In this review, we discuss the pathogenesis of some socially significant diseases associated with the development of oxidative stress, such as atherosclerosis, diabetes, and radiation sickness, as ...well as the possibilities of the therapeutic application of low-molecular-weight natural and synthetic antioxidants for the correction of free radical-induced pathologies. The main focus of this review is the role of two phylogenetically close families of hydroperoxide-reducing antioxidant enzymes peroxiredoxins and glutathione peroxidases – in counteracting oxidative stress. We also present examples of the application of exogenous recombinant antioxidant enzymes as therapeutic agents in the treatment of pathologies associated with free-radical processes and discuss the prospects of the therapeutic use of exogenous antioxidant enzymes, as well as the ways to improve their therapeutic properties.
Background
Illicitly manufactured fentanyl and its analogues are appearing in countries throughout the world, often disguised as heroin or counterfeit prescription pills, with resulting high overdose ...mortality. Possible explanations for this phenomenon include reduced costs and risks to heroin suppliers, heroin shortages, user preferences for a strong, fast‐acting opioid and the emergence of Dark Web cryptomarkets. This paper addresses these potential causes and asks three questions: (1) can users identify fentanyl; (2) do users desire fentanyl; and (3) if users want fentanyl, can they express this demand in a way that influences the supply?
Argument/analysis
Existing evidence, while limited, suggests that some users can identify fentanyl, although not reliably, and some desire it, but because fentanyl is frequently marketed deceptively as other drugs, users lack information and choice to express demand effectively. Even when aware of fentanyl's presence, drug users may lack fentanyl‐free alternatives. Cryptomarkets, while difficult to quantify, appear to offer buyers greater information and competition than offline markets. However, access barriers and patterns of fentanyl‐related health consequences make cryptomarkets unlikely sources of user influence on the fentanyl supply. Market condition data indicate heroin supply shocks and shortages prior to the introduction of fentanyl in the United States and parts of Europe, but the much lower production cost of fentanyl compared with heroin may be a more significant factor
Conclusion
Current evidence points to a supply‐led addition of fentanyl to the drug market in response to heroin supply shocks and shortages, changing prescription opioid availability and/or reduced costs and risks to suppliers. Current drug users in affected regions of the United States, Canada and Europe appear largely to lack both concrete knowledge of fentanyl's presence in the drugs they buy and access to fentanyl‐free alternatives.
Opioid and methamphetamine co-use is increasing across the USA with overdoses involving these drugs also rising. West Virginia (WV) has led the US in opioid overdose death rates since at least 2013 ...and rising co-use of methamphetamine with opioids has played a greater role in deaths over the last 5 years.
This study used rapid ethnography to examine methods and motivations behind opioids and methamphetamine co-use from the viewpoint of their consumers. Participants (n = 30) were people who injected heroin/fentanyl also using methamphetamine who participated in semi-structured interviews.
We found multiple methods of co-using opioids and methamphetamine, whether alternately or simultaneously and in varying order. Most prioritized opioids, with motives for using methamphetamine forming three thematic categories: 'intrinsic use', encompassing both inherent pleasure of combined use greater than using both drugs separately or for self-medication of particular conditions; 'opioid assisting use' in which methamphetamine helped people manage their existing heroin/fentanyl use; and 'reluctant or indifferent use' for social participation, reflecting methamphetamine's low cost and easy availability.
Methamphetamine serves multiple functions among people using opioids in WV. Beliefs persist that methamphetamine can play a role in preventing and reversing opioid overdose, including some arguments for sequential use being protective of overdose. 'Reluctant' uptake attests to methamphetamine's social use and the influence of supply. The impact on overdose risk of the many varied co-use patterns needs further investigation.
Peroxiredoxin 6 (Prdx6) is a multifunctional eukaryotic antioxidant enzyme. Mammalian Prdx6 possesses peroxidase activity against a wide range of organic and inorganic hydroperoxides, as well as ...exhibits phospholipase A2 (aiPLA2) activity, which plays an important role in the reduction of oxidized phospholipids and cell membrane remodeling. Exogenous Prdx6 has recently been shown to be able to penetrate inside the cell. We hypothesized that this entry may be due to the phospholipase activity of Prdx6. Experiments using exogenous Prdx6 in three cell lines (3T3, A549, RAW 264.7) demonstrated that it is the phospholipase activity that promotes its penetration into the cell. Overoxidation of Prdx6 led to a suppression of the peroxidase activity and a 3-to-4-fold growth of aiPLA2, which enhanced the efficiency of its transmembrane transport into the cells by up to 15 times. A mutant form of Prdx6-S32A with an inactivated phospholipase center turned out to be unable to enter the cells in both the reduced and oxidized state of the peroxidase active center. Previously, we have shown that exogenous Prdx6 has a significant radioprotective action. However, the role of phospholipase activity in the radioprotective effects of Prdx6 remained unstudied. Trials with the mutant Prdx6-S32A form, with the use of a total irradiation model in mice, showed a nearly 50% reduction of the radioprotective effect upon aiPLA2 loss. Such a significant decrease in the radioprotective action may be due to the inability of Prdx6-S32A to penetrate animal cells, which prevents its reduction by the natural intracellular reducing agent glutathione S-transferase (πGST) and lowers the efficiency of elimination of peroxides formed from the effect of ionizing radiation. Thus, phospholipase activity may play an important role in the reduction of oxidized Prdx6 and manifestation of its antioxidant properties.
Internationally, overdose is the primary cause of death among people injecting drugs. However, since 2001, heroin-related overdose deaths in the United States (US) have risen sixfold, paralleled by a ...rise in the death rate attributed to synthetic opioids, particularly the fentanyls. This paper considers the adaptations some US heroin injectors are making to protect themselves from these risks.
Between 2015 and 2016, a team of ethnographers collected data through semi-structured interviews and observation captured in field notes and video recording of heroin preparation/consumption. Ninety-one current heroin injectors were interviewed (Baltimore, n = 22; Chicago, n = 24; Massachusetts and New Hampshire, n = 36; San Francisco, n = 9). Experience injecting heroin ranged from < 1-47 years. Eight participants, who were exclusively heroin snorters, were also interviewed. Data were analyzed thematically.
Across the study sites, multiple methods of sampling "heroin" were identified, sometimes used in combination, ranging from non-injecting routes (snorting, smoking or tasting a small amount prior to injection) to injecting a partial dose and waiting. Partial injection took different forms: a "slow shot" where the user injected a portion of the solution in the syringe, keeping the needle in the injection site, and continuing or withdrawing the syringe or a "tester shot" where the solution was divided into separate injections. Other techniques included getting feedback from others using heroin of the same batch or observing those with higher tolerance injecting heroin from the same batch before judging how much to inject themselves. Although a minority of those interviewed described using these drug sampling techniques, there is clearly receptivity among some users to protecting themselves by using a variety of methods.
The use of drug sampling as a means of preventing an overdose from injection drug use reduces the quantity absorbed at any one time allowing users to monitor drug strength and titrate their dose accordingly. Given the highly unpredictable potency of the drugs currently being sold as heroin in the US, universal precautions should be adopted more widely. Further research is needed into facilitators and barriers to the uptake of these drug sampling methods.
The review presents current concepts of the molecular mechanisms of oxidative stress development and describes main stages of the free-radical reactions in oxidative stress. Endogenous and exogenous ...factors of the oxidative stress development, including dysfunction of cell oxidoreductase systems, as well as the effects of various external physicochemical factors, are discussed. The review also describes the main components of the antioxidant defense system and stages of its evolution, with a special focus on peroxiredoxins, glutathione peroxidases, and glutathione S-transferases, which share some phylogenetic, structural, and catalytic properties. The substrate specificity, as well as the similarities and differences in the catalytic mechanisms of these enzymes, are discussed in detail. The role of peroxiredoxins, glutathione peroxidases, and glutathione S-transferases in the regulation of hydroperoxide-mediated intracellular and intercellular signaling and interactions of these enzymes with receptors and non-receptor proteins are described. An important contribution of hydroperoxide-reducing enzymes to the antioxidant protection and regulation of such cell processes as growth, differentiation, and apoptosis is demonstrated.
Illicitly manufactured fentanyls and stimulants are implicated in the escalating US mortality from drug overdose. San Francisco, California (SF) has seen declining fentanyl injection while smoking ...has increased. Beliefs and behaviors surrounding this development are not well understood.
The study used rapid ethnography to explore fentanyl and methamphetamine use in SF. The team conducted semi-structured interviews (n = 34) with participants recruited from syringe service programs. Video-recorded smoking sequences (n = 12), photography and daily field notes supplemented interview data.
Difficulty injecting and fear of overdose motivated transitions from injecting to smoking. Fentanyl was extremely cheap-$10/gram-with variability in quality. Foil was the most commonly used smoking material but glass bubbles, bongs and dabbing devices were also popular. No reliable visible methods for determining fentanyl quality existed, however, participants could gauge potency upon inhalation, and developed techniques to regulate dosage. Several participants reported at least hourly use, some reporting one or more grams of daily fentanyl consumption. Smoking was also very social, with people sharing equipment, drugs and information. Participants raised concerns about hygiene and overdose risk to others arising from shared equipment. Reportedly potent fentanyl 'residue' accumulated on smoking materials and was commonly shared/traded/stolen or consumed accidentally with diverse preferences for its use.
Our data highlight fentanyl residue as a new overdose risk with potential mismatch between the potency of the residual drug and the recipient's tolerance. Further, large doses of fentanyl are being consumed (estimated at approximately 50 mg of pure fentanyl/day). Smoking fentanyl has potential health benefits over injecting and may be protective against overdose, but substantial uncertainty exists. However, SF overdose mortality hit a record high in 2023. Recommendations to reduce fentanyl smoking overdose risks through pacing, greater awareness of dosages consumed and checking tolerance of residue recipients are potentially viable interventions deserving further exploration.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hydration plays a fundamental role in DNA structure and functioning. However, the hydration shell has been studied only up to the scale of 10-20 water molecules per nucleotide. In the current work, ...hydration shells of DNA were studied in a solution by terahertz time-domain spectroscopy. The THz spectra of three DNA solutions (in water, 40 mm MgCl
and 150 mM KCl) were transformed using an effective medium model to obtain dielectric permittivities of the water phase of solutions. Then, the parameters of two relaxation bands related to bound and free water molecules, as well as to intermolecular oscillations, were calculated. The hydration shells of DNA differ from undisturbed water by the presence of strongly bound water molecules, a higher number of free molecules and an increased number of hydrogen bonds. The presence of 40 mM MgCl
in the solution almost does not alter the hydration shell parameters. At the same time, 150 mM KCl significantly attenuates all the found effects of hydration. Different effects of salts on hydration cannot be explained by the difference in ionic strength of solutions, they should be attributed to the specific action of Mg
and K
ions. The obtained results significantly expand the existing knowledge about DNA hydration and demonstrate a high potential for using the THz time-domain spectroscopy method.
Peroxiredoxin 1 (Prx1) is known to be a multifunctional antioxidant enzyme playing an essential role in protecting the organism against oxidative stress. We hypothesized that administration of ...exogenous recombinant Prx1 may provide additional protection of the mammalian organism during the development of acute oxidative stress induced by ionizing radiation. Hence, the aim of the present work was to study the radioprotective properties of exogenous Prx1.
Recombinant Prx1 was obtained by genetic engineering. The properties of Prx1 were studied using physicochemical methods. An immunoblotting and ELISA were used for the determination of the level of endogenous and exogenous Prx1 in animal blood. The survival rate of irradiated animals was assessed for 30 days with various modes of administration (intraperitoneal, intramuscular, intravenously) Prx1. Using a hematological analyzer and microscopic analysis, the changes in the level of leukocytes and platelets were assessed in animals that received and did not receive an intravenous injection of Prx1 before irradiation. Genoprotective properties of Prx1 were confirmed by micronucleus test. Real-time PCR was used to investigate the effect of Prx1 on the expression of genes involved in response to oxidative stress.
Recombinant Prx1 was shown to significantly reduce oxidative damage to biological macromolecules. Prx1 is an effective radioprotector which decreases the severity of radiation-induced leuko- and thrombocytopenia, plus protects bone marrow cells from damage. The half-life of Prx1 in the bloodstream is more than 1 h, while within 1 h there is a loss of the antioxidant activity of Prx1 by almost 50%, which limits its use long (2 h) before irradiation. The introduction of Prx1 after irradiation has no significant radiomitigating effect. The most effective way of using Prx1 is intravenous administration shortly (15–30 min) before exposure to ionizing radiation, with a dose reduction factor of 1.3. Under the action of ionizing radiation a dose-dependent appearance of endogenous Prx1 in the bloodstream was also observed. The appearance of Prx1 in the bloodstream alters the expression of stress response genes (especial antioxidant response and DNA repair) in the cells of red bone marrow, promoting the activation of repair processes.
The recombinant Prx1 can be considered as an effective radioprotector for minimizing the risks of injury of animal's body by ionizing radiation.
Duchenne muscular dystrophy (DMD) is characterized by a pronounced and progressive degradation of the structure of skeletal muscles, which decreases their strength and lowers endurance of the ...organism. At muscular dystrophy, mitochondria are known to undergo significant functional changes, which is manifested in a decreased efficiency of oxidative phosphorylation and impaired energy metabolism of the cell. It is believed that the DMD-induced functional changes of mitochondria are mainly associated with the dysregulation of Ca2+ homeostasis. This work examines the kinetic parameters of Ca2+ transport and the opening of the Ca2+-dependent MPT pore in the skeletal-muscle mitochondria of the dystrophin-deficient C57BL/10ScSn-mdx mice. As compared to the organelles of wild-type animals, skeletal-muscle mitochondria of mdx mice have been found to be much less efficient in respect to Ca2+ uniport, with the kinetics of Na+-dependent Ca2+ efflux not changing. The data obtained indicate that the decreased rate of Ca2+ uniport in the mitochondria of mdx mice may be associated with the increased level of the dominant negative subunit of Ca2+ uniporter (MCUb). The experiments have also shown that in mdx mice, skeletal-muscle mitochondria have low resistance to the induction of MPT, which may be related to a significantly increased expression of adenylate translocator (ANT2), a possible structural element of the MPT pore. The paper discusses how changes in the expression of calcium uniporter and putative components of the MPT pore caused by the development of DMD can affect Ca2+ homeostasis of skeletal-muscle mitochondria.
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•DMD is accompanied by deterioration of the skeletal muscle structure.•DMD is characterized by a decreased efficiency of oxidative phosphorylation.•MCUb overexpression causes a decrease in the rate of Ca2+ uptake in DMD mitochondria.•ANT2 overexpression lowers resistance of DMD mitochondria to MPT induction.
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