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Background.Reactive oxygen species and particularly free radical induced lipid peroxidative tissue damage have been implicated in the pathogenesis of various renal diseases. Lipid peroxidation is assessed indirectly by the measurement of secondary products, such as malondialdehyde (MDA), using the widely employed thiobarbituric acid reactive substances (TBARS) method. However, this method lacks sensitivity and specificity. We have therefore developed and validated an HPLC (high-performance liquid chromatography) method for measurement of MDA and applied this to a variety of plasma samples in renal patients. [ABSTRACT FROM PUBLISHER]

In the following examples, the time frames and ultimate results are measured in years, not days or months. In particular, the application of genetic techniques to complex systems requires many investigators and a multitude of false leads. The areas chosen are all related to the identification and use of techniques from many scientific fields. Except for the necessity of describing the many years of work required to identify and then utilize the genetic information from yet uncultivated microbes, and identifying the true sources of the dolastatins, the rest of the examples are quite short with commentaries on most of the references given., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests., (Copyright © 2024. Published by Elsevier Ltd.)

Abstract: Agar-Newman, DJ, MacRae, F, Tsai, M-C, and Klimstra, M. Predicting sprint performance from the vertical and horizontal jumps in National Football League Combine athletes. J Strength Cond Res 38(8): 1433-1439, 2024-Identifying fast athletes is an important part of the National Football League (NFL) Combine. However, not all athletes partake in the 36.58-m sprint, and relying on this single test may miss potentially fast athletes. Therefore, the purpose of this study was to determine whether sprinting times can be predicted using simple anthropometric and jumping measures. Data from the NFL Combine between the years 1999-2020 inclusive were used (n = 4,149). Subjects had a mean (±SD) height = 1.87 ± 0.07 m and body mass = 111.96 ± 20.78 kg. The cross-validation technique was used, partitioning the data into a training set (n = 2,071) to develop regression models to predict time over the 9.14-, 9.14- to 18.29-, 18.29- to 36.58-m, and 36.58-m segments using vertical jump, broad jump, height, and mass as the independent variables. The models were then evaluated against a test set (n = 2,070) for agreement. Statistically significant (p < 0.01) models were determined for 9.14-m time (adjusted R2 = 0.76, SEE = 0.05 seconds), 9.14- to 18.29-m time (adjusted R2 = 0.74, SEE = 0.04 seconds), 18.29- to 36.59-m time (adjusted R2 = 0.79, SEE = 0.07 seconds), and 36.58-m time (adjusted R2 = 0.84, SEE = 0.12 seconds). When evaluated against the test set, the models showed biases of -0.05, -0.04, -0.02, and -0.02 seconds and root-mean-square error of 0.07, 0.05, 0.07, and 0.12 seconds for the 9.14-, 9.14- to 18.29-, 18.29- to 36.58-m, and 36.58-m segments, respectively. However, 5-6% of the predictions lay outside of the limits of agreement. This study provides 4 formulae that can be used to predict sprint performance when the 36.58-m sprint test is not performed, and practitioners can use these equations to determine training areas of opportunity when working with athletes preparing for the NFL Combine., (Copyright © 2024 National Strength and Conditioning Association.)

The isolation, structure determination, and biological evaluation of constituents from the organic extract of Turraea delphinensis Wahlert (Meliaceae) resulted in the isolation of 51 secondary metabolites, including 14 new terpenoids (six cycloartanes, four tirucallanes/euphanes, three limonoids, and a 7-keto sterol). Among the new compounds, 1 is the first triterpenoid with a trioxaspiro[4.4]nonane side chain, while 11 - 13 are the first 17-γ-lactone tetranortriterpenoids with four oxygenated functional groups at C-1, -3, -6, and -7. The isolated compounds were evaluated for antiproliferative activity against five human tumor cell lines, including a vinblastine-resistant cell line.

Diabetes type 2 (T2DM) is the non-insulin-linked disease that is now becoming a major problem not only in the West but also in Asia (particularly in China and close geographic areas). Unlike the childhood onset diabetic disease (T1DM), which is effectively due to lack of insulin production and is maintained by insulin injection, T2DM is best thought of as an adult disease often being caused by what is now considered "metabolic syndrome" or the culmination of too many insults to the body, in particular obesity and its "coupled diseases" including heart problems. Its symptoms were described in ancient times not only in Europe but also in Asia and with later (1600s) anecdotal reports from South America. In all cases, the diagnostic was "sweet urine" due to the excretion of large amounts of glucose in the urine. This review covers the non-insulin agents approved from 1990 to 2021 from a historical aspect and discussions of the latest agents and can be considered an extension of the author's previous drug source reviews, but this time concentrating on nominally one disease entity, though metabolic syndrome is a collection of ailments.

Four cytotoxic heptacyclic caged-xanthones [gambogefic acids B-E ( 1 - 4 )], a cytotoxic hexacyclic caged-xanthone [garcilatelic acid ( 5 )], and four biphenyl derivatives [garcilatelibiphenyls A-D ( 6 - 9 )] were newly isolated in a phytochemical study of a 50% MeOH/CH 2 Cl 2 extract of Garcinia lateriflora (Clusiaceae). The isolated compounds were evaluated for antiproliferative activity against five human tumor cell lines including a vincristine-resistant line. The new caged-xanthones displayed potent activity with IC 50 values from 0.5 to 6.7 μM against all tested tumor cell lines.

Eight vilasinin-class limonoids, including the unusually chlorinated rubescins K-M ( 1 - 3 ), the 2,3-epoxylated rubescin N ( 4 ), and rubescins O-R ( 5 - 8 ), were newly isolated from Trichilia rubescens . The structures of the isolated compounds were determined through spectroscopic and spectrometric analyses, as well as ECD calculations. The natural occurrence of chlorinated limonoids 1 - 3 was confirmed by chemical methods and HPLC analysis of a roughly fractionated portion of the plant extract. Eight selected limonoids, including previously known and new compounds, were evaluated for antiproliferative activity against five human tumor cell lines. All tested limonoids, except 8 , exhibited significant potency, with IC 50 values of <10 μM; in particular, limonoid 14 strongly inhibited tumor cell growth, with IC 50 values of 0.54-2.06 μM against all tumor cell lines, including multi-drug-resistant cells.

ABSTARCTThe PUSH band 2.0 is a wearable technology used to measure mean and peak velocity and power in strength-based movements. The agreement between the PUSH band 2.0 and the criterion measure (force plates) during progressively loaded squat jumps was assessed. Fifteen participants performed 3 squat jumps at increasing loads. Linear regression and Bland-Altman plots assessed data simultaneously recorded from both devices. Mean velocity and power showed deviation from the identity line and an overestimation of 7.40% and 25%, respectively. Peak velocity and power showed an overestimation of 14% and underestimation of 6%, respectively. The results support the use of Push Band 2.0 to measure velocity during ballistic squat movements. However, errors in power measurement are greater than acceptable to support in-field use. While peak velocity maintains a consistent overestimation bias across various velocities, mean velocity error increases at higher velocities and can only be considered valid at slow velocities.

INTRODUCTION: Astronauts exercise to reduce microgravity-induced bone loss, but the resultant skeletal loading may not be sufficient to reduce fracture risk on an extended Mars mission. Adding additional exercise increases the risk of a negative caloric balance. Neuromuscular electrical stimulation (NMES) induces involuntary muscle contractions, which load the skeleton. The metabolic cost of NMES is not fully understood. On Earth, walking is a common source of skeletal loading. If the metabolic cost of NMES were equal to or less than walking, it could offer a low metabolic cost option for increasing skeletal loading. METHODS: We measured the oxygen consumed and carbon dioxide produced from 10 subjects during 5-min bouts of walking at 2 mph, 3 mph, and 2 mph on a 6° incline, and of NMES to the legs at duty cycles of 1 s on and 5 s, 4 s, or 3 s off. Metabolic cost was calculated using the Brockway equation and the percent increase above resting for each NMES bout was compared to walking. RESULTS: Metabolic cost increased 64.9 ± 52.8% from rest in the most intense NMES duty cycle (1 s/3 s) and 120.4 ± 26.5%, 189.3 ± 59.5%, 281.7 ± 66.8%, for the 2 mph, 3 mph, and incline walking, respectively. The metabolic cost did not differ significantly between the three NMES duty cycles. DISCUSSION: The increase in metabolic cost of the fastest NMES bout was less than that of the slowest walk, indicating that numerous NMES bouts offer a way to increase skeletal loading at a modest metabolic cost. This might allow for more daily skeletal loading cycles, potentially further reducing bone loss. Abitante TJ, Alemi MM, Newman DJ, Duda KR. Metabolic cost of a proposed NMES spaceflight countermeasure compared to walking in active adults . Aerosp Med Hum Perform. 2023; 94(7):523-531.

The spaceflight environment, including microgravity and radiation, may have considerable effects on the health and performance of astronauts, especially for long-duration and Martian missions. Conventional on-ground and in-space experimental approaches have been employed to investigate the comprehensive biological effects of the spaceflight environment. As a class of recently emerging bioengineered in vitro models, tissue chips are characterized by a small footprint, potential automation, and the recapitulation of tissue-level physiology, thus promising to help provide molecular and cellular insights into space medicine. Here, we briefly review the technical advantages of tissue chips and discuss specific on-chip physiological recapitulations. Several tissue chips have been launched into space, and more are poised to come through multi-agency collaborations, implying an increasingly important role of tissue chips in space medicine., Competing Interests: Declaration of Competing Interest YSZ sits on Scientific Advisory Board of 3D Systems and Xellar, which however, did not support or bias this work. The other authors declare no competing interest., (Copyright © 2022. Published by Elsevier B.V.)

INTRODUCTION: For future long-duration spaceflight missions, additional methods of loading the skeleton may be required to supplement exercise to minimize bone loss. Neuromuscular electrical stimulation (NMES) can elicit muscular contractions that create strain on bone. However, the potential effectiveness of NMES on the proximal femur during disuse is not known. METHODS: We measured the maximum isometric force of NMES-induced contractions of the rectus femoris and the hamstrings of 10 subjects (5 male, 5 female), sitting with the hips and knees at 90 degrees of flexion. We employed 2-D biomechanical models of the knee and hip to estimate the hip joint reaction forces, applied these forces to a generic femur finite element analysis model, and qualitatively compared the peak principal strains of the proximal femoral neck to the peak strains modeled in previous studies for other forms of exercise. RESULTS: The average peak tensile/compressive strains were 1380 ± 719 µε/-2179 ± 1130 µε and 573 ± 345 µε/-900 ± 543 µε for the male and female subjects, respectively. While results varied between studies, the strains achieved during NMES generally were comparable to those achieved during walking or stairs, with some individuals matching higher intensity activities. DISCUSSION: This study demonstrated that isometric NMES contractions of the thigh muscles can create strain in the proximal femoral neck similar to that achieved during low impact activities. While NMES alone will unlikely create a sufficient daily strain stimulus to prevent bone loss, it will likely improve the current spaceflight countermeasures by adding more frequent loading throughout the day. Abitante TJ, Bouxsein ML, Duda KR, Newman DJ. Potential of neuromuscular electrical stimulation as a bone loss countermeasure in microgravity. Aerosp Med Hum Perform. 2022; 93(11):774-782.

This review covers the recent history of a series of very important natural products and their derivatives that are currently in use or under evaluation in the areas of anti-infectives, important cancer treatments that include antibody drug conjugates, followed by a discussion of type 2 diabetes (T2DM) drugs and angiotensin converting enzyme inhibitors. The current structures of the agents are shown, though in the case of some peptides used in T2DM drugs the standard single letter abbreviation for an amino acid is used., (© The Author(s) 2022. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd.)

The purpose of this study was to explore the effect an individual's exercise training type will have on muscle fatigability during repetitive contractions induced by Neuromuscular Electrical Stimulation (NMES). Thirty-four subjects comprising of competitive athletes and controls were recruited into three cohorts: Endurance (runners/cyclists) n = 13; nine male, four female; 27 ± 8 years old, Explosive (Lifters/Sprinters) n = 11; nine male, two female; 30 ± 7 years old, and controls n = 10, six male, four female, 26 ± 4 years old. Subjects were placed in a custom-made leg extension rig, and received NMES against a fixed resistance (NMES-FR), to the Vastus Medialis muscle resulting in isometric leg extensions, at a duty cycle of 1 s on/3 s rest, for 20 min. The force of the isometric contractions was recorded using a Hogan MicroFet2 dynamometer, and three separate fatigue metrics were calculated to compare the different cohorts, sports within each cohort, and gender within each cohort. For every fatigue metric, the endurance group fatigued significantly less than both the explosive and control cohorts, with no difference observed between the explosive and the controls. Within each cohort, no significant difference was observed in any fatigue metric between sport or gender, but these comparisons lacked power. The results show that only high capacity endurance activity will have any effect on reducing one's fatigability during repetitive NMES. The implications of this conclusion can aid in the development of NMES regimens for use in healthy populations, such as athletic training or astronaut musculoskeletal countermeasures, as well as clinical applications when fatigue is to be minimized., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Abitante, Rutkove, Duda and Newman.)

Due to the lack of new antibiotics with efficacy against the ESKAPE and other resistant microbes, coupled to the demise of major pharmaceutical company antibiotic discovery programs, due to a number of factors but mainly ROI calculations and the lack of efficacy of combinatorial chemistry as a substitute, the search for novel antibiotics may well have moved to the utilization of older structures with significant synthetic chemistry input. This short review demonstrates how modern synthetic chemistry, when applied to either modification of current resistant antibiotics such as glycopeptides, or production of novel peptidic agents based on natural product sourced antimicrobial peptides (AMPs) and other potential initial peptide-based agents from genomic searches and baiting techniques, have produced active agents of significant utility. In addition, synthetic chemistry practitioners have now shown that they can produce bioactive molecules of greater than 800 Daltons in kilogram quantities under cGMP conditions., Competing Interests: Conflict of interest. There are no COI’s to report. All work was performed by me including the structures from public sources., (Copyright © 2022 by the authors.)

Drug discovery from natural sources is going through a renaissance, having spent many decades in the shadow of synthetic molecule drug discovery, despite the fact that natural product-derived compounds occupy a much greater chemical space than those created through synthetic chemistry methods. With this new era comes new possibilities, not least the novel targets that have emerged in recent times and the development of state-of-the-art technologies that can be applied to drug discovery from natural sources. Although progress has been made with some immunomodulating drugs, there remains a pressing need for new agents that can be used to treat the wide variety of conditions that arise from disruption, or over-activation, of the immune system; natural products may therefore be key in filling this gap. Recognising that, at present, there is no authoritative article that details the current state-of-the-art of the immunomodulatory activity of natural products, this in-depth review has arisen from a joint effort between the International Union of Basic and Clinical Pharmacology (IUPHAR) Natural Products and Immunopharmacology Sections, with contributions from a number of world-leading researchers in the field of natural product drug discovery, to provide a "position statement" on what natural products has to offer in the search for new immunomodulatory argents. To this end, we provide a historical look at previous discoveries of naturally occurring immunomodulators, present a picture of the current status of the field and provide insight into the future opportunities and challenges for the discovery of new drugs to treat immune-related diseases., (Copyright © 2022. Published by Elsevier Ltd.)

Covering: 1981 to 2019Natural products continue to play a major role in drug discovery, with half of new chemical entities based structurally on a natural product. Herein, we report a cheminformatic analysis of the structural and physicochemical properties of natural product-based drugs in comparison to top-selling brand-name synthetic drugs, and a selection of chemical probes recently discovered from diversity-oriented synthesis libraries. In this analysis, natural product-based drugs covered a broad range of chemical space based on size, polarity, and three-dimensional structure. Natural product-based structures were also more prevalent in top-selling drugs of 2018 compared to 2006. Further, the drugs clustered well according to biosynthetic origins, but less so based on therapeutic classes. Macrocycles occupied distinctive and relatively underpopulated regions of chemical space, while chemical probes largely overlapped with synthetic drugs. This analysis highlights the continued opportunities to leverage natural products and their pharmacophores in modern drug discovery.

Marine environments are underexplored terrains containing fungi that produce a diversity of natural products given unique environmental pressures and nutrients. While bacteria are commonly the most studied microorganism for natural products in the marine world, marine fungi are also abundant but remain an untapped source of bioactive metabolites. Given that their terrestrial counterparts have been a source of many blockbuster antitumor agents and anti-infectives, including camptothecin, the penicillins, and cyclosporin A, marine fungi also have the potential to produce new chemical scaffolds as leads to potential drugs. Fungi are more phylogenetically diverse than bacteria and have larger genomes that contain many silent biosynthetic gene clusters involved in making bioactive compounds. However, less than 5% of all known fungi have been cultivated under standard laboratory conditions. While the number of reported natural products from marine fungi is steadily increasing, their number is still significantly lower compared to those reported from their bacterial counterparts. Herein, we discuss many varied cytotoxic and anti-infective fungal metabolites isolated from extreme marine environments, including symbiotic associations as well as extreme pressures, temperatures, salinity, and light. We also discuss cultivation strategies that can be used to produce new bioactive metabolites or increase their production. This review presents a large number of reported structures though, at times, only a few of a large number of related structures are shown.

For a significant number of years, scientists of many persuasions have assayed natural product materials ranging from crude extracts to pure compounds, in a multitude of assays causally related to some biological processes. However, in a very significant number of submitted papers and published articles, what may be considered as canned biological assays were used, and if a positive effect was observed, then the authors would claim that the material assayed was a potential drug lead. This also occurred with pure synthetic compounds and compounds derived from natural products by simple chemical modifications. However, what has now become quite obvious-with all such classes of materials-is that there are many promiscuous players with multiple bioactivities. These can range from relatively crude extracts, pure compounds from natural products, synthetic processes that produce natural product derivatives, and even compounds that are truly synthetic in origin. There is also a potential problem with the data from crude to purified extracts being used to claim some form of beneficial activities for such materials, to sell that particular mixture to the lay public, by very careful descriptions of its possible uses due to legal hurdles. With the advent of artificial intelligence and very large compound databases, some of which may well contain impure materials, scientists from a variety of backgrounds have begun to utilize such listings to obtain compounds for their low to high throughput biological screens, without realizing that there are very significant numbers of active compounds (eg, pan assay interference compounds and invalid metabolic panaceas), that will hit in many different screens for a variety of reasons, thus leading to significant wasted efforts and published scientific articles that have incorrect results. This commentary gives some of the history of such materials but is designed to be used as a warning to both researchers and in particular, journal editors, and reviewers, that reports of biological results that are claimed to be the result of the compounds used, need to be very carefully screened for results due to such promiscuous compounds, irrespective of their nominal source(s). All literature searches were made by the author and the background knowledge has come from more than 55 years of research in industry and governmental laboratories in both the United Kingdom and the United States, for enzyme inhibitors/activators as well as antimicrobial and antitumor lead compounds mainly from natural product sources. The conclusion that I came up with as a result is this: Caveat emptor. ( Curr Ther Res Clin Exp . 2021; 82:XXX-XXX) © 2021 Elsevier HS Journals, Inc., (© 2021 The Author(s).)

Correction for 'Antiviral drug discovery: preparing for the next pandemic' by Catherine S. Adamson et al., Chem. Soc. Rev., 2021, 50, 3647-3655, DOI: .

As of early November 2020, there are 10 approved antibody drug conjugates (ADCs) plus two others that are not usually listed. In addition, there are 70 ADCs at stages from phase I to phase III and 23 that are at the preclinical stage. The warheads of all of these drugs and drug candidates have their origins in natural product structures. The sources and modifications are discussed in general and then specifically commented on in each case with either the generic name if known and/or the ADC's ID names. Interestingly, almost all warheads listed are from microbial sources though initially a number were thought to have been from plants. The latest NCT numbers from Clintrials.gov of all phase I to phase III candidates are also given. Three unusual ADCs are also discussed, two of which (an antitumor agent and one directed against autoimmune diseases) are not usually listed as ADCs, with the third being an anti-infective.

Clinically approved antiviral drugs are currently available for only 10 of the more than 220 viruses known to infect humans. The SARS-CoV-2 outbreak has exposed the critical need for compounds that can be rapidly mobilised for the treatment of re-emerging or emerging viral diseases, while vaccine development is underway. We review the current status of antiviral therapies focusing on RNA viruses, highlighting strategies for antiviral drug discovery and discuss the challenges, solutions and options to accelerate drug discovery efforts.

The reported numbers of Covid-19 cases and deaths were compared for 18 countries (14 in Western Europe, plus Australia, Brazil, Israel and the USA) to assess the effect of historic and current national BCG immunizations. In view of the high death rate for Covid-19 patients over 70 years of age, and given the fact that BCG vaccination is typically given early in life, we compared countries that had introduced BCG in the 1950s with those that had not. No effect on Covid-19 case fatality rate (CFR) or number of deaths per population could be demonstrated. Since some countries test for Covid-19 more than others, the effect of tests performed per million population on reported deaths per million was also assessed, but again did not demonstrate an effect of BCG vaccination in the 1950s. Whether countries had never used the vaccine, had historically used it but since ceased to do so, or were presently vaccinating with BCG did not correlate with national total number of deaths or CFR. We conclude that there is currently no evidence for a beneficial effect of BCG vaccination on Covid-19 reported cases or fatalities., (© 2020 The Society for Applied Microbiology.)