The importance of sex differences is increasingly acknowledged in the incidence and treatment of disease. Accumulating clinical evidence demonstrates that sex differences are noticeable in COVID-19, and the prevalence, severity, and mortality rate of COVID-19 are higher among males than females. Sex-related genetic and hormonal factors and immunological responses may underlie the sex bias in COVID-19 patients. Angiotensin-converting enzyme 2 ( ACE2 ) and transmembrane protease/serine subfamily member 2 ( TMPRSS2 ) are essential proteins involved in the cell entry of SARS-CoV-2. Since ACE2 is encoded on the X-chromosome, a double copy of ACE2 in females may compensate for virus-mediated downregulation of ACE2 , and thus ACE2 -mediated cellular protection is greater in females. The X chromosome also contains the largest immune-related genes leading females to develop more robust immune responses than males. Toll-like receptor-7 (TLR-7), one of the key players in innate immunity, is linked to sex differences in autoimmunity and vaccine efficacy, and its expression is greater in females. Sex steroids also affect immune cell function. Estrogen contributes to higher CD4 + and CD8 + T cell activation levels, and females have more B cells than males. Sex differences not only affect the severity and progression of the disease, but also alter the efficacy of pharmacological treatment and adverse events related to the drugs/vaccines used against COVID-19. Administration of different drugs/vaccines in different doses or intervals may be useful to eliminate sex differences in efficacy and side/adverse effects. It should be noted that studies should include sex-specific analyses to develop further sex-specific treatments for COVID-19.

It is aimed to investigate the central antinociceptive effect of protocatechuic acid and the involvement of stimulation of opioidergic, serotonin 5-HT, α2-adrenergic and muscarinic receptors in protocatechuic acid-induced central analgesia in mice. Time-dependent antinociceptive effects of protocatechuic acid at the oral doses of 75, 150 and 300 mg/kg were tested in hot-plate (integrated supraspinal response) and tail-immersion (spinal reflex) tests in mice. To investigate the mechanisms of action; the mice administered 300 mg/kg protocatechuic acid (p.o.) were pre-treated with non-specific opioid antagonist naloxone (5 mg/kg, i.p.), serotonin 5-HT receptor antagonist ketanserin (1 mg/kg, i.p.), α2-adrenoceptor antagonist yohimbine (1 mg/kg, i.p.) and non-specific muscarinic antagonist atropine (5 mg/kg, i.p.), respectively. The antinociceptive effect of protocatechuic acid was observed at the doses of 75, 150 and 300 mg/kg in tail-immersion test, at the doses of 150 and 300 mg/kg in hot-plate test at different time interval. The enhancement in the latency of protocatechuic acid-induced response to thermal stimuli was antagonized by yohimbine, naloxone and atropine in tail-immersion test, while it was antagonized only by yohimbine and naloxone pretreatments in hot-plate test. These results indicated that protocatechuic acid has the central antinociceptive action that is probably organized by spinal mediated cholinergic and opiodiergic, also spinal and supraspinal mediated noradrenergic modulation. However, further studies are required to understand how protocatechuic acid organizes the interactions of these modulatory systems. As a whole, these findings reinforce that protocatechuic acid is a potential agent that might be used for pain relief. Additionally, the clarification of the effect and mechanisms of action of protocatechuic acid will contribute to new therapeutic approaches and provide guidance for new drug development studies.

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BACKGRAUND: There is evidence that the adverse effects of metamizole occur due to the effect of the drug on the hematopoietic stem/progenitor cells, and therefore, the disruption of hematopoiesis. Therefore, our study aimed to evaluate the effects of metamizole on hematopoietic stem/progenitor cells using cell culture techniques. MATERIAL AND METHODS: In our study, samples were taken from stem cell products of healthy allogeneic stem cell transplant donors. The colony-forming unit (CFU) assay was used for the cells obtained from these samples. In addition, the drug effects on cell proliferation were evaluated with the MTT. Furthermore, the cell colonies were labelled with immunofl uorescent antibodies and the effects of metamizole on cell types formed in culture were evaluated. RESULTS: We determined that metamizole negatively affects the proliferation of cells, especially starting from 10 μM. As a result of the evaluation of colonization, we saw that the number of colonies decreased with increasing concentrations. Granulocyte-macrophage colonies were more affected at increasing concentrations than other colonies. As a result of the evaluations of our in vitro study, it was also shown as an important fi nding that the individual effects of the drug were highly variable. CONCLUSION: CFU method can be used as a suitable method to investigate the effects of drugs and toxic substances on hematopoiesis. We also think it may be suitable for pre-analysing hematopoietic side effects in new drug research. In addition, using stem cell samples in studies may contribute more easily to the in vitro simulation of hematopoietic differentiations (Fig. 7, Ref. 29).

Patern tanıma reseptörleri içinde en iyi tanımlanmış olan Toll-benzeri reseptörler, santral sinir sisteminde "makrofaj benzeri" fonksiyona sahip mikroglia hücrelerinde bulunurlar. Amiloid-beta (Aβ) proteini ve agrege α-sinüklein gibi hasarla ilişkili moleküler motifleri tanıyan Toll-benzeri reseptörler, mikroglia hücrelerinin proinflamatuar fenotipe kaymasına neden olarak ve tümör nekroz faktör-alfa (TNF-α), interlökin (IL)-1, IL-6, IL-12 gibi proinflamatuar mediyatörler aracılığıyla inflamasyonu tetikler. Nörodejeneratif hastalıklarda mikroglial Toll-benzeri reseptör aracılı sinyalizasyonun önemli bir role sahip olduğu gösterildiği için Alzheimer ve Parkinson hastalıklarında (i) aşılar, (ii) küçük moleküllü inhibitörler, (iii) var olan ilaçların yeni bir endikasyon için kullanılması ve (iv) doğal bileşikler gibi Toll-benzeri reseptörleri hedef alan yeni tedavi yaklaşımları bulunmaktadır. Preklinik çalışmalarda başarılı sonuçlar göstermiş olan ilaç adaylarının birçoğu klinik fazlarda aynı başarıyı yakalayamamıştır. Buna rağmen, Toll-benzeri reseptörler ve sinyal yolakları üzerinde etkili moleküllerle ilgili çalışmaların sayısı artmaya devam etmektedir.