Sodium nitroprusside,a NO donor,modifies Ca2+ transport and mechanical properties in frog skeletal muscle

Recently it has been hypothesized that, in skeletal muscle, NO produced directly by high-frequency stimulation could produce contraction through reactions with thiol groups on the sarcoplasmic reticulum (SR). However, a possible cGMP-mediated relaxing effect, similar to that seen in smooth muscle, has also been demonstrated. We used purified SR preparations and single fibres from frog fast muscles incubated with different concentrations of sodium nitroprusside (SNP) in this study. The results obtained from a long low-frequency stimulation, together with those from a study on Ca2+ transport regulation, showed that the presence of NO precursor induced: an acceleration of the onset of fatigue in single fibres; a decreased vesicular Ca2+ content due to increased Ca2+ release; a shift to open status in SR Ca2+ channels; an increase in SR Ca2+ pump activity. The data presented in this paper seem to indicate that the increased NO in the muscle fibres can influence muscle activity in different ways, perhaps depending on the metabolic status of the muscle and target (filaments, sarcolemma, SR) with which the NO (or its derivatives) acts.     

Age and sex influence on oxidative damage and functional status in human skeletal muscle

A reduction in muscle mass, with consequent decrease in strength and resistance, is commonly observed with advancing age. In this study we measured markers of oxidative damage to DNA, lipids and proteins, some antioxidant enzyme activities as well Ca²⁺ transport in sarcoplasmic reticulum membranes in muscle biopsies from vastus lateralis of young and elderly healthy subjects of both sexes in order to evaluate the presence of age- and sex- related differences. We found a significant increase in oxidation of DNA and lipids in the elderly group, more evident in males, and a reduction in catalase and glutathione transferase activities. The experiments on Ca²⁺ transport showed an abnormal functional response of aged muscle after exposure to caffeine, which increases the opening of Ca²⁺ channels, as well a reduced activity of the Ca²⁺ pump in elderly males. From these results we conclude that oxidative stress play an important role in muscle aging and that oxidative damage is much more evident in elderly males, suggesting a gender difference maybe related to hormonal factors.This revised version was published online in September 2005 with corrections to the Cover Date.     

Effect of Probiotic Supplement on Cytokine Levels in HIV-Infected Individuals: A Preliminary Study

Inflammation persists in patients infected with HIV. Reduction of inflammatory cytokines and microbial translocation might be one way that this could be managed. Purpose: The anti-inflammatory properties of certain probiotic strains prompted us to investigate whether a probiotic could reduce the inflammatory index of HIV-infected patients. Methods: The study involved 30 HIV+ males on antiretroviral therapy, who were given one bottle of fermented milk Yakult Light^® containing Lactobacillus casei Shirota (LcS) twice a day for four weeks. Results: The probiotic LcS was associated with an increase of T lymphocytes and a significant increase of CD56+ cells (p = 0.04). There was also a significant decrease of mRNA levels of TGFβ, IL-10 and IL-12 (p < 0.001) and IL-1β expression (p < 0.001) and an increase of serum IL-23 (p = 0.03). In addition, decreased inflammation and cardiovascular risk were observed, as shown by a reduction of cystatin C (p < 0.001). Conclusions: These data provide preliminary evidence that probiotic supplementation may modulate certain immunological parameters and some of the cytokines that were analyzed. Thus, we propose that LcS may be an inexpensive and practical strategy to support the immune function of HIV+ patients.     

Role of monoclonal antibody drugs in the treatment of COVID-19

Currently clinicians all around the world are experiencing a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The clinical presentation of this pathology includes fever, dry cough, fatigue and acute respiratory distress syndrome that can lead to death infected patients. Current studies on coronavirus disease 2019 (COVID-19) continue to highlight the urgent need for an effective therapy. Numerous therapeutic strategies have been used until now but, to date, there is no specific effective treatment for SARS-CoV-2 infection. Elevated inflammatory cytokines have been reported in patients with COVID-19. Evidence suggests that elevated cytokine levels, reflecting a hyperinflammatory response secondary to SARS-CoV-2 infection, are responsible for multi-organ damage in patients with COVID-19. For these reason, numerous randomized clinical trials are currently underway to explore the effectiveness of biopharmaceutical drugs, such as, interleukin-1 blockers, interleukin-6 inhibitors, Janus kinase inhibitors, in COVID-19. The aim of the present paper is to briefly summarize the pathogenetic rationale and the state of the art of therapeutic strategy blocking hyperinflammation.     

RANTES (CCL5) potentiates calcium ionophore in the production of LTB4 in rat adherent macrophages from granuloma induced by KMnO4: inhibiton by NDGA.

The activation of monocytes/macrophages by several stimuli is an initial event in the inflammatory response. To ascertain the importance of LTB(4) and 5-lypoxigenase in the inflammatory site, we isolated and stimulated rat adherent granuloma macrophages (RAGMs) with calcium ionophore in the presence or absence of regulated on activation, normal T expressed and secreted (RANTES) [CCL5] at different concentrations. We tested the hypothesis that RANTES may influence the production of LTB(4) stimulated by calcium ionophore A23187 (2.5 microM/ml) in rat adherent granuloma macrophages derived from granuloma induced by potassium permanganate diluted 1:40 saturated solution. To test this hypothesis, we measured LTB(4) production, in rat granuloma macrophages stimulated with A23187 (2.5 microM) alone and in combination with RANTES at different concentrations. In these studies, the cell-free supernatant of stimulated RAGMs with the ionophore A23187, resulted in a drastic increase of LTB(4). However, when the cells were treated with the combination RANTES plus A23187 the stimulatory effect was more pronounced than A23187 alone. LTB(4) production was quantitated. The calcium ionophore A23187 directly induced LTB(4) in macrophages, this production was markedly enhanced when the cells were pretreated with RANTES. However, the addition of RANTES in the absence of calcium ionophore A23187 did not directly induce LTB(4) release, nor was lypoxigenase expression augmented. Preincubation of RAGMs with NDGA (nordihydroguiaretic acid) (10(-5)M) completely abolished the production of LTB4 on RAGMSs challenged with A23187 in combination with RANTES or A23187 alone in the supernatants. Similar effects were obtained when the cells were pretreated with dexamethasone. These data suggest, for the first time, that RANTES may stimulate the release of LTB(4), only when it is associated to other stimuli and for this reason we conclude that RANTES modulates inflammatory diseases, and may require other stimuli to be effective in amplifying its spectrum of action(s).     

Effects of topical diclofenac (DHEP plaster) on skin, subcutis and muscle pain thresholds in subjects without spontaneous pain

The aim of this study was to determine whether topical application of diclofenac hydroxyethylpyrrolidine (DHEP) modifies somatic pain sensitivity in subjects without spontaneous pain. Twenty male subjects (aged 19-40 years), who had not reported any pain for at least 1 month, underwent measurement of pain thresholds to bilateral electrical stimulation in the quadriceps muscle and overlying subcutis and skin. Following the double-blind study design, one diclofenac adhesive plaster (13 x 10 cm; 180 mg DHEP) was then applied over one quadriceps while a matched placebo plaster was placed contralaterally. Each subject was given two other plasters (diclofenac and placebo) and instructed to substitute those over the quadriceps after 12 h and to wear them for a further 12 h. Thirty minutes after removal of the second plasters, thresholds. were remeasured in all subjects as on the previous day. Thresholds at the first evaluation were within normal range in nine subjects (group 1) and below normal in muscle (hyperalgesia) in the remaining 11 (group 2). No significant changes were observed in skin or subcutis thresholds after diclofenac or placebo treatment in either group. In contrast, muscle thresholds significantly increased after diclofenac compared with placebo treatment (group 1: p < 0.05; group 2: p < 0.007); the increase was significantly higher in group 2 than in group 1 (p < 0.002). Topical application of diclofenac had a selective hypoalgesic effect on muscles, which was more pronounced in the case of hyperalgesia. These results suggest that the preparation is particularly effective in the treatment of algogenic conditions of deep somatic tissues.     

Influence of L-carnitine administration on maximal physical exercise

Summary The effects of L-carnitine administration on maximal exercise capacity were studied in a double-blind, cross-over trial on ten moderately trained young men. A quantity of 2 g of L-carnitine or a placebo were administered orally in random order to these subjects 1 h before they began exercise on a cycle ergometer. Exercise intensity was increased by 50-W increments every 3 min until they became exhausted. After 72-h recovery, the same exercise regime was repeated but this time the subjects, who had previously received L-carnitine, were now given the placebo and vice versa. The results showed that at the maximal exercise intensity, treatment with L-carnitine significantly increased both maximal oxygen uptake, and power output. Moreover, at similar exercise intensities in the L-carnitine trial oxygen uptake, carbon dioxide production, pulmonary ventilation and plasma lactate were reduced. It is concluded that under these experimental conditions pretreatment with L-carnitine favoured aerobic processes resulting in a more efficient performance. Possible mechanisms producing this effect are discussed.