organism itself. Normal functioning of these cells can be ensured only upon correct functioning of the cytoplasm clean-up system and availability of all required nutrients and energy sources. One of the central problems in gerontology is the age-related disruption of glucose metabolism leading to obesity, diabetes, metabolic syndrome, and other related pathologies. Along with the adipose tissue, skeletal muscles are the main consumers of insulin; hence the physical activity of muscles, which supports their energy metabolism, delays the onset of insulin resistance. Insulin resistance disrupts the metabolism of cardiomyocytes, so that they fail to utilize the nutrients to perform their functions even being surrounded by a nutrient-rich environment, which contributes to the development of age-related cardiovascular diseases. Metabolic pathologies also alter the nutrient sensitivity of neurons, thus disrupting the action of insulin in the central nervous system. In addition, there is evidence that neurons can develop insulin resistance as well. It has been suggested that affecting nutritional sensors (e.g., AMPK) in postmitotic cells might improve the state of the entire multicellular organism, slow down its aging, and increase the lifespan.

Efficacy and safety of GP40021 insulin lispro biphasic compared with Humalog Mix 25 in Type 2 diabetes mellitus patients.

Aim: To compare safety (immunogenicity) and efficacy of a biosimilar insulin GP-Lis25 and a reference insulin Ly-Lis25 (Humalog Mix 25) in Type 2 diabetes mellitus (T2D) patients. Materials & methods: This randomized open-label, 26-week clinical trial enrolled 210 T2D patients, randomized 1:1 to twice-daily GP-Lis25 or Ly-Lis25. The primary end point was immune response at 26th week. Noninferiority margin for HbA1c was 0.4%. Results: Immune response frequency was similar in GP-Lis25 and Ly-Lis25 groups both at week 12 (p = 0.651) and 26 (p = 0.164). The difference of HbA1c change at week 26 was (95% CI) 0.01 (-0.27-0.28)%. Fasting plasma glucose, seven-point glucose profile and insulin dose were similar between groups. Safety did not differ between groups. Conclusion: GP-Lis25 and Ly-Lis25 demonstrated similar safety and efficacy. ClincalTrials.gov identifier: NCT04023344.

Modeling of Ca2+ transients initiated by GPCR agonists in mesenchymal stromal cells.

The integrative study that included experimentation and mathematical modeling was carried out to analyze dynamic aspects of transient Ca2+ signaling induced by brief pulses of GPCR agonists in mesenchymal stromal cells from the human adipose tissue (AD-MSCs). The experimental findings argued for IP3/Ca2+-regulated Ca2+ release via IP3 receptors (IP3Rs) as a key mechanism mediating agonist-dependent Ca2+ transients. The consistent signaling circuit was proposed to formalize coupling of agonist binding to Ca2+ mobilization for mathematical modeling. The model properly simulated the basic phenomenology of agonist transduction in AD-MSCs, which mostly produced single Ca2+ spikes upon brief stimulation. The spike-like responses were almost invariantly shaped at different agonist doses above a threshold, while response lag markedly decreased with stimulus strength. In AD-MSCs, agonists and IP3 uncaging elicited similar Ca2+ transients but IP3 pulses released Ca2+ without pronounced delay. This suggested that IP3 production was rate-limiting in agonist transduction. In a subpopulation of AD-MSCs, brief agonist pulses elicited Ca2+ bursts crowned by damped oscillations. With properly adjusted parameters of IP3R inhibition by cytosolic Ca2+, the model reproduced such oscillatory Ca2+ responses as well. GEM-GECO1 and R-CEPIA1er, the genetically encoded sensors of cytosolic and reticular Ca2+, respectively, were co-expressed in HEK-293 cells that also responded to agonists in an "all-or-nothing" manner. The experimentally observed Ca2+ signals triggered by ACh in both compartments were properly simulated with the suggested signaling circuit. Thus, the performed modeling of the transduction process provides sufficient theoretical basis for deeper interpretation of experimental findings on agonist-induced Ca2+ signaling in AD-MSCs.

Safety and efficacy of GP40061 compared with originator insulin glargine (Lantus®): a randomized open-label clinical trial.

Aim: To compare safety (immunogenicity) and efficacy of GP40061 insulin glargine (GP-Gla) and Lantus® (Sanofi glargine, Sa-Gla) in people with diabetes mellitus. Materials & methods: This randomized open-label, 26-week clinical trial enrolled 180 Type 1 diabetes mellitus patients (HbA1c 6.5-12.0%), randomized 1:1 to once daily GP-Gla (n = 90) or Sa-Gla (n = 90). The primary end point was immune response at 26th week. Results: The frequency of immune response was similar in GP-Gla and Sa-Gla (p = 1.000). Groups were similar in terms of other safety end points. Mean HbA1c change from baseline was -0.66% for GP-Gla and -0.77% for Sa-Gla, and did not differ between groups (p = 0.326). Insulin doses, fasting plasma glucose and seven-point glucose profiles were similar between groups. Conclusion: GP-Gla and Sa-Gla demonstrated similar safety and efficacy. ClinicalTrials.gov Identifier: NCT04022993.

Coupling of P2Y receptors to Ca2+ mobilization in mesenchymal stromal cells from the human adipose tissue.

The purinergic transduction was examined in mesenchymal stromal cells (MSCs) from the human adipose tissue, and several nucleotides, including ATP, UTP, and ADP, were found to mobilize cytosolic Ca2+. Transcripts for multiple purinoreceptors were detected in MSC preparations, including A1, A2A, A2B, P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y13, P2Y14, P2X2, P2X4, and P2X7. Cellular responses to nucleotides were insignificantly sensitive to bath Ca2+, pointing at a minor contribution of Ca2+ entry, and were suppressed by U73122 and 2-APB, implicating the phosphoinositide cascade in coupling P2Y receptors to Ca2+ release. While individual cells were sensitive to several P2Y agonists, responsiveness to a given nucleotide varied from cell to cell, suggesting that particular MSCs could employ different sets of purinoreceptors. Caged Ca2+ stimulated Ca2+-induced Ca2+ release (CICR) that was mediated largely by IP3 receptors, and resultant Ca2+ transients were similar to nucleotide responses by magnitude and kinetics. A variety of findings hinted at CICR to be a universal mechanism that finalizes Ca2+ signaling initiated by agonists in MSCs. Individual MSCs responded to nucleotides in an all-or-nothing manner. Presumably just CICR provided invariant Ca2+ responses observed in MSCs at different nucleotide concentrations. The effects of isoform specific agonists and antagonists suggested that both P2Y1 and P2Y13 were obligatory for ADP responses, while P2Y4 and P2Y11 served as primary UTP and ATP receptors, respectively. Extracellular NAD+ stimulated Ca2+ signaling in each ATP-responsive MSC by involving P2Y11. The overall data indicate that extracellular nucleotides and NAD+ can serve as autocrine/paracrine factors regulating MSC functions.

A 2-year Double-Blind RCT Follow-up Study with Fermented Papaya Preparation (FPP) Modulating Key Markers in Middle-Age Subjects with Clustered Neurodegenerative Disease-Risk Factors.

In recent years a number of studies have reported the significant relationship between metabolic syndrome and neurodegenerative disease. There is accumulating evidence that the interplay of combined genetic and environmental risk factors (from diet to life style to pollutants) to intrinsic age-related oxi-inflammatory changes may be advocated for to explain the pandemic of neurodegenerative diseases. In recent years a specific Fermented Papaya Preparation (FPP) has been shown to significantly affect a number of redox signalling abnormalities in a variety of chronic diseases and as well in aging mechanisms either on experimental and on clinical ground. The aim of the present study was to evaluate FPP use in impending metabolic disease patients with potentially neurodegenerative disease clustered risk factors. The study population consisted of 90 patients aged 45-65 years old, with impending metabolic syndrome and previously selected as to be ApoE4 genotype negative. By applying a RCT, double-blind method, one group received FPP 4.5 g twice a day (the most common dosage utilized in prior clinical studies) while the other received an oral antioxidant cocktail (trans-resveratrol, selenium, vitamin E, vitamin C). Then, after 21 month treatment period, a selected heavy metal chelator was added at the dosage of 3 g/nocte for the final 3 months study treatment. The parameters tested were: routine tests oxidized LDL-cholesterol, anti-oxidised LDL, Cyclophilin-A (CyPA), plasminogen activator inhibitor-1 and CyPA gene expression. From this study it would appear that FPP, unlike the control antioxidant, significantly decreased oxidized-LDL and near normalizing the anti-Ox-LDL/Ox-LDL ratio (p<0.001) although unaffecting the lipid profile per sè. Moreover, only FPP decreased cyclophilin-A plasma level and plasminogen activator-inhibitor (p<0.01) together with downregulating cyclophilin-A gene expression (p<0.01). Insulin resistance was only mildly improved. Heavy metals gut clearance proved to be effectively enhanced by the chelator (p<0.01) and this was not affected by any of the nutraceuticals, nor it added any further benefit to the biological action of FPP.

Effect of change in spindle structure on proliferation inhibition of osteosarcoma cells and osteoblast under simulated microgravity during incubation in rotating bioreactor.

In order to study the effect of microgravity on the proliferation of mammalian osteosarcoma cells and osteoblasts, the changes in cell proliferation, spindle structure, expression of MAD2 or BUB1, and effect of MAD2 or BUB1 on the inhibition of cell proliferation is investigated by keeping mammalian osteosarcoma cells and osteoblasts under simulated microgravity in a rotating wall vessel (2D-RWVS) bioreactor. Experimental results indicate that the effect of microgravity on proliferation inhibition, incidence of multipolar spindles, and expression of MAD2 or BUB1 increases with the extension of treatment time. And multipolar cells enter mitosis after MAD2 or BUB1 is knocked down, which leads to the decrease in DNA content, and decrease the accumulation of cells within multipolar spindles. It can therefore be concluded that simulated microgravity can alter the structure of spindle microtubules, and stimulate the formation of multipolar spindles together with multicentrosomes, which causes the overexpression of SAC proteins to block the abnormal cells in metaphase, thereby inhibiting cell proliferation. By clarifying the relationship between cell proliferation inhibition, spindle structure and SAC changes under simulated microgravity, the molecular mechanism and morphology basis of proliferation inhibition induced by microgravity is revealed, which will give experiment and theoretical evidence for the mechanism of space bone loss and some other space medicine problems.

Does aging need its own program, or is the program of development quite sufficient for it? Stationary cell cultures as a tool to search for anti-aging factors.

According to our conception, the aging process is caused by cell proliferation restriction-induced accumulation of various macromolecular defects (mainly DNA damage) in cells of a mature organism or in a cell population. In the case of cell cultures, the proliferation restriction is related to so-called contact inhibition and to the Hayflick's limit, while in the case of multicellular organisms, it is related to the appearance, in the process of differentiation, of organs and tissues consisting of postmitotic and very slowly dividing cells. It is assumed that the proliferation of intact cells prevents accumulation of various errors in a cell population. However, the continuous propagation of all the cells in a multicellular organism is absolutely incompatible with its normal functioning. Thus, the program of development, when it generates postmitotic or slowly dividing cells, automatically leads also to the onset of the aging process (mortality increase with age). Therefore, any additional special program for aging simply becomes unnecessary. This, however, doesn't reject, for some organisms, the reasonability of programmed death, which makes possible the elimination of harmful, from the species point of view, individuals. It is also very important to emphasize that increase or decrease of an organism's lifespan under the effects of various external factors is not always necessarily related to modification of the aging process, though the experimental results in the field are usually interpreted in just this way. I called the experimental-gerontological models similar to the Hayflick's model "correlative", since they are based on some correlations only and not related necessarily to the gist of the aging phenomenon. So, for the Hayflick's model, it is the relationship between population doubling level and donor age, between population doubling potential and species lifespan, between some cell changes in vivo and in vitro, and so forth. If the rationale of the "Hayflick phenomenon" is used, we can't explain why we age. Nevertheless, many authors virtually put a sign of equality between aging in vitro and aging in vivo, which generates conclusions that are of quite doubtful accuracy. A classic illustration of this is the telomere concept of aging. Originally, the principle of shortening end-segments of DNA (telomeres) during each cell division was formulated at the beginning of seventies by the Russian scientist Aleksey Olovnikov and used by him to explain the limited "proliferative" lifespan in vitro of normal cells. Subsequently, the existence of this phenomenon was confirmed by the results of many research reports, the culmination of which was a publication in which the authors demonstrated the possibility of increasing the proliferative potential of normal cells by introducing the enzyme telomerase to them, thus restoring the lost telomere segments. At the moment it looks like the telomere shortening contributes to aging in vitro only, but not to aging in vivo because an organism never realizes the full proliferative potential of its cells. Besides, the most "responsive to aging" are the organs and tissues consisting of postmitotic cells, for which the concept of proliferative potential loses any meaning in practical terms. We developed another "correlative" model--a model for testing of geroprotectors and geropromoters--the "cell kinetics model." It is based on the well-known correlation between the "age" of cultured cells (age of their donor) and their saturation density. The model allowed us to perform preliminary testing of a lot of different compounds and factors that are interesting from a gerontological point of view, but it revealed no information about the real mechanisms of aging. However, the second model we use in our studies--the "stationary phase aging" model--obviously, is a "gist" model. It is based on the assumption that in the cells of stationary cultures various intracellular changes similar to those of an aging organism can be observed. The proliferation restriction in the case is provided, as a rule, just by contact inhibition. Many experimental results confirming this assumption were obtained. "Age-related" changes that are well known from organismal studies were shown to really occur in our experimental stationary cell culture model. Besides, such experiments can be carried out on nearly any type of cells from various biological species. Thus, the evolutionary approach to analysis of the data is provided. Moreover, the changes in the stationary cell cultures become detectable very soon--as a rule, in 2 to 3 weeks after beginning the experiment. All this allows us to suppose that the "stationary phase aging" model should provide a very effective approach to testing of different substances and their cocktails on their activities in terms of accelerating or retarding aging--of course, if their effect is realized on the cell level only.

Efficacy and safety of flavocoxid compared with naproxen in subjects with osteoarthritis of the knee- a subset analysis.

OBJECTIVE: twice-daily flavocoxid, a cyclooxygenase and 5-lipoxygenase inhibitor with potent antioxidant activity of botanical origin, was evaluated for 12 weeks in a randomized, double-blind, active-comparator study against naproxen in 220 subjects with moderate-severe osteoarthritis (OA) of the knee. As previously reported, both groups noted a significant reduction in the signs and symptoms of OA with no detectable differences in efficacy between the groups when the entire intent-to-treat population was considered. This post-hoc analysis compares the efficacy of flavocoxid to naproxen in different subsets of patients, specifically those related to age, gender, and disease severity as reported at baseline for individual response parameters. METHODS: in the original randomized, double-blind study, 220 subjects were assigned to receive either flavocoxid (500 mg twice daily) or naproxen (500 mg twice daily) for 12 weeks. In this subgroup analysis, primary outcome measures including the Western Ontario and McMaster Universities OA index and subscales, timed walk, and secondary efficacy variables, including investigator global assessment for disease and global response to treatment, subject visual analog scale for discomfort, overall disease activity, global response to treatment, index joint tenderness and mobility, were evaluated for differing trends between the study groups. RESULTS: subset analyses revealed some statistically significant differences and some notable trends in favor of the flavocoxid group. These trends became stronger the longer the subjects continued on therapy. These observations were specifically noted in older subjects (>60 years), males and in subjects with milder disease, particularly those with lower subject global assessment of disease activity and investigator global assessment for disease and faster walking times at baseline. CONCLUSIONS: initial analysis of the entire intent-to-treat population revealed that flavocoxid was as effective as naproxen in managing the signs and symptoms of OA of the knee. Detailed analyses of subject subsets demonstrated distinct trends in favor of flavocoxid for specific groups of subjects.

Efficacy and safety of flavocoxid, a novel therapeutic, compared with naproxen: a randomized multicenter controlled trial in subjects with osteoarthritis of the knee.

INTRODUCTION: Flavocoxid is a novel flavonoid-based "dual inhibitor" of the 5-lipoxygenase (5-LOX) enzyme and the cyclooxygenase (COX) enzymes. This study was designed to compare the effectiveness and safety of flavocoxid to naproxen in subjects with moderate to severe osteoarthritis (OA) of the knee. METHODS: In this randomized, multicenter, double-blind study, 220 subjects were assigned to receive either flavocoxid (500 mg twice daily) or naproxen (500 mg twice daily) for 12 weeks. The trial was structured to show noninferiority of flavocoxid to naproxen. Primary outcome measures included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and subscales and a timed walk. RESULTS: More than 90% of the subjects in both groups noted significant reduction in the signs and symptoms of knee OA. There were no statistically significant differences in efficacy between the flavocoxid and naproxen groups when the entire intent-to-treat population was analyzed. The flavocoxid group had significantly fewer upper gastrointestinal (UGI) and renal (edema) adverse events (AEs) as well as a strong trend toward fewer respiratory AEs. CONCLUSION: Flavocoxid, a first-in-class flavonoid-based therapeutic that inhibits COX-1 and COX-2 as well as 5-LOX, was as effective as naproxen in managing the signs and symptoms of OA of the knee. Flavocoxid demonstrated better UGI, renal (edema), and respiratory safety profiles than naproxen.

Flavocoxid is as effective as naproxen for managing the signs and symptoms of osteoarthritis of the knee in humans: a short-term randomized, double-blind pilot study.

Flavocoxid (Limbrel), a proprietary mixture of flavonoid molecules (baicalin and catechin), was tested against a traditional nonsteroidal anti-inflammatory drug, naproxen, for the management of the signs and symptoms of moderate osteoarthritis (OA) in humans. Discomfort and global disease activity were used as the primary end points, and safety assessments were also taken for both treatments as a secondary endpoint. In this double-blind study, 103 subjects were randomly assigned to receive either flavocoxid [500 mg twice daily (BID)] or naproxen (500 mg BID) in a 1-month onset of action trial. Outcome measures included the short Western Ontario and McMaster University Osteoarthritis Index, subject Visual Analogue Scale for discomfort and global response, and investigator Visual Analogue Scale for global response and fecal occult blood. Both flavocoxid and naproxen showed significant reduction in the signs and symptoms of knee OA (P < or = .001). There were no statistically detectable differences between the flavocoxid and naproxen groups with respect to any of the outcome variables. Similarly, there were no statistically detectable differences between the groups with respect to any adverse event, although there was a trend toward a higher incidence of edema and nonspecific musculoskeletal discomfort in the naproxen group. In this short-term pilot study, flavocoxid was as effective as naproxen in controlling the signs and symptoms of OA of the knee and would present a safe and effective option for those individuals on traditional nonsteroidal anti-inflammatory drugs or cyclooxygenase-2 inhibitors. A low incidence of adverse events was reported for both groups.

Voltage dependence of ATP secretion in mammalian taste cells.

Mammalian type II taste cells release the afferent neurotransmitter adenosine triphosphate (ATP) through ATP-permeable ion channels, most likely to be connexin (Cx) and/or pannexin hemichannels. Here, we show that ion channels responsible for voltage-gated (VG) outward currents in type II cells are ATP permeable and demonstrate a strong correlation between the magnitude of the VG current and the intensity of ATP release. These findings suggest that slowly deactivating ion channels transporting the VG outward currents can also mediate ATP secretion in type II cells. In line with this inference, we studied a dependence of ATP secretion on membrane voltage with a cellular ATP sensor using different pulse protocols. These were designed on the basis of predictions of a model of voltage-dependent transient ATP efflux. Consistently with curves that were simulated for ATP release mediated by ATP-permeable channels deactivating slowly, the bell-like and Langmuir isotherm-like potential dependencies were characteristic of ATP secretion obtained for prolonged and short electrical stimulations of taste cells, respectively. These observations strongly support the idea that ATP is primarily released via slowly deactivating channels. Depolarizing voltage pulses produced negligible Ca(2+) transients in the cytoplasm of cells releasing ATP, suggesting that ATP secretion is mainly governed by membrane voltage under our recording conditions. With the proviso that natural connexons and pannexons are kinetically similar to exogenously expressed hemichannels, our findings suggest that VG ATP release in type II cells is primarily mediated by Cx hemichannels.