Biological aging involves an interplay of conserved and targetable molecular mechanisms, summarized as the hallmarks of aging. Metformin, a biguanide that combats age-related disorders and improves ...health span, is the first drug to be tested for its age-targeting effects in the large clinical trial—TAME (targeting aging by metformin). This review focuses on metformin’s mechanisms in attenuating hallmarks of aging and their interconnectivity, by improving nutrient sensing, enhancing autophagy and intercellular communication, protecting against macromolecular damage, delaying stem cell aging, modulating mitochondrial function, regulating transcription, and lowering telomere attrition and senescence. These characteristics make metformin an attractive gerotherapeutic to translate to human trials.
Metformin is the first drug to be tested for its age-targeting effects in a large clinical trial. In this perspective, Kulkarni et al. review how metformin acts on its primary and secondary targets to attenuate the hallmarks of aging, highlighting its utility as an effective gerotherapeutic intervention.
•There is an emerging need for new therapies for rare diseases in a shorter time frame.•Drug repurposing could arise from serendipitous observations or exploiting side effects.•Today, researchers ...have addressed drug repurposing in a systematic manner but there are challenges to be overcome for successful repurposing in the future.
Traditional drug discovery and development involves several stages for the discovery of a new drug and to obtain marketing approval. It is necessary to discover new strategies for reducing the drug discovery time frame. Today, drug repurposing has gained importance in identifying new therapeutic uses for already-available drugs. Typically, repurposing can be achieved serendipitously (unintentional fortunate observations) or through systematic approaches. Numerous strategies to discover new indications for FDA-approved drugs are discussed in this article. Drug repurposing has therefore become a productive approach for drug discovery because it provides a novel way to explore old drugs for new use but encounters several challenges. Some examples of different approaches are reviewed here.
We report the first plausible optical electromagnetic counterpart to a (candidate) binary black hole merger. Detected by the Zwicky Transient Facility, the electromagnetic flare is consistent with ...expectations for a kicked binary black hole merger in the accretion disk of an active galactic nucleus B. McKernan, K. E. S. Ford, I. Bartoset al., Astrophys. J. Lett.884, L50 (2019) and is unlikely <O(0.01%)) due to intrinsic variability of this source. The lack of color evolution implies that it is not a supernova and instead is strongly suggestive of a constant temperature shock. Other false-positive events, such as microlensing ora tidal disruption event, are ruled out or constrained to be <O(0.1%). If the flare is associated withS190521g, we find plausible values of total mass M(BBH) ∼ 100 Mꙩ, kick velocity v(k) ∼ 200 km/s at θ ∼ 60° in a disk with aspect ratio H/a ∼ 0.01(i.e., disk height H at radius a) and gas density ρ ∼ 10^(−10)g/cu.cm. The merger could have occurred at a disk migration trap (a ∼ 700 r(g); r(g) ≡ GM(SMBH)/sq.c, where M(SMBH) is the mass of the active galactic nucleus supermassive black hole). The combination of parameters implies a significant spin for at least one of the black holes in S190521g. The timing of our spectroscopy prevents useful constraints on broad-line asymmetry due to an off-center flare. We predict a repeat flare in this source due to a reencountering with the disk in ∼ 1.6 yr(M(SMBH)/10^(8) Mꙩ)(a/10^(3)r(g))^(3/2).
GW170817 was the first gravitational-wave detection of a binary neutron-star merger. It was accompanied by radiation across the electromagnetic spectrum and localized to the galaxy NGC 4993 at a ...distance of 40 megaparsecs. It has been proposed that the observed γ-ray, X-ray and radio emission is due to an ultra-relativistic jet being launched during the merger (and successfully breaking out of the surrounding material), directed away from our line of sight (off-axis). The presence of such a jet is predicted from models that posit neutron-star mergers as the drivers of short hard-γ-ray bursts. Here we report that the radio light curve of GW170817 has no direct signature of the afterglow of an off-axis jet. Although we cannot completely rule out the existence of a jet directed away from the line of sight, the observed γ-ray emission could not have originated from such a jet. Instead, the radio data require the existence of a mildly relativistic wide-angle outflow moving towards us. This outflow could be the high-velocity tail of the neutron-rich material that was ejected dynamically during the merger, or a cocoon of material that breaks out when a jet launched during the merger transfers its energy to the dynamical ejecta. Because the cocoon model explains the radio light curve of GW170817, as well as the γ-ray and X-ray emission (and possibly also the ultraviolet and optical emission), it is the model that is most consistent with the observational data. Cocoons may be a ubiquitous phenomenon produced in neutron-star mergers, giving rise to a hitherto unidentified population of radio, ultraviolet, X-ray and γ-ray transients in the local Universe.
Since their discovery in 2007
, much effort has been devoted to uncovering the sources of the extragalactic, millisecond-duration fast radio bursts (FRBs)
. A class of neutron stars known as ...magnetars is a leading candidate source of FRBs
. Magnetars have surface magnetic fields in excess of 10
gauss, the decay of which powers a range of high-energy phenomena
. Here we report observations of a millisecond-duration radio burst from the Galactic magnetar SGR 1935+2154, with a fluence of 1.5 ± 0.3 megajansky milliseconds. This event, FRB 200428 (ST 200428A), was detected on 28 April 2020 by the STARE2 radio array
in the 1,281-1,468 megahertz band. The isotropic-equivalent energy released in FRB 200428 is 4 × 10
times greater than that of any radio pulse from the Crab pulsar-previously the source of the brightest Galactic radio bursts observed on similar timescales
. FRB 200428 is just 30 times less energetic than the weakest extragalactic FRB observed so far
, and is drawn from the same population as the observed FRB sample. The coincidence of FRB 200428 with an X-ray burst
favours emission models that describe synchrotron masers or electromagnetic pulses powered by magnetar bursts and giant flares
. The discovery of FRB 200428 implies that active magnetars such as SGR 1935+2154 can produce FRBs at extragalactic distances.
Bacterial glycoproteins and oligosaccharides contain several rare deoxy amino l-sugars which are virtually absent in the human cells. This structural difference between the bacterial and host cell ...surface glycans can be exploited for the development of carbohydrate based vaccines and target specific drugs. However, the unusual deoxy amino l-sugars present in the bacterial glycoconjugates are not available from natural sources. Thus, procurement of orthogonally protected rare l-sugar building blocks through efficient chemical synthesis is a crucial step toward the synthesis of structurally well-defined and homogeneous complex glycans. Herein, we report a general and expedient methodology to access a variety of unusual deoxy amino l-sugars starting from readily available l-rhamnose and l-fucose via highly regioselective, one-pot double serial and double parallel displacements of the corresponding 2,4-bistriflates using azide and nitrite anions as nucleophiles. Alternatively, regioselective monotriflation at O2, O3, and O4 of l-rhamnose/l-fucose allowed selective inversions at respective positions leading to diverse rare sugars. The orthogonally protected deoxy amino l-sugar building blocks could be stereoselectively assembled to obtain biologically relevant bacterial O-glycans, as exemplified by the first total synthesis of the amino linker-attached, conjugation-ready tetrasaccharide of O-PS of Yersinia enterocolitica O:50 strain 3229 and the trisaccharide of Pseudomonas chlororaphis subsp. aureofaciens strain M71.
Intense, millisecond-duration bursts of radio waves (named fast radio bursts) have been detected from beyond the Milky Way
. Their dispersion measures-which are greater than would be expected if they ...had propagated only through the interstellar medium of the Milky Way-indicate extragalactic origins and imply contributions from the intergalactic medium and perhaps from other galaxies
. Although several theories exist regarding the sources of these fast radio bursts, their intensities, durations and temporal structures suggest coherent emission from highly magnetized plasma
. Two of these bursts have been observed to repeat
, and one repeater (FRB 121102) has been localized to the largest star-forming region of a dwarf galaxy at a cosmological redshift of 0.19 (refs.
). However, the host galaxies and distances of the hitherto non-repeating fast radio bursts are yet to be identified. Unlike repeating sources, these events must be observed with an interferometer that has sufficient spatial resolution for arcsecond localization at the time of discovery. Here we report the localization of a fast radio burst (FRB 190523) to a few-arcsecond region containing a single massive galaxy at a redshift of 0.66. This galaxy is different from the host of FRB 121102, as it is a thousand times more massive, with a specific star-formation rate (the star-formation rate divided by the mass) a hundred times smaller.
Withania somnifera: An Indian ginseng Kulkarni, S.K.; Dhir, Ashish
Progress in neuro-psychopharmacology & biological psychiatry,
07/2008, Letnik:
32, Številka:
5
Journal Article
Recenzirano
Withania somnifera, popularly known as Ashwagandha is widely considered as the Indian ginseng. In Ayurveda, it is classified as a rasayana (rejuvenation) and expected to promote physical and mental ...health, rejuvenate the body in debilitated conditions and increase longevity. Having wide range of activity, it is used to treat almost all disorders that affect the human health. The present review discusses the pharmacological basis of the use of
W. somnifera in various central nervous system (CNS) disorders, particularly its indication in epilepsy, stress and neurodegenerative diseases such as Parkinson's and Alzheimer's disorders, tardive dyskinesia, cerebral ischemia, and even in the management of drug addiction.
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