17ß-estradiol induces hyperresponsiveness in guinea pig airway smooth muscle by inhibiting the plasma membrane Ca2+-ATPase.

High serum estrogen concentrations are associated with asthma development and severity, suggesting a link between estradiol and airway hyperresponsiveness (AHR). 17ß-estradiol (E2) has non-genomic effects via Ca2+ regulatory mechanisms; however, its effect on the plasma membrane Ca2+-ATPases (PMCA1 and 4) and sarcoplasmic reticulum Ca2+-ATPase (SERCA) is unknown. Hence, in the present study, we aim to demonstrate if E2 favors AHR by increasing intracellular Ca2+ concentrations in guinea pig airway smooth muscle (ASM) through a mechanism involving Ca2+-ATPases. In guinea pig ASM, Ca2+ microfluorometry, muscle contraction, and Western blot were evaluated. Then, we performed molecular docking analysis between the estrogens and Ca2+ ATPases. In tracheal rings, E2 produced AHR to carbachol. In guinea pig myocytes, acute exposure to physiological levels of E2 modified the transient Ca2+ peak induced by caffeine to a Ca2+ plateau. The incubation with PMCA inhibitors (lanthanum and carboxyeosin, CE) partially reversed the E2-induced sustained plateau in the caffeine response. In contrast, cyclopiazonic acid (SERCA inhibitor), U-0126 (an inhibitor of ERK 1/2), and choline chloride did not modify the Ca2+ plateau produced by E2. The mitochondrial uniporter activity and the capacitative Ca2+ entry were unaffected by E2. In guinea pig ASM, Western blot analysis demonstrated PMCA1 and PMCA4 expression. The results from the docking modeling demonstrate that E2 binds to both plasma membrane ATPases. In guinea pig tracheal smooth muscle, inhibiting the PMCA with CE, induced hyperresponsiveness to carbachol. 17ß-estradiol produces hyperresponsiveness by inhibiting the PMCA in the ASM and could be one of the mechanisms responsible for the increase in asthmatic crisis in women.

Chamaecyparis lawsoniana and Its Active Compound Quercetin as Ca2+ Inhibitors in the Contraction of Airway Smooth Muscle.

The Cupressaceae family includes species considered to be medicinal. Their essential oil is used for headaches, colds, cough, and bronchitis. Cedar trees like Chamaecyparis lawsoniana (C. lawsoniana) are commonly found in urban areas. We investigated whether C. lawsoniana exerts some of its effects by modifying airway smooth muscle (ASM) contractility. The leaves of C. lawsoniana (363 g) were pulverized mechanically, and extracts were obtained by successive maceration 1:10 (w:w) with methanol/CHCl3. Guinea pig tracheal rings were contracted with KCl, tetraethylammonium (TEA), histamine (HIS), or carbachol (Cch) in organ baths. In the Cch experiments, tissues were pre-incubated with D-600, an antagonist of L-type voltage-dependent Ca2+ channels (L-VDCC) before the addition of C. lawsoniana. Interestingly, at different concentrations, C. lawsoniana diminished the tracheal contractions induced by KCl, TEA, HIS, and Cch. In ASM cells, C. lawsoniana significantly diminished L-type Ca2+ currents. ASM cells stimulated with Cch produced a transient Ca2+ peak followed by a sustained plateau maintained by L-VDCC and store-operated Ca2+ channels (SOCC). C. lawsoniana almost abolished this last response. These results show that C. lawsoniana, and its active metabolite quercetin, relax the ASM by inhibiting the L-VDCC and SOCC; further studies must be performed to obtain the complete set of metabolites of the extract and study at length their pharmacological properties.

Potential of olfactory neuroepithelial cells as a model to study schizophrenia: A focus on GPCRs (Review).

Schizophrenia (SZ) is a multifactorial disorder characterized by volume reduction in gray and white matter, oxidative stress, neuroinflammation, altered neurotransmission, as well as molecular deficiencies such as punctual mutation in Disrupted­in­Schizophrenia 1 protein. In this regard, it is essential to understand the underlying molecular disturbances to determine the pathophysiological mechanisms of the disease. The signaling pathways activated by G protein­coupled receptors (GPCRs) are key molecular signaling pathways altered in SZ. Convenient models need to be designed and validated to study these processes and mechanisms at the cellular level. Cultured olfactory stem cells are used to investigate neural molecular and cellular alterations related to the pathophysiology of SZ. Multipotent human olfactory stem cells are undifferentiated and express GPCRs involved in numerous physiological functions such as proliferation, differentiation and bioenergetics. The use of olfactory stem cells obtained from patients with SZ may identify alterations in GPCR signaling that underlie dysfunctional processes in both undifferentiated and specialized neurons or derived neuroglia. The present review aimed to analyze the role of GPCRs and their signaling in the pathophysiology of SZ. Culture of olfactory epithelial cells constitutes a suitable model to study SZ and other psychiatric disorders at the cellular level.

Hypoxia Induces Alterations in the Circadian Rhythm in Patients with Chronic Respiratory Diseases.

The function of the circadian cycle is to determine the natural 24 h biological rhythm, which includes physiological, metabolic, and hormonal changes that occur daily in the body. This cycle is controlled by an internal biological clock that is present in the body's tissues and helps regulate various processes such as sleeping, eating, and others. Interestingly, animal models have provided enough evidence to assume that the alteration in the circadian system leads to the appearance of numerous diseases. Alterations in breathing patterns in lung diseases can modify oxygenation and the circadian cycles; however, the response mechanisms to hypoxia and their relationship with the clock genes are not fully understood. Hypoxia is a condition in which the lack of adequate oxygenation promotes adaptation mechanisms and is related to several genes that regulate the circadian cycles, the latter because hypoxia alters the production of melatonin and brain physiology. Additionally, the lack of oxygen alters the expression of clock genes, leading to an alteration in the regularity and precision of the circadian cycle. In this sense, hypoxia is a hallmark of a wide variety of lung diseases. In the present work, we intended to review the functional repercussions of hypoxia in the presence of asthma, chronic obstructive sleep apnea, lung cancer, idiopathic pulmonary fibrosis, obstructive sleep apnea, influenza, and COVID-19 and its repercussions on the circadian cycles.

Hypoxic Effects on Matrix Metalloproteinases' Expression in the Tumor Microenvironment and Therapeutic Perspectives.

The tumor microenvironment (TME) is characterized by an acidic pH and low oxygen concentrations. Hypoxia induces neoplastic cell evasion of the immune surveillance, rapid DNA repair, metabolic reprogramming, and metastasis, mainly as a response to the hypoxic inducible factors (HIFs). Likewise, cancer cells increase matrix metalloproteinases' (MMPs) expression in response to TME conditions, allowing them to migrate from the primary tumor to different tissues. Since HIFs and MMPs are augmented in the hypoxic TME, it is easy to consider that HIFs participate directly in their expression regulation. However, not all MMPs have a hypoxia response element (HRE)-HIF binding site. Moreover, different transcription factors and signaling pathways activated in hypoxia conditions through HIFs or in a HIF-independent manner participate in MMPs' transcription. The present review focuses on MMPs' expression in normal and hypoxic conditions, considering HIFs and a HIF-independent transcription control. In addition, since the hypoxic TME causes resistance to anticancer conventional therapy, treatment approaches using MMPs as a target alone, or in combination with other therapies, are also discussed.

Phytoestrogen-Based Hormonal Replacement Therapy Could Benefit Women Suffering Late-Onset Asthma.

It has been observed that plasmatic concentrations of estrogens, progesterone, or both correlate with symptoms in asthmatic women. Fluctuations in female sex steroid concentrations during menstrual periods are closely related to asthma symptoms, while menopause induces severe physiological changes that might require hormonal replacement therapy (HRT), that could influence asthma symptoms in these women. Late-onset asthma (LOA) has been categorized as a specific asthmatic phenotype that includes menopausal women and novel research regarding therapeutic alternatives that might provide relief to asthmatic women suffering LOA warrants more thorough and comprehensive analysis. Therefore, the present review proposes phytoestrogens as a promising HRT that might provide these females with relief for both their menopause and asthma symptoms. Besides their well-recognized anti-inflammatory and antioxidant capacities, phytoestrogens activate estrogen receptors and promote mild hormone-like responses that benefit postmenopausal women, particularly asthmatics, constituting therefore a very attractive potential therapy largely due to their low toxicity and scarce side effects.

Hip and trunk kinematics during reaching on a mobile and stable seat.

Reaching movements are often used to assess selective trunk control in people with neurological conditions. Also, it is known that reaching performance after stroke is increased through training on a mobile seat compared to conventional physical therapy. However, the effect of a mobile seat on joint kinematics has not yet been investigated. This study aimed to quantify differences in the range of motion of the hip and trunk during reaching exercises on a mobile and stable sitting surface. Fifteen healthy participants performed reaching beyond arm's length on a mobile and a stable seat in four different directions: ipsilateral, anterior, contralateral, and contralateral diagonal. Biomechanical data were collected, including kinematics of the hip and trunk, and surface electromyography of the trunk muscles. The mobile sitting surface led to a higher range of motion in the trunk and the hip in the frontal and sagittal plane, but not in the rotational plane. Differences between reaching directions were found in all joint directions, except that of trunk flexion. Hence, movement patterns of the hip and trunk differ during reaching on different sitting surfaces and in different directions. A larger range of motion in the frontal or sagittal plane while training on the mobile seat provides added neuromuscular stimuli to the trunk muscles (= a higher demand on trunk muscles), which could result in more efficient training and therefore, increased trunk control after stroke. However, this has to be investigated in a future study with people after stroke.

Estrogenic Modulation of Ionic Channels, Pumps and Exchangers in Airway Smooth Muscle.

To preserve ionic homeostasis (primarily Ca2+, K+, Na+, and Cl-), in the airway smooth muscle (ASM) numerous transporters (channels, exchangers, and pumps) regulate the influx and efflux of these ions. Many of intracellular processes depend on continuous ionic permeation, including exocytosis, contraction, metabolism, transcription, fecundation, proliferation, and apoptosis. These mechanisms are precisely regulated, for instance, through hormonal activity. The lipophilic nature of steroidal hormones allows their free transit into the cell where, in most cases, they occupy their cognate receptor to generate genomic actions. In the sense, estrogens can stimulate development, proliferation, migration, and survival of target cells, including in lung physiology. Non-genomic actions on the other hand do not imply estrogen's intracellular receptor occupation, nor do they initiate transcription and are mostly immediate to the stimulus. Among estrogen's non genomic responses regulation of calcium homeostasis and contraction and relaxation processes play paramount roles in ASM. On the other hand, disruption of calcium homeostasis has been closely associated with some ASM pathological mechanism. Thus, this paper intends to summarize the effects of estrogen on ionic handling proteins in ASM. The considerable diversity, range and power of estrogens regulates ionic homeostasis through genomic and non-genomic mechanisms.

Theophylline-Induced Relaxation Is Enhanced after Testosterone Treatment via Increased KV1.2 and KV1.5 Protein Expression in Guinea Pig Tracheal Smooth Muscle.

Theophylline is a drug commonly used to treat asthma due to its anti-inflammatory and bronchodilatory properties. Testosterone (TES) has been suggested to reduce the severity of asthma symptoms. This condition affects boys more than girls in childhood, and this ratio reverses at puberty. We reported that guinea pig tracheal tissue chronic exposure to TES increases the expression of ß2-adrenoreceptors and enhances salbutamol-induced K+ currents (IK+). Herein, we investigated whether the upregulation of K+ channels can enhance the relaxation response to methylxanthines, including theophylline. Chronic incubation of guinea pig tracheas with TES (40 nM, 48 h) enhanced the relaxation induced by caffeine, isobutylmethylxanthine, and theophylline, an effect that was abolished by tetraethylammonium. In tracheal myocytes, chronic incubation with TES increased theophylline-induced IK+; flutamide reversed this effect. The increase in IK+ was blocked by 4-aminopyridine by ~82%, whereas iberiotoxin reduced IK+ by ~17%. Immunofluorescence studies showed that chronic TES exposure increased the expression of KV1.2 and KV1.5 in airway smooth muscle (ASM). In conclusion, chronic exposure to TES in guinea pig ASM promotes upregulation of KV1.2 and KV1.5 and enhances theophylline relaxation response. Therefore, gender should be considered when prescribing methylxanthines, as teenage boys and males are likely to respond better than females.

Biomechanical comparison of walking with a new, wearable rehabilitation training device to Nordic walking and regular walking in people with chronic low back pain.

Physical activity, particularly walking, is commonly used for the treatment of diseases such as low back pain. In this study, the effects of walking wearing the new ToneFit Reha training belt (TFR) were compared to both Nordic walking and regular walking. The TFR is intended to intensify the effects of walking through the integration of two adjustable resistance handles. Ten patients with low back pain performed regular walking, Nordic walking, and walking with the TFR in a movement laboratory. The kinematics of the trunk, upper extremities, and lower extremities were measured, and the activity of the trunk and upper extremity muscles recorded. Data were analyzed by repeated-measures ANOVA and paired t-test. Kinematics indicated that walking with the TFR introduces instability that was mitigated by a delayed peak trunk rotation (peak at 63.3% gait cycle, vs. 52.8% in walking (p = .001) and 51.0% in NW (p = .007)). Upper extremity kinematics (constrained elbow flexion, high peak shoulder abduction) showed movement patterns that need to be considered when training over a longer period. Increased muscle activity was observed especially for upper extremity muscles, when training with TFR. Overall, walking with the TFR was found to be a suitable therapy for use in a rehabilitation setting.

The Effect on Muscle Activity of Reaching Beyond Arm's Length on a Mobile Seat: A Pilot Study for Trunk Control Training for People After Stroke.

Objective: This pilot study compared muscle activity during lateral reaching tasks between mobile and stable sitting using a novel therapy chair in people after stroke and healthy controls. Design: Observational pilot study. Setting: This study was conducted in a rehabilitation center for people after stroke and at the university's movement laboratory for healthy participants. Participants: A total of eleven people after stroke and fifteen healthy people (N=26) took part. Interventions: Lateral reaching exercises to the ipsilateral and contralateral sides were performed on a mobile and a stable seat. Main Outcome Measure: Muscular activity of the multifidus, erector spinae and external oblique was measured bilaterally. A within-subject linear mixed model was applied to analyze the effects of seat condition, task, muscle side, and group. Results: A seat condition effect was found for the multifidus and external oblique that was dependent on the muscle side and task. During ipsilateral reaching, the activity of the multifidi decreased for people after stroke on the mobile seat, while increasing for healthy participants. The erector spinae showed no condition effect. Decreased activity of the external oblique was found for both groups on the mobile seat. Conclusions: Mobile sitting influences muscular activity. However, these preliminary results should be further investigated in order to generate recommendations for rehabilitation.

Exosomal Micro-RNAs as Intercellular Communicators in Idiopathic Pulmonary Fibrosis.

Communication between neighboring or distant cells is made through a complex network that includes extracellular vesicles (EVs). Exosomes, which are a subgroup of EVs, are released from most cell types and have been found in biological fluids such as urine, plasma, and airway secretions like bronchoalveolar lavage (BAL), nasal lavage, saliva, and sputum. Mainly, the cargo exosomes are enriched with mRNAs and microRNAs (miRNAs), which can be transferred to a recipient cell consequently modifying and redirecting its biological function. The effects of miRNAs derive from their role as gene expression regulators by repressing or degrading their target mRNAs. Nowadays, various types of research are focused on evaluating the potential of exosomal miRNAs as biomarkers for the prognosis and diagnosis of different pathologies. Nevertheless, there are few reports on their role in the pathophysiology of idiopathic pulmonary fibrosis (IPF), a chronic lung disease characterized by progressive lung scarring with no cure. In this review, we focus on the role and effect of exosomal miRNAs as intercellular communicators in the onset and progression of IPF, as well as discussing their potential utility as therapeutic agents for the treatment of this disease.

Matrix Metalloproteinases and Stress Hormones in Lung Cancer Progression.

Several matrix metalloproteinases (MMPs) and psychological stress are associated with poor cancer prognosis. The current work goal was to determine MMPs' and stress hormones' blood concentrations from lung adenocarcinoma (LAC) patients. Patients were divided into the following groups: tobacco smokers (TS), wood smoke-exposed (W), passive smokers (PS), TS exposed to wood smoke (TW), and patients with no recognizable risk factor (N). MMPs, tissue inhibitors of metalloproteinases (TIMPs), adrenaline, noradrenaline, and cortisol blood concentrations were measured by ELISA. Zymography and Western blot assays were performed to determine MMP-2 and MMP-9 active and latent forms. MMP-2, MMP-3, MMP-9, and TIMP-1 blood concentrations, and MMP-9 gelatinase activity were augmented, while MMP-12, MMP-14, and TIMP-2 were diminished in LAC patients. Cortisol was increased in LAC samples. Adrenaline concentrations were higher in W, TS, and TW, and noradrenaline was increased in W and N groups. Positive correlations were observed among cortisol and TIMP-1 (r s = 0.392) and TIMP-2 (r s = 0.409) in the W group and between noradrenaline and MMP-2 (r s = 0.391) in the N group. MMPs' blood concentration increments can be considered as lung cancer progression markers. Although stress hormones were also augmented, only weak correlations were observed between them and MMPs and TIMPs.

Surface electromyographic activity of trunk muscles during trunk control exercises for people after stroke; effect of a mobile and stable seat for rehabilitation.

The aim of this study was to explore differences in trunk muscle activity on a stable and mobile seat for people after stroke and healthy participants. Trunk control exercises are known to have a beneficial effect on trunk control, balance, and mobility after stroke. The effect of such exercises could be enhanced by the use of a mobile seat to provide further training stimuli. However, little research on the musculoskeletal effects of trunk training on mobile seats has been carried out. On a stable and a mobile seat, thirteen people after stroke and fifteen healthy participants performed two selective trunk control exercises, which were lateral flexion initiated by the pelvis and the thorax. The maximal surface electromyography relative to static sitting of the muscles multifidus, erector spinae, and obliquus externus was recorded bilaterally. The effects of group, seat condition, trunk control exercise, and muscle side were investigated employing within-subject linear-mixed-models. Compared to the stable seat, the maximal muscle activity of people after stroke on the mobile seat was higher during the thorax-initiated exercise and lower during the pelvis-initiated exercise. Healthy participants showed opposite results with higher muscle activity on the mobile seat during the pelvis-initiated exercise. For trunk control training on a mobile seat with high muscle activation people after stroke should perform trunk control exercises initiated by the thorax, for training with lower muscle activity people after stroke should initiate selective trunk movements by the pelvis. The results can support the planning of progressive trunk control rehabilitation programs.

Role of MicroRNAs in Signaling Pathways Associated with the Pathogenesis of Idiopathic Pulmonary Fibrosis: A Focus on Epithelial-Mesenchymal Transition.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease with high mortality and unclear etiology. Previous evidence supports that the origin of this disease is associated with epigenetic alterations, age, and environmental factors. IPF initiates with chronic epithelial lung injuries, followed by basal membrane destruction, which promotes the activation of myofibroblasts and excessive synthesis of extracellular matrix (ECM) proteins, as well as epithelial-mesenchymal transition (EMT). Due to miRNAs' role as regulators of apoptosis, proliferation, differentiation, and cell-cell interaction processes, some studies have involved miRNAs in the biogenesis and progression of IPF. In this context, the analysis and discussion of the probable association of miRNAs with the signaling pathways involved in the development of IPF would improve our knowledge of the associated molecular mechanisms, thereby facilitating its evaluation as a therapeutic target for this severe lung disease. In this work, the most recent publications evaluating the role of miRNAs as regulators or activators of signal pathways associated with the pathogenesis of IPF were analyzed. The search in Pubmed was made using the following terms: "miRNAs and idiopathic pulmonary fibrosis (IPF)"; "miRNAs and IPF and signaling pathways (SP)"; and "miRNAs and IPF and SP and IPF pathogenesis". Additionally, we focus mainly on those works where the signaling pathways involved with EMT, fibroblast differentiation, and synthesis of ECM components were assessed. Finally, the importance and significance of miRNAs as potential therapeutic or diagnostic tools for the treatment of IPF are discussed.

Nanotechnology and Matrix Metalloproteinases in Cancer Diagnosis and Treatment.

Cancer is still one of the leading causes of death worldwide. This great mortality is due to its late diagnosis when the disease is already at advanced stages. Although the efforts made to develop more effective treatments, around 90% of cancer deaths are due to metastasis that confers a systemic character to the disease. Likewise, matrix metalloproteinases (MMPs) are endopeptidases that participate in all the events of the metastatic process. MMPs' augmented concentrations and an increased enzymatic activity have been considered bad prognosis markers of the disease. Therefore, synthetic inhibitors have been created to block MMPs' enzymatic activity. However, they have been ineffective in addition to causing considerable side effects. On the other hand, nanotechnology offers the opportunity to formulate therapeutic agents that can act directly on a target cell, avoiding side effects and improving the diagnosis, follow-up, and treatment of cancer. The goal of the present review is to discuss novel nanotechnological strategies in which MMPs are used with theranostic purposes and as therapeutic targets to control cancer progression.

Theophylline: Old Drug in a New Light, Application in COVID-19 through Computational Studies.

Theophylline (3-methyxanthine) is a historically prominent drug used to treat respiratory diseases, alone or in combination with other drugs. The rapid onset of the COVID-19 pandemic urged the development of effective pharmacological treatments to directly attack the development of new variants of the SARS-CoV-2 virus and possess a therapeutical battery of compounds that could improve the current management of the disease worldwide. In this context, theophylline, through bronchodilatory, immunomodulatory, and potentially antiviral mechanisms, is an interesting proposal as an adjuvant in the treatment of COVID-19 patients. Nevertheless, it is essential to understand how this compound could behave against such a disease, not only at a pharmacodynamic but also at a pharmacokinetic level. In this sense, the quickest approach in drug discovery is through different computational methods, either from network pharmacology or from quantitative systems pharmacology approaches. In the present review, we explore the possibility of using theophylline in the treatment of COVID-19 patients since it seems to be a relevant candidate by aiming at several immunological targets involved in the pathophysiology of the disease. Theophylline down-regulates the inflammatory processes activated by SARS-CoV-2 through various mechanisms, and herein, they are discussed by reviewing computational simulation studies and their different applications and effects.

Could Lower Testosterone in Older Men Explain Higher COVID-19 Morbidity and Mortalities?

The health scourge imposed on humanity by the COVID-19 pandemic seems not to recede. This fact warrants refined and novel ideas analyzing different aspects of the illness. One such aspect is related to the observation that most COVID-19 casualties were older males, a tendency also noticed in the epidemics of SARS-CoV in 2003 and the Middle East respiratory syndrome in 2012. This gender-related difference in the COVID-19 death toll might be directly involved with testosterone (TEST) and its plasmatic concentration in men. TEST has been demonstrated to provide men with anti-inflammatory and immunological advantages. As the plasmatic concentration of this androgen decreases with age, the health benefit it confers also diminishes. Low plasmatic levels of TEST can be determinant in the infection's outcome and might be related to a dysfunctional cell Ca2+ homeostasis. Not only does TEST modulate the activity of diverse proteins that regulate cellular calcium concentrations, but these proteins have also been proven to be necessary for the replication of many viruses. Therefore, we discuss herein how TEST regulates different Ca2+-handling proteins in healthy tissues and propose how low TEST concentrations might facilitate the replication of the SARS-CoV-2 virus through the lack of modulation of the mechanisms that regulate intracellular Ca2+ concentrations.

Stability boots for the treatment of Achilles tendon injuries: Gait analysis of healthy participants.

BACKGROUND: Achilles tendon injuries are commonly treated with stability boots that secure the ankle at a specific position and aim to reduce loading of the tendon. These boots allow full weight bearing by limiting the range of movement. It is, however, unknown, to what extent these boots can reduce tendon loading and if the biomechanics are altered during walking. RESEARCH QUESTION: How do orthopedic boots influence lower extremity biomechanics during walking? METHODS: For this cross-sectional study, ten healthy participants walked with three orthopedic boots (Oped Vacoped, Kuenzli Ortho Rehab Absolut, Orthotech Variostabil) commonly used to treat Achilles tendon injuries. Kinematics and kinetics of the lower extremity of the booted leg and spatiotemporal parameters of both sides were collected using motion-capturing system and dynamometry. Each boot was tested in the maximally plantarflexed position. Group differences between boot conditions were analyzed by means of repeated-measures ANOVA and post-hoc paired t-test. RESULTS: The boot dorsiflexion range of motion differed significantly between boots with Vacoped (1.8° (0.3)) showing the smallest range, followed by Kuenzli (5.0° (1.3)) and Orthotech (7.9° (1.7)). Orthotech displayed a higher peak plantarflexion moment (1.36 Nm/kg (0.09)) than both Kuenzli (1.06 Nm/kg (0.12)) and Vacoped (1.04 Nm/kg (0.14)). Concerning loading over time, significant differences in the plantarflexion impulse were found, with the highest impulse in Vacoped (0.42 Nms/kg (0.06)), followed by Orthotech (0.29 Nms/kg (0.03)) and Kuenzli (0.25 Nms/kg (0.05)). In addition, asymmetries were seen in stance and step length for the booted and contralateral sides. SIGNIFICANCE: The lower extremity biomechanics were affected by the boots, with Kuenzli showing the lowest joint loading, Vacoped the smallest joint motion and Orthotech the most natural gait pattern. Future research is needed to determine the most relevant variable expressing the risk of re-rupture of the Achilles tendon in order to conclude which boot may be most favorable to use in clinical practice.

Possible Beneficial Actions of Caffeine in SARS-CoV-2.

The COVID-19 pandemic has established an unparalleled necessity to rapidly find effective treatments for the illness; unfortunately, no specific treatment has been found yet. As this is a new emerging chaotic situation, already existing drugs have been suggested to ameliorate the infection of SARS-CoV-2. The consumption of caffeine has been suggested primarily because it improves exercise performance, reduces fatigue, and increases wakefulness and awareness. Caffeine has been proven to be an effective anti-inflammatory and immunomodulator. In airway smooth muscle, it has bronchodilator effects mainly due to its activity as a phosphodiesterase inhibitor and adenosine receptor antagonist. In addition, a recent published document has suggested the potential antiviral activity of this drug using in silico molecular dynamics and molecular docking; in this regard, caffeine might block the viral entrance into host cells by inhibiting the formation of a receptor-binding domain and the angiotensin-converting enzyme complex and, additionally, might reduce viral replication by the inhibition of the activity of 3-chymotrypsin-like proteases. Here, we discuss how caffeine through certain mechanisms of action could be beneficial in SARS-CoV-2. Nevertheless, further studies are required for validation through in vitro and in vivo models.