178 research outputs found
COVID-19 therapy: from myths to reality and hopes
The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, is unprecedented for the 21st century and has already affected countries with a total population of billions of people. The number of infected has already surpassed 30 million people and the number of deaths has exceeded 1 million. Unfor-tunately, Russia is still one of the five countries with the largest number of infected people, although mortality from COVID-19 is significantly lower than in many other countries. Since the virus and the pathogenesis caused by it have a lot of new and unexpected features, high-tech and specific anti-viral drugs and vaccines have not yet been created. The most promising targets for future drug development are enzymes necessary for the life cycle of this particular virus (such as components of the replicase complex or viral proteases). Unexpected circumstances are pushing the evaluation of a number of previously developed and existing drugs directed toward other RNA viruses, some of which have already been shown effective in clinical trials against SARS-CoV-2. There is no doubt that soon prototypes of drugs of this class with higher specificity and effective-ness will be found. Another group of potential drugs are known drugs that are directed against various aspects of the pathogenesis caused by SARS-CoV-2, in particular, cytokine storm or coagulopathy. It should be emphasized that the genome of the virus encodes about 10 additional proteins, some of which may be related to unusual aspects of pathogenesis during COVID-19. Basic research should determine which of these proteins can be targets for specific therapy. Finally, the fact that neutralizing antibodies are found in the blood plasma of many patients and can be used for the prevention and treatment of COVID-19, indicates the potential of using recombinant neutralizing antibodies as drugs, and secondly, confirms the possibility of creating effective vaccines. This mini-review discusses therapeutic approaches and the status of clinical trials using drugs that already existed before the pandemic and were originally developed against other infectious agents or for the treatment of autoimmune pathologies. These drugs are part of today's arsenal in therapeutic protocols and are used in an attempt to cope with the COVID-19 epidemic in different countries
Macrophages from naked mole-rat possess distinct immunometabolic signatures upon polarization
The naked mole-rat (NMR) is a unique long-lived rodent which is highly resistant to age-associated disorders and cancer. The immune system of NMR possesses a distinct cellular composition with the prevalence of myeloid cells. Thus, the detailed phenotypical and functional assessment of NMR myeloid cell compartment may uncover novel mechanisms of immunoregulation and healthy aging. In this study gene expression signatures, reactive nitrogen species and cytokine production, as well as metabolic activity of classically (M1) and alternatively (M2) activated NMR bone marrow-derived macrophages (BMDM) were examined. Polarization of NMR macrophages under pro-inflammatory conditions led to expected M1 phenotype characterized by increased pro-inflammatory gene expression, cytokine production and aerobic glycolysis, but paralleled by reduced production of nitric oxide (NO). Under systemic LPS-induced inflammatory conditions NO production also was not detected in NMR blood monocytes. Altogether, our results indicate that NMR macrophages are capable of transcriptional and metabolic reprogramming under polarizing stimuli, however, NMR M1 possesses species-specific signatures as compared to murine M1, implicating distinct adaptations in NMR immune system
Reproductive effects of the tumor necrosis factor (TNF) deficiency in mice
TNF is a multifunctional cytokine that, at physiological concentrations, maintains the balance between apoptosis and survival of male germ cells and, at higher concentrations, has adverse effects on various stages of the reproductive process. Although ant-cytokine therapies have been used in millions of patients, the consequences of cytokine deficiency for reproductive functions are poorly understood and need attention. In this work, we have studied behavioral interactions between males and females, spermatogenesis, male fertility, and embryonic developmental characteristics of the progeny in TNFΞ± knockout mice (TNF-/-). We have demonstrated that TNF is involved in the regulation of sexual behavior, spermatogenesis, pre- and postimplantation development. Complete TNF deficiency led to decreased reproductive efficiency: a lower number of viable embryos were observed in TNF-/- mice than in wild-type mice. The decrease in fertility was caused by preimplantation embryo loss in TNF-/- mice. Preimplantation loss in females might be caused by asospermia in TNF-/- males. Additionally, the sensitivity of reproductive functions to female stimuli was different between TNF-/- mice and wild-type mice, while interactions with females increased the concentrations of sperΒmatozoids in both TNF-/- and wild-type mice. Still higher levels were observed in knockout animals, which led to increase in the number of immature spermatozoids in epididymides
Novel Biodegradable Polymeric Microparticles Facilitate Scarless Wound Healing by Promoting Re-epithelialization and Inhibiting Fibrosis
Despite decades of research, the goal of achieving scarless wound healing remains elusive. One of the approaches, treatment with polymeric microcarriers, was shown to promote tissue regeneration in various in vitro models of wound healing. The in vivo effects of such an approach are attributed to transferred cells with polymeric microparticles functioning merely as inert scaffolds. We aimed to establish a bioactive biopolymer carrier that would promote would healing and inhibit scar formation in the murine model of deep skin wounds. Here we characterize two candidate types of microparticles based on fibroin/gelatin or spidroin and show that both types increase re-epithelialization rate and inhibit scar formation during skin wound healing. Interestingly, the effects of these microparticles on inflammatory gene expression and cytokine production by macrophages, fibroblasts, and keratinocytes are distinct. Both types of microparticles, as well as their soluble derivatives, fibroin and spidroin, significantly reduced the expression of profibrotic factors Fgf2 and Ctgf in mouse embryonic fibroblasts. However, only fibroin/gelatin microparticles induced transient inflammatory gene expression and cytokine production leading to an influx of inflammatory Ly6C+ myeloid cells to the injection site. The ability of microparticle carriers of equal proregenerative potential to induce inflammatory response may allow their subsequent adaptation to treatment of wounds with different bioburden and fibrotic content
Π¦ΠΈΡΠΎΠΊΠΈΠ½Ρ, ΠΎΠ±ΡΠ°ΡΠ½Π°Ρ Π³Π΅Π½Π΅ΡΠΈΠΊΠ° ΠΈ Π°Π½ΡΠΈΡΠΈΡΠΎΠΊΠΈΠ½ΠΎΠ²Π°Ρ ΡΠ΅ΡΠ°ΠΏΠΈΡ
Cytokines comprise the molecular language of communication between the cells, which is needed to maintain the homeostatic functions of the body (including the immune system) and mediate various diseases. Many aspects of inflammation, autoimmune diseases and neoplasia are associated with cytokine signaling through specific receptors. The establishment of new physiological functions of βoldβ cytokines and understanding the molecular and cellular mechanisms of their involvement in disease pathogenesis, as well as the search for new therapeutic targets and development of innovative approaches to anti-cytokine therapy, present a fundamental problem. When assessing the tremendous success of anti-cytokine therapy in treatment of certain autoimmune diseases, we should not forget that (a) this treatment does not eliminate the causes of the disease:autoreactive T-cell clones; and that (b) less than half of the patients respond to this therapy; and that (c) anti-cytokine therapy has serious side effects.Π¦ΠΈΡΠΎΠΊΠΈΠ½Ρ β ΠΌΠΎΠ»Π΅ΠΊΡΠ»ΡΡΠ½ΡΠΉ ΡΠ·ΡΠΊ ΠΊΠΎΠΌΠΌΡΠ½ΠΈΠΊΠ°ΡΠΈΠΉ ΠΌΠ΅ΠΆΠ΄Ρ ΠΊΠ»Π΅ΡΠΊΠ°ΠΌΠΈ, ΠΈΡΠΏΠΎΠ»ΡΠ·ΡΠ΅ΠΌΡΠΉ ΠΊΠ°ΠΊ Π΄Π»Ρ ΠΏΠΎΠ΄Π΄Π΅ΡΠΆΠ°Π½ΠΈΡ Π³ΠΎΠΌΠ΅ΠΎΡΡΠ°Π·Π° ΠΎΡΠ³Π°Π½ΠΈΠ·ΠΌΠ° (Π² ΡΠΎΠΌ ΡΠΈΡΠ»Π΅ ΠΈΠΌΠΌΡΠ½Π½ΠΎΠΉ ΡΠΈΡΡΠ΅ΠΌΡ), ΡΠ°ΠΊ ΠΈ ΠΏΡΠΈ ΡΠ°Π·Π»ΠΈΡΠ½ΡΡ
Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΡΡ
. ΠΠ½ΠΎΠ³ΠΈΠ΅ Π°ΡΠΏΠ΅ΠΊΡΡ Π²ΠΎΡΠΏΠ°Π»Π΅Π½ΠΈΡ, Π°ΡΡΠΎΠΈΠΌΠΌΡΠ½Π½ΡΡ
Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ ΠΈ Π½Π΅ΠΎΠΏΠ»Π°Π·ΠΈΠΉ ΡΠ²ΡΠ·Π°Π½Ρ Ρ Π΄Π΅ΠΉΡΡΠ²ΠΈΠ΅ΠΌ ΡΠΈΡΠΎΠΊΠΈΠ½ΠΎΠ² ΡΠ΅ΡΠ΅Π· ΡΠΏΠ΅ΡΠΈΡΠΈΡΠ΅ΡΠΊΠΈΠ΅ ΡΠ΅ΡΠ΅ΠΏΡΠΎΡΡ. Π€ΡΠ½Π΄Π°ΠΌΠ΅Π½ΡΠ°Π»ΡΠ½ΡΡ Π½Π°ΡΡΠ½ΡΡ ΠΏΡΠΎΠ±Π»Π΅ΠΌΡ ΠΏΡΠ΅Π΄ΡΡΠ°Π²Π»ΡΡΡ ΡΡΡΠ°Π½ΠΎΠ²Π»Π΅Π½ΠΈΠ΅ Π½ΠΎΠ²ΡΡ
ΡΠΈΠ·ΠΈΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΈΡ
ΡΡΠ½ΠΊΡΠΈΠΉ Β«ΡΡΠ°ΡΡΡ
Β» ΡΠΈΡΠΎΠΊΠΈΠ½ΠΎΠ², ΠΏΠΎΠ½ΠΈΠΌΠ°Π½ΠΈΠ΅ ΠΌΠΎΠ»Π΅ΠΊΡΠ»ΡΡΠ½ΡΡ
ΠΈ ΠΊΠ»Π΅ΡΠΎΡΠ½ΡΡ
ΠΌΠ΅Ρ
Π°Π½ΠΈΠ·ΠΌΠΎΠ² ΠΈΡ
ΡΠ°Π±ΠΎΡΡ Π² Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΡΡ
, ΠΏΠΎΠΈΡΠΊ Π½ΠΎΠ²ΡΡ
ΡΠ΅ΡΠ°ΠΏΠ΅Π²ΡΠΈΡΠ΅ΡΠΊΠΈΡ
ΠΌΠΈΡΠ΅Π½Π΅ΠΉ ΠΈ ΡΠ°Π·ΡΠ°Π±ΠΎΡΠΊΠ° ΠΈΠ½Π½ΠΎΠ²Π°ΡΠΈΠΎΠ½Π½ΡΡ
ΠΏΠΎΠ΄Ρ
ΠΎΠ΄ΠΎΠ² ΠΊ Π°Π½ΡΠΈΡΠΈΡΠΎΠΊΠΈΠ½ΠΎΠ²ΠΎΠΉ ΡΠ΅ΡΠ°ΠΏΠΈΠΈ. ΠΡΠΈ ΠΎΡΠ΅Π½ΠΊΠ΅ Π³ΡΠ°Π½Π΄ΠΈΠΎΠ·Π½ΠΎΠ³ΠΎ ΡΡΠΏΠ΅Ρ
Π° Π°Π½ΡΠΈΡΠΈΡΠΎΠΊΠΈΠ½ΠΎΠ²ΠΎΠΉ ΡΠ΅ΡΠ°ΠΏΠΈΠΈ Π² Π»Π΅ΡΠ΅Π½ΠΈΠΈ Π½Π΅ΠΊΠΎΡΠΎΡΡΡ
Π°ΡΡΠΎΠΈΠΌΠΌΡΠ½Π½ΡΡ
Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ Π½Π΅Π»ΡΠ·Ρ Π·Π°Π±ΡΠ²Π°ΡΡ ΠΎ ΡΠΎΠΌ, ΡΡΠΎ, Π²ΠΎ-ΠΏΠ΅ΡΠ²ΡΡ
, ΡΡΠΎ Π»Π΅ΡΠ΅Π½ΠΈΠ΅ Π½Π΅ ΡΡΡΡΠ°Π½ΡΠ΅Ρ ΠΏΡΠΈΡΠΈΠ½Ρ Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΡ β Π°ΡΡΠΎΡΠ΅Π°ΠΊΡΠΈΠ²Π½ΡΡ
Π’-ΠΊΠ»Π΅ΡΠΎΡΠ½ΡΡ
ΠΊΠ»ΠΎΠ½ΠΎΠ², Π²ΠΎ-Π²ΡΠΎΡΡΡ
, Π½Π° Π½Π΅Π΅ ΠΎΡΠ²Π΅ΡΠ°Π΅Ρ ΠΌΠ΅Π½Π΅Π΅ ΠΏΠΎΠ»ΠΎΠ²ΠΈΠ½Ρ ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ², ΠΈ, Π²-ΡΡΠ΅ΡΡΠΈΡ
, Ρ Π½Π΅Π΅ Π΅ΡΡΡ ΡΠ΅ΡΡΠ΅Π·Π½ΡΠ΅ ΠΏΠΎΠ±ΠΎΡΠ½ΡΠ΅ ΡΡΡΠ΅ΠΊΡΡ
Three allele combinations associated with Multiple Sclerosis
BACKGROUND: Multiple sclerosis (MS) is an immune-mediated disease of polygenic etiology. Dissection of its genetic background is a complex problem, because of the combinatorial possibilities of gene-gene interactions. As genotyping methods improve throughput, approaches that can explore multigene interactions appropriately should lead to improved understanding of MS. METHODS: 286 unrelated patients with definite MS and 362 unrelated healthy controls of Russian descent were genotyped at polymorphic loci (including SNPs, repeat polymorphisms, and an insertion/deletion) of the DRB1, TNF, LT, TGFΞ²1, CCR5 and CTLA4 genes and TNFa and TNFb microsatellites. Each allele carriership in patients and controls was compared by Fisher's exact test, and disease-associated combinations of alleles in the data set were sought using a Bayesian Markov chain Monte Carlo-based method recently developed by our group. RESULTS: We identified two previously unknown MS-associated tri-allelic combinations: -509TGFΞ²1*C, DRB1*18(3), CTLA4*G and -238TNF*B1,-308TNF*A2, CTLA4*G, which perfectly separate MS cases from controls, at least in the present sample. The previously described DRB1*15(2) allele, the microsatellite TNFa9 allele and the biallelic combination CCR5Ξ32, DRB1*04 were also reidentified as MS-associated. CONCLUSION: These results represent an independent validation of MS association with DRB1*15(2) and TNFa9 in Russians and are the first to find the interplay of three loci in conferring susceptibility to MS. They demonstrate the efficacy of our approach for the identification of complex-disease-associated combinations of alleles
Optical and electrostatic potential investigations of electrical breakdown phenomena in a low-pressure gas discharge lamp
- β¦