Centella asiatica and Its Metabolite Asiatic Acid: Wound Healing Effects and Therapeutic Potential.

An intense effort has been focused on new therapeutic approaches and the development of technologies for more efficient and rapid wound healing. The research for plants used for long time in traditional medicine in the treatment of wound has become a promising strategy to obtain drugs therapeutically useful in the acute and chronic wound management. In this context, Centella asiatica (Apiaceae) has been used to treat a variety of skin diseases, such as leprosy, lupus, varicose ulcers, eczema and psoriasis, in Asiatic traditional medicine for thousands of years. Studies have shown that Centella asiatica extracts (CAE) display activity in tissue regeneration, cell migration and wound repair process by promoting fibroblast proliferation and collagen synthesis. Preliminary findings have shown that the asiatic acid is one of the main active constituents of C. asiatica, directly associated with its healing activity. Thus, this study discusses aspects of the effects of Centella asiatica and its active component, asiatic acid, in different stages of the healing process of cutaneous wounds, including phytochemical and antimicrobial aspects that contribute to its therapeutic potential.

The Essential Oil of Hyptis crenata Inhibits the Increase in Secretion of Inflammatory Mediators.

Background: Hyptis crenata is a plant of great ethnopharmacological importance widely distributed in South American countries. In Northeast Brazil, teas or infusions of its aerial parts are used in folk medicine to treat several acute and chronic inflammatory diseases. In a previous work we have demonstrated that the essential oil of H. crenata (EOHc) has an antiedematogenic effect. The aim of this work was to evaluate the effect of EOHc on cytokines secretion and cellular infiltration. Methods: Peritonitis and paw edema models induced by carrageenan were used to determine leucocyte count, myeloperoxidase (MPO) activity, nitrite, and cytokines secretion. Results: EOHc (10−300 mg/kg) significantly inhibited leucocyte migration and reduced the neutrophil count (control: 1.46 × 103 ± 0.031 × 103/mL) of the total leucocytes population in extracellular exudate (control: 2.14 × 103 ± 0.149 × 103/mL) by 15.00%, 43.29%, 65.52%, and 72.83% for the doses of 10, 30, 100, and 300 mg/kg EOHc, respectively (EC50: 24.15 mg/kg). EOHc (100 mg/kg) inhibited the increase in myeloperoxidase activity and completely blocked the increase in nitrite concentration induced by carrageenan. EOHc markedly reduced the pro-inflammatory cytokines (IL-6, MCP-1, IFN-γ, TNF-α, and IL-12p70) and increased IL-10, an anti-inflammatory cytokine (compared to control group, p < 0.05). Conclusions: This study demonstrates that EOHc has a long-lasting anti-inflammatory effect mediated through interference on MPO activity, and nitrite, and cytokines secretion. This effect, coupled with low EOHc toxicity, as far as results obtained in mice could be translated to humans, suggests that EOHc has great potentiality as a therapeutic agent.

Renoprotective Effects of Luteolin: Therapeutic Potential for COVID-19-Associated Acute Kidney Injuries.

Acute kidney injury (AKI) has been increasingly reported in critically-ill COVID-19 patients. Moreover, there was significant positive correlation between COVID-19 deaths and renal disorders in hospitalized COVID-19 patients with underlying comorbidities who required renal replacement therapy. It has suggested that death in COVID-19 patients with AKI is 3-fold higher than in COVID-19 patients without AKI. The pathophysiology of COVID-19-associated AKI could be attributed to unspecific mechanisms, as well as COVID-19-specific mechanisms such as direct cellular injury, an imbalanced renin-angiotensin-aldosterone system, pro-inflammatory cytokines elicited by the viral infection and thrombotic events. To date, there is no specific treatment for COVID-19 and its associated AKI. Luteolin is a natural compound with multiple pharmacological activities, including anticoronavirus, as well as renoprotective activities against kidney injury induced by sepsis, renal ischemia and diverse nephrotoxic agents. Therefore, in this review, we mechanistically discuss the anti-SARS-CoV-2 and renoprotective activities of luteolin, which highlight its therapeutic potential in COVID-19-AKI patients.

"H" is not for hydroxychloroquine-"H" is for heparin: lack of efficacy of hydroxychloroquine and the role of heparin in COVID-19-preliminary data of a prospective and interventional study from Brazil.

BACKGROUND: COVID-19 pandemic is the major public health problem in the world actually. It's associated with high morbidity and mortality. To date, no therapeutic measure has a curative potential. Hydroxychloroquine (HCQ) is a drug with immunomodulatory properties that has demonstrated antiviral efficacy in in vitro experiments, with conflicting results in in vivo studies. METHODS: A single-center, prospective and interventional study, that evaluates the impact on mortality of the HCQ use in 154 patients hospitalized with COVID-19 in a Brazilian public hospital. The study also aims to determine prognostic factors that predict mortality, ICU admission and endotracheal intubation in this population. RESULTS: 154 patients diagnosed with COVID-19 confirmed by RT-PCR and hospitalized were included. There was a male predominance (87/154, 56.5%), median age 60 years and 88% (136/154) had comorbidities. Among these, 76% (117/154) were admitted to the ICU and 29.2% (45/154) experienced EOT. The OMR was 51.3% (79/154). There was no difference in mortality between patients treated with HCQ (N = 95) and non-HCQ (N = 59) (44.1% × 55.8%, p = 0.758). In univariate analysis, age ≥ 60 years (HR 3.62, p < 0.001), need for mechanical ventilation (HR 2.17, p = 0.001), ≥ 2 comorbidities (HR 1.83, p = 0.049), SAH (HR: 1.56, p = 0.054) were predictors of mortality, as well as no use of prophylactic or therapeutic heparin (HR 3.60, p = 0.02). Multivariate analysis identified admission to the ICU (HR 8.98, p = 0.002) and advanced age (HR 3.37, p < 0.01) as independent predictors of mortality, although, use of heparin (HR 0.25, p = 0.001) was independently associated with a favorable outcome. CONCLUSION: This study confirmed the absence of a benefit associated with the use of HCQ in Brazilian patients hospitalized with COVID-19. However, prophylactic or therapeutic heparin was an independent predictor for reducing mortality in this population.

Catechins: Therapeutic Perspectives in COVID-19-Associated Acute Kidney Injury.

Data obtained from several intensive care units around the world have provided substantial evidence of the strong association between impairment of the renal function and in-hospital deaths of critically ill COVID-19 patients, especially those with comorbidities and requiring renal replacement therapy (RRT). Acute kidney injury (AKI) is a common renal disorder of various etiologies characterized by a sudden and sustained decrease of renal function. Studies have shown that 5-46% of COVID-19 patients develop AKI during hospital stay, and the mortality of those patients may reach up to 100% depending on various factors, such as organ failures and RRT requirement. Catechins are natural products that have multiple pharmacological activities, including anti-coronavirus and reno-protective activities against kidney injury induced by nephrotoxic agents, obstructive nephropathies and AKI accompanying metabolic and cardiovascular disorders. Therefore, in this review, we discuss the anti-SARS-CoV-2 and reno-protective effects of catechins from a mechanistic perspective. We believe that catechins may serve as promising therapeutics in COVID-19-associated AKI due to their well-recognized anti-SARS-CoV-2, and antioxidant and anti-inflammatory properties that mediate their reno-protective activities.

Bioactive Terpenes and Their Derivatives as Potential SARS-CoV-2 Proteases Inhibitors from Molecular Modeling Studies.

The coronavirus disease 2019 (COVID-19) pandemic is caused by a novel coronavirus; the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Millions of cases and deaths to date have resulted in a global challenge for healthcare systems. COVID-19 has a high mortality rate, especially in elderly individuals with pre-existing chronic comorbidities. There are currently no effective therapeutic approaches for the prevention and treatment of COVID-19. Therefore, the identification of effective therapeutics is a necessity. Terpenes are the largest class of natural products that could serve as a source of new drugs or as prototypes for the development of effective pharmacotherapeutic agents. In the present study, we discuss the antiviral activity of these natural products and we perform simulations against the Mpro and PLpro enzymes of SARS-CoV-2. Our results strongly suggest the potential of these compounds against human coronaviruses, including SARS-CoV-2.

Mechanistic Aspects and Therapeutic Potential of Quercetin against COVID-19-Associated Acute Kidney Injury.

The inflammatory mediator and oxidant agent storm caused by the SARS-CoV-2 infection has been strongly associated with the failure of vital organs observed in critically ill patients with coronavirus disease 2019 (COVID-19) and the death of thousands of infected people around the world. Acute kidney injury (AKI) is a common renal disorder characterized by a sudden and sustained decrease in renal function with a critical influence on poor prognosis and lethal clinical outcomes of various etiologies, including some viral infection diseases. It is known that oxidative stress and inflammation play key roles in the pathogenesis and development of AKI. Quercetin is a natural substance that has multiple pharmacological properties, such as anti-inflammatory action, and is used as a dietary supplement. There is evidence of the anti-coronavirus activities of this compound, including against the target SARS-CoV-2 3CLpro. The ability to inhibit coronavirus and its inflammatory processes is strongly desired in a new drug for the treatment of COVID-19. Therefore, in this review, the dual effect of quercetin is discussed from a mechanistic perspective in relation to AKI kidney injury and its nephroprotective potential to SARS-CoV-2 patients.

Natural Antioxidants: A Review of Studies on Human and Animal Coronavirus.

The outbreaks of viruses with wide spread and mortality in the world population have motivated the research for new therapeutic approaches. There are several viruses that cause a biochemical imbalance in the infected cell resulting in oxidative stress. These effects may be associated with the development of pathologies and worsening of symptoms. Therefore, this review is aimed at discussing natural compounds with both antioxidant and antiviral activities, specifically against coronavirus infection, in an attempt to contribute to global researches for discovering effective therapeutic agents in the treatment of coronavirus infection and its severe clinical complications. The contribution of the possible action of these compounds on metabolic modulation associated with antiviral properties, in addition to other mechanisms of action, is presented.

Antidepressant Potential of Cinnamic Acids: Mechanisms of Action and Perspectives in Drug Development.

Depression is a health problem that compromises the quality of life of the world's population. It has different levels of severity and a symptomatic profile that affects social life and performance in work activities, as well as a high number of deaths in certain age groups. In the search for new therapeutic options for the treatment of this behavioral disorder, the present review describes studies on antidepressant activity of cinnamic acids, which are natural products found in medicinal plants and foods. The description of the animal models used and the mechanisms of action of these compounds are discussed.

Electrophysiologic alterations in the excitability of the sciatic and vagus nerves during early stages of sepsis.

BACKGROUND: Nonspecific and delayed diagnosis of neurologic damage contributes to the development of neuropathies in patients with severe sepsis. The present study assessed the electrophysiologic parameters related to the excitability and conductibility of sciatic and vagus nerves during early stages of sepsis. MATERIALS AND METHODS: Twenty-four hours after sepsis induced by cecal ligation and puncture (CLP) model, sciatic and vagus nerves of septic (CLP group) and control (sham group) rats were removed, and selected electric stimulations were applied to measure the parameters of the first and second components of the compound action potential. The first component originated from fibers with motor and sensory functions (Types Aα and Aß fibers) with a large conduction velocity (70-120 m/s), and the second component originated from fibers (Type Aγ) with sensorial function. To evaluate the presence of sensorial alterations, the sensitivity to non-noxious mechanical stimuli was measured by using the von Frey test. Hematoxylin and eosin staining of the nerves was performed. RESULTS: We observed an increase of rheobase followed by a decrease in the first component amplitude and a higher paw withdrawal threshold in response to the application of von Frey filaments in sciatic nerves from the CLP group compared to the sham group. Differently, a decrease in rheobase and an increase in the first component amplitude of vagal C fibers from CLP group were registered. No significant morphologic alteration was observed. CONCLUSION: Our data showed that the electrophysiologic alterations in peripheral nerves vary with the fiber type and might be identified in the first 24 h of sepsis, before clinical signs of neuromuscular disorders.

Hepatoprotective Effect of Essential Oils from Hyptis crenata in Sepsis-Induced Liver Dysfunction.

No specific therapeutics are available for the treatment of sepsis-induced liver dysfunction, a clinical complication strongly associated with the high mortality rate of septic patients. This study investigated the effect of the essential oil of Hyptis crenata (EOHc), a lamiaceae plant used to treat liver disturbances in Brazilian folk medicine, on liver function during early sepsis. Sepsis was induced by the cecal ligation and puncture (CLP) model. Rats were divided into four groups: Sham, Sham+EOHc, CLP, and CLP+EOHc. EOHc (300 mg/kg) was orally administered 12 and 24 h after surgery. The animals were sacrificed for blood collection and liver tissue samples 48 h after surgery. Hepatic function was evaluated by measuring serum bilirubin, alkaline phosphatase (ALP), aspartate aminotransferase, and alanine aminotransferase (ALT) levels. The levels of malondialdehyde and the activity of superoxide dismutase, catalase, and GSH peroxidase (GSH-Px) were measured for assessment of oxidative stress. Liver morphology was analyzed by hematoxylin and eosin staining. EOHc normalized serum ALP, ALT, and bilirubin levels and inhibited morphological changes. In addition, we observed that EOHc inhibited elevation in hepatic lipid peroxidation and reduction of the glutathione peroxidase activity induced by sepsis. Our data show that EOHc plays a protective effect against liver injury induced by sepsis.

Rapid on-site cytopathological examination (ROSE) performed by endosonagraphers and its improvement in the diagnosis of pancreatic solid lesions.

PURPOSE: To evaluate the diagnosis improvement of EUS-FNA when using ROSE performed by the endosonographer. METHODS: A retrospective study was conducted. A total of 48 pancreatic solid masses EUS-FNA were divided into two groups according to the availability of on-site cytology (ROSE) - the first 24 patients (group A-without ROSE) and the latter 24 cases (group B-with ROSE). Sensitivity, specificity, positive predictive value, negative predictive value, accuracy, complications and inadequacy rate of EUS-FNA were determined and compared. RESULTS: Among the 48 EUS-FNA, the overall performance was: sensitivity 82%; specificity 100%; positive predictive value (PPV) 100%; negative predictive value (NPV) 70% and accuracy 87%. The sensitivity of the Group A was 71%, versus 94% in-group B (p=0.61). Moreover, the negative predictive value was 58% versus 87% (p=0.72). The accuracy rate increased from 79% to 96% (p=0.67) in the ROSE group. The number of punctures was similar between the groups. No major complications were reported. CONCLUSION: Rapid on-site cytopathological examination, even when performed by the endosonographer, may improve the diagnostic performance in the diagnosis of solid pancreatic lesions, regardless of the slight increase in the number of punctures.

Fecal microbiota transplant by push enteroscopy to treat diarrhea caused by Clostridium difficile.

Clostridium difficile is the major etiological agent of pseudomembranous colitis and is found in up to 20% of adult inpatients. The recommended treatment is antibiotic therapy with metronidazole and/or vancomycin. However, the recurrence rate may reach up to 25% and it increases in each episode. The newest alternative to treat diarrhea due to recurrent Clostridium difficile is fecal microbiota transplantation. The procedure was performed in 12 patients, with a 6-month follow-up on 10 of them. Of the ten cases, bacterial recurrence was diagnosed in only one patient, after a course of antibiotic to treat urinary tract infection, without presenting with diarrhea. The particularity of our study, besides being an unprecedented event in South America, is the way to perform the infusion of fecal microbiota by enteroscopy.

Rapid on-site cytopathological examination (ROSE) performed by endosonagraphers and its improvement in the diagnosis of pancreatic solid lesions

PURPOSE: To evaluate the diagnosis improvement of EUS-FNA when using ROSE performed by the endosonographer. METHODS: A retrospective study was conducted. A total of 48 pancreatic solid masses EUS-FNA were divided into two groups according to the availability of on-site cytology (ROSE) - the first 24 patients (group A-without ROSE) and the latter 24 cases (group B-with ROSE). Sensitivity, specificity, positive predictive value, negative predictive value, accuracy, complications and inadequacy rate of EUS-FNA were determined and compared. RESULTS: Among the 48 EUS-FNA, the overall performance was: sensitivity 82%; specificity 100%; positive predictive value (PPV) 100%; negative predictive value (NPV) 70% and accuracy 87%. The sensitivity of the Group A was 71%, versus 94% in-group B (p=0.61). Moreover, the negative predictive value was 58% versus 87% (p=0.72). The accuracy rate increased from 79% to 96% (p=0.67) in the ROSE group. The number of punctures was similar between the groups. No major complications were reported. CONCLUSION: Rapid on-site cytopathological examination, even when performed by the endosonographer, may improve the diagnostic performance in the diagnosis of solid pancreatic lesions, regardless of the slight increase in the number of punctures. .

Rapid on-site cytopathological examination (ROSE) performed by endosonagraphers and its improvement in the diagnosis of pancreatic solid lesions

PURPOSE: To evaluate the diagnosis improvement of EUS-FNA when using ROSE performed by the endosonographer. METHODS: A retrospective study was conducted. A total of 48 pancreatic solid masses EUS-FNA were divided into two groups according to the availability of on-site cytology (ROSE) - the first 24 patients (group A-without ROSE) and the latter 24 cases (group B-with ROSE). Sensitivity, specificity, positive predictive value, negative predictive value, accuracy, complications and inadequacy rate of EUS-FNA were determined and compared. RESULTS: Among the 48 EUS-FNA, the overall performance was: sensitivity 82%; specificity 100%; positive predictive value (PPV) 100%; negative predictive value (NPV) 70% and accuracy 87%. The sensitivity of the Group A was 71%, versus 94% in-group B (p=0.61). Moreover, the negative predictive value was 58% versus 87% (p=0.72). The accuracy rate increased from 79% to 96% (p=0.67) in the ROSE group. The number of punctures was similar between the groups. No major complications were reported. CONCLUSION: Rapid on-site cytopathological examination, even when performed by the endosonographer, may improve the diagnostic performance in the diagnosis of solid pancreatic lesions, regardless of the slight increase in the number of punctures.(AU)

Gastroprotective effect of alpha-pinene and its correlation with antiulcerogenic activity of essential oils obtained from Hyptis species.

BACKGROUND: Alpha-pinene (α-pinene) is a monoterpene commonly found in essential oils with gastroprotective activity obtained from diverse medicinal plants, including Hyptis species. The genus Hyptis (lamiaceae) consists of almost 400 species widespread in tropical and temperate regions of America. In the north and northeastern Brazil, some Hyptis species are used in traditional medicine to treat gastrointestinal disturbances. OBJECTIVE: The present study has investigated the gastoprotective effect of purified α-pinene in experimental gastric ulcer induced by ethanol and indomethacin in mice. MATERIALS AND METHODS: Gastric ulcers were induced in male Swiss mice (20-30 g) by oral administration of absolute ethanol or indomethacin 45 min after oral pretreatment with vehicle, standard control drugs or α-pinene (10, 30, and 100 mg/kg). One hour after the ulcerative challenges, the stomach were removed, and gastric lesions areas measured. The effects of α-pinene on the gastric juice acidity were determined by pylorus ligation model. The gastrointestinal motility and mucus depletion were determined by measuring the gastric levels of phenol red and alcian blue, respectively. Hematoxylin and eosin stained sections of gastric mucosa of the experimental groups were used for histology analysis. RESULTS: α-pinene pretreatment inhibited ethanol-induced gastric lesions, reduced volume and acidity of the gastric juice and increased gastric wall mucus (P < 0.05). Furthermore, we showed an interesting correlation between concentration of α-pinene and gastroprotective effect of Hyptis species (P Pearson = 0.98). CONCLUSION: Our data showed that the α-pinene exhibited significant antiulcerogenic activity and a great correlation between concentration of α-pinene and gastroprotective effect of Hyptis species was also observed.

Rectal cancer staging: Correlation between the evaluation with radial echoendoscope and rigid linear probe.

BACKGROUND AND OBJECTIVES: The National Cancer Institute estimated 40,340 new cases of rectal cancer in the United States in 2013. The correct staging of rectal cancer is fundamental for appropriate treatment of this disease. Transrectal ultrasound is considered one of the best methods for locoregional staging of rectal tumors, both radial echoendoscope and rigid linear probes are used to perform these procedures. The objective of this study is to evaluate the correlation between radial echoendoscopy and rigid linear endosonography for staging rectal cancer. PATIENTS AND METHODS: A prospective analysis of 48 patients who underwent both, radial echoendoscopy and rigid linear endosonography, between April 2009 and May 2011, was done. Patients were staged according to the degree of tumor invasion (T) and lymph node involvement (N), as classified by the American Joint Committee on Cancer. Anatomopathological staging of surgical specimen was the gold standard for discordant evaluations. The analysis of concordance was made using Kappa index. RESULTS: The general Kappa index for T staging was 0.827, with general P < 0.001 (confidence interval [CI]: 95% 0.627-1). The general Kappa index for N staging was 0.423, with general P < 0.001 (CI: 95% 0.214-0.632). CONCLUSION: The agreement between methods for T staging was almost perfect, with a worse outcome for T2, but still with substantial agreement. The findings may indicate equivalence in the diagnostic value of both flexible and rigid devices. For lymph node staging, there was moderate agreement between the methods.

Poly ɛ-caprolactone nanoparticles loaded with Uncaria tomentosa extract: preparation, characterization, and optimization using the Box-Behnken design.

PURPOSE: The aim of this research was to develop and optimize a process for obtaining poly ɛ-caprolactone (PCL) nanoparticles loaded with Uncaria tomentosa (UT) extract. METHODS: Nanoparticles were produced by the oil-in-water emulsion solvent evaporation method. Preliminary experiments determined the initial conditions of the organic phase (OP) and of the aqueous phase (AP) that would be utilized for this study. Ultimately, a three-factor three-level Box-Behnken design (BBD) was employed during the optimization process. PCL and polyvinyl alcohol (PVA) concentrations (X(1) and X(2), respectively) and the AP/OP volume ratio (X(3)) were the independent variables studied, while entrapment efficiency (Y(1)), particle mean diameter (Y(2)), polydispersity (Y(3)), and zeta potential (Y(4)) served as the evaluated responses. RESULTS: PRELIMINARY EXPERIMENTS REVEALED THAT THE OPTIMAL INITIAL CONDITIONS FOR THE PREPARATION OF NANOPARTICLES WERE AS FOLLOWS: OP composed of 5 mL ethyl acetate/acetone (3/2) mixture containing UT extract and PCL, and an AP of buffered PVA (pH 7.5) solution. Statistical analysis of the BBD results indicated that all of the studied factors had significant effects on the responses Y(1), Y(2), and Y(4,) and these effects are closely described or fitted by regression equations. Based on the obtained models and the selected desirability function, the nanoparticles were optimized to maximize Y(1) and minimize Y(2). These optimal conditions were achieved using 3% (w/v) PCL, 1% (w/v) PVA, and an AP/OP ratio of 1.7, with predicted values of 89.1% for Y(1) and 280 nm for Y(2). Another batch was produced under the same optimal conditions. The entrapment efficiency of this new batch was measured at 81.6% (Y(1)) and the particles had a mean size of 247 nm (Y(2)) and a polydispersity index of 0.062 (Y(3)). CONCLUSION: This investigation obtained UT-loaded nanoparticle formulations with desired characteristics. The BBD approach was a useful tool for nanoparticle development and optimization, and thus should be useful especially in the realm of phytotherapeutics, in which varied compositions may be assessed in quantitative and qualitative terms.