Introduction

In Brazil's Unified Health System, integrative and complementary health practices (PICS) are crucial in achieving one of its foundational principles: Integrality. These practices represent treatments that draw on traditional knowledge and utilize therapeutic resources aimed at preventing a range of diseases, including hypertension and diabetes mellitus (DM). Thus, applying these practices can promote health beyond the physical realm, considering they encompass social, cultural, and emotional concerns within a multidisciplinary approach ^1,2.

Currently, approximately 29 PICS are available at no cost within Brazil's public healthcare system, with the utilization of medicinal plants being particularly notable. These plants, whether cultivated or wild, can be administered through various methods, such as orally or via infusion, and possess therapeutic effects. However, similar to any medication, they must be employed judiciously due to potential risks of adverse effects, contraindications, or interactions ².

Brazil boasts the highest level of biodiversity worldwide, accounting for 15-20 % of all known species. Plant life, a key component of this biodiversity, is the foundation for home remedies in traditional medicine. Furthermore, Brazil's rich cultural and ethnic diversity has fostered a wealth of knowledge about managing and utilizing medicinal plants, which has been endowed through successive generations ^3,4.

In 2019, chronic non-communicable diseases (NCDs) accounted for 75 % of morbidity and mortality among the Brazilian population ⁵; NCDs are chronic conditions generally attributable to multiple factors, characterized by a gradual onset and prolonged or indefinite duration ⁶. They arise from lifestyle-related factors such as unhealthy diets, physical inactivity, smoking, and alcohol consumption ⁷.

When used responsibly, medicinal plants can play a pivotal role as a complementary and integrative approach to treating NCDs. Various species offer therapeutic benefits and functional properties, in addition to being accessible and cost-effective ⁸. Among the native plants of Brazil, many are acknowledged for their therapeutic and nutritional value by both traditional and scientific medicine ⁹. For example, Anredera cordifolia (Ten.) Steenis is a species native to Brazil found in various regions but is not endemic ¹⁰. A. cordifolia is primarily recognized for its nutritional value; it is a plant with high nutrient content and biomass yield, classified as an unconventional food plant ¹¹.

Studies on A. cordifolia have highlighted its varied popular names in Brazil, including bertalhacoração, madeira vine, and folha gorda^12-14. In traditional medicine, the plant is valued for its therapeutic properties in treating skin diseases, DM, and hypertension ¹³. There is also documentation on its anti-inflammatory, antibacterial, anti-ulcer, and healing properties ^15-17. However, despite experimental studies confirming those effects, the understanding of its properties remains in the early stages ^15-17.

Hence, examining the existing evidence concerning its use and potentially identifying gaps in our knowledge is essential. Given the context described and the increasing interest in therapeutic practices involving medicinal plants, particularly the therapeutic potential of A. cordifolia, the significance of this study is evident. This study sought to survey both national and international scientific literature on the properties of A. cordifolia within the therapeutic management of NCDs.

Materials and Method

This study comprises a scoping review, a type of systematic literature review that adopts the PCC research approach, where P stands for population, C for concept, and the second C for context. This type of review is utilized to map the key concepts underpinning a research field and elucidate the definitions and conceptual limits of a topic (i.e., provide an overview or evidence map) ¹⁸.

The purposes of this method include serving as a precursor to a systematic review, identifying the types of evidence available in a specific field, analyzing knowledge gaps, elucidating the main concepts/definitions in the literature, examining research methodologies within a given topic or field, and identifying the principal characteristics or factors related to a concept ¹⁹.

A scoping review initiates with the development of a protocol, which acts as a blueprint and is crucial to minimize bias occurrence ¹⁸. For this study, a protocol was formulated and registered on the Open Science Framework platform. The review question posed was as follows: What are the properties of A. cordifolia in the therapeutic process of NCDs in laboratory studies involving humans, animals, and cell models?

The inclusion criteria were: a) studies involving human beings, animals, or cell models; b) studies investigating the therapeutic properties of the plant in NCDs; c) experiments executed in a laboratory setting; d) primary studies; e) studies regardless of the language, country of origin, or timeframe. The exclusion criteria consisted of incomplete or unavailable articles; duplicates were also excluded.

The search was conducted in July and August 2022 and updated in August 2023, using the Medline/PubMed, Scopus, and Web of Science databases, as well as the reference lists of the included studies after an exhaustive reading. The controlled descriptor searches were conducted in the Descriptors in Health Sciences (DeCS) and Medical Subject Headings (MeSH) databases, while non-controlled descriptors were identified by reviewing the titles and abstracts of previously published studies. The search strategies applied to each data source are described in Table 1.

The selection of evidence was conducted in a double-independent manner, with a third reviewer available in case of any disagreements. The studies retrieved from the data sources were transferred to the Rayyan software; their titles and abstracts were reviewed, followed by a full reading of the selected articles and a critical assessment of the reference lists.

For data extraction, a script was devised containing relevant information to map the data, including author/year, country of study/ language, part of the plant and type of extract used, experimental model utilized, NCD or clinical marker researched, and the therapeutic properties of the plant in NCDs.

The data underwent coding and content analysis, as proposed in the literature (20). The results will be presented below, accompanied by descriptive summaries and in-depth discussions based on the existing literature.

Results

The search yielded 635 studies, of which 31 were selected for comprehensive review. Among them, eight were excluded due to duplication, and, upon detailed review, four more were excluded for failing to meet the selection criteria. This resulted in a total of 19 articles. Further evaluation of the reference lists of these studies led to the inclusion of an additional 11 studies, composing a final corpus of 27 articles (Figure 1).

Source: Elaborated by the authors.

Figure 1 Study's design Flowchart Based on the PRISMA Extension for Scoping Reviews (PRISMA-ScR), Santa Maria, Rio Grande do Sul, Brazil, 2023 

All the studies were conducted in Asia, written predominantly in English, and conducted by the same researchers (Table 2).

Table 2 also indicates that 26 studies utilized ethanolic leaf extract, and one used leaf powder ²⁴, with only five studies specifying the concentration of the extract ^{22,26,33,37,38}. The most common dose used in the experiments was 100 mg/kg, as noted in 11 studies ^{25,27,30-32,35-37,39,43,45}.

Furthermore, DM and HT were the most frequently studied NCDs, with 9 studies on DM ^{21,33,34,36,38,42,45-47}, and 6 studies on HT ^{23,26,30,37,40,44}. Three studies examined clinical markers of chronic kidney disease (CKD) ^25,27,29, 6 investigated serum cholesterol and triglyceride levels ^{24,28,31,32,39,43}, 3 focused on obesity ^35,38,39, 1 on cataracts ²², and another one on serum uric acid levels ⁴¹.

As per the selection criteria for this review, all of the studies included had an experimental design with quantitative/statistical analysis: 1 with an in vitro population ²², 22 in vivo^{21,23-39,41-43,45-47}, and 2 studies that used both in vitro and in vivo models ^40,44. Of the in vitro studies, 1 was performed on goat lenses ²² and 2 on rabbit aortic rings ^40,44. The in vivo research comprised 21 studies conducted on rats ^{21,23,25-32,34,35,37-39,41-43,45-47}, 2 on frogs ^40,44, 1 on rabbits ³³, 1 on mice ³⁶, and 1 on humans ²⁴. Regarding the plant's therapeutic properties, the results of the studies included in this review are detailed in Table 3.

Notably, the properties with the most scientific evidence pertain to a hypoglycemic effect or reduction in blood glucose levels ^{21,24,34,36,42,45-47}. These are closely followed by those demonstrating reduced triglyceride levels ^{24,28,31,32,39} and decreased total cholesterol levels ^{28,31,32,39,43}. Furthermore, the plant has shown beneficial effects on the healing of diabetic wounds ^33,38, in lowering systolic, diastolic blood pressure, and overall blood pressure ^23,26,30,44, in addressing obesity ^35,38,39, and in treating CKD. This treatment for CKD is evidenced by the reduction of creatinine levels ^25,27,29 and serum urea concentrations ^25,27, along with an increase in antioxidant enzyme levels ^27,29.

Discussion

Commonly, the first treatment option for chronic conditions includes drug therapy along with encouraging patients to change their lifestyles. An alternative, however, which remains underutilized, is the use of herbal medicine as a complement to conventional medication ⁴⁸. In Brazil, policies have been implemented to encourage the therapeutic use and production of herbal medicine under the supervision of the National Health Surveillance Agency ⁴⁹.

Diabetes mellitus is one of the most prevalent NCDs in the world. In 2021, 537 million individuals were diagnosed with DM, with Brazil accounting for 14.3 million of these cases ⁵⁰. It is characterized by persistent hyperglycemia ⁵¹, and various studies have demonstrated the hypoglycemic effect of various treatments ^{21,24,34,36,42,45-47}. Hyperglycemia arises due to a deficiency in insulin production, action, or both ⁵¹. Specifically, the oral ingestion of the ethanolic extract of A. cordifolia has been documented to enhance insulin secretion ⁴². In the context of DM, pancreatic beta cells may be deficient, which are critical for insulin secretion and glucose tolerance ^51,52. It has been shown that oral treatment with this plant extract can repair these cells and improve glucose tolerance ^21,45,47.

Moreover, an increase in the concentration of essential amino acids has been observed regarding DM ²¹. These amino acid chains play a pivotal role in protein synthesis within living organisms and are essential for muscle tissue strength, improved intestinal function, and blood sugar level regulation, among other functions ⁵³. They are crucial supplements for individuals with DM, as they can lower blood glucose levels, enhance insulin resistance, and alleviate oxidative stress ⁵⁴. Furthermore, they can reduce the likelihood of complications associated with DM, effectively diminishing the condition's damage ⁵⁵.

As for DM complications, the most prevalent and significant are microvascular alterations, particularly diabetic neuropathy. Diabetic peripheral neuropathy, the most common form, results from chronic hyperglycemia and cardiovascular risk factors, manifesting as a symmetrical, diffuse, distal, and progressive lesion of both autonomic and sensory-motor fibers. Affected individuals experience pain in the impacted area, negatively affecting their quality of life, functionality, and mood. It can lead to additional comorbidities such as anxiety, depression, insomnia, loss of functionality, and, notably, the diabetic foot ⁵².

With the global rise in DM prevalence, incidents of foot complications (e.g., diabetic foot) and infection and amputation rates have increased, constituting the most debilitating complications and leading to significant loss of functionality ^52,56. Two studies featured in this scoping review demonstrated the positive effects of A. cordifolia on healing diabetic wounds, with one utilizing an ointment combining the ethanolic extracts of the A. cordifolia and Centella asiatica plants at a 2 % concentration and the other employing a gel of the A. cordifolia leaf extract at concentrations of 10 and 30 % ^33,38. Its application has also been associated with an increase in fibroblast cell proliferation ³³, which is critical for the healing process as these cells form a layer differing in function and structure from the original tissue, thereby generating the scar and contributing to regeneration.

One study reported that ingesting the ethanolic extract of the plant led to a reduction in liver weight ²¹. The liver is crucial for carbohydrate metabolism, and the regulation of glucose homeostasis, and excessive fat deposition constitutes non-alcoholic fatty liver, a chronic liver disease linked with obesity, insulin resistance, and type 2 DM, affecting up to 30 % of the general population and significantly predisposing individuals to type 2 DM ⁵⁸.

Additionally, the oral administration of A. cordifolia extract has been shown to increase water intake and reduce fatty acid levels ^21,38. Fatty acids, while essential for the normal functionality of beta cells, can lead to fat accumulation in muscles, liver, and pancreas when in excess ⁴⁵. Regarding water intake, hydration is critical in preventing and controlling DM, and low water consumption is associated with an increased risk of type 2 DM and cardiovascular, liver, and kidney problems ⁵⁹.

In terms of HT, the studies present promising outcomes. HT is characterized by a persistent rise in blood pressure, confirmed using the correct technique at least two separate times in the absence of antihypertensive medication. Controlling blood pressure to normal levels is vital for diminishing the risk of both micro and macrovascular complications ⁶⁰. In this context, the ethanolic extract from the leaves of A. cordifolia has proven effective in treating hypertension by reducing both systolic, diastolic blood ^23,30 and total blood pressure ^26,44.

Some factors directly influence blood pressure such as heart rate, which, when high, becomes a risk factor for the occurrence of adverse events and mortality in users with hypertension ⁶¹. Studies have shown that the plant's leaf extract reduces heart rate ^37,40, suggesting that research should be carried out on human beings, as the plant could be used to benefit people with hypertension.

Moreover, in experiments where the vasodilator effect was examined, the results were affirmatively in favor of using the extract ^40,44. The mechanisms of vasodilation and the application of drugs or phytomedicine that facilitate it are critically important in individuals with HT, as this process increases blood flow to the tissues and decreases blood pressure and central venous pressure, ultimately reducing cardiac workload ⁶².

Furthermore, the plant has demonstrated an ability to elevate nitric oxide levels and exhibited diuretic properties ^30,37. Nitric oxide plays a significant role in vasodilation, which leads to lower blood pressure and provides positive cardiac, renal, and vascular effects ⁶². Conversely, diuretics work to reduce intravascular volume through increased renal excretion of water and sodium. In cases of hypertension, the decline in intravascular volume results in decreased cardiac output and, consequently, a lowering of blood pressure ⁶³.

Continuing with NCDs, CKD is characterized by a long-term and gradual deterioration of kidney function, with the most common causes being diabetic nephropathy (a complication of DM) and hypertensive nephrosclerosis (a complication of HT) ⁶⁴. The diagnosis is based on various tests, including serum creatinine and urea levels. Creatinine is one of the biomarkers for CKD, whereas urea is extensively utilized in clinical settings to assess kidney function ⁶⁵. Research demonstrating the effects of A. cordifolia on rats with CKD has shown its efficacy in reducing serum creatinine levels and serum urea concentrations ^25,27,29. In addition, in the context of CKD, the use of the extract has led to improvements in kidney structure ²⁷, increased antioxidant enzymes catalase and superoxide dismutase levels ^27,29, and reduced hydronephrosis ²⁹. Antioxidant enzymes play a crucial role in the kidney's defensive mechanisms and in mitigating oxidative stress ⁶⁶, while hydronephrosis is a condition characterized by kidney enlargement due to the obstruction of urine flow into the bladder, caused by a blockage in the ureter ²⁹.

Another NCD for which evidence has been found is obesity. The application of the plant's ethanolic extract resulted in the inhibition of body weight increase and a diminution of the fat layer ^35,38,39. Obesity is a NCD of multifactorial origin, implying that excess weight is associated with the population's lifestyle, shaped by historical, biological, ecological, social, economic, cultural, and political factors ⁶⁷. It is also a risk factor for other NCDs, such as HT and DM ⁶⁸.

Turning to clinical markers influenced positively by A. cordifolia, the lipid profile (total cholesterol, low-intensity lipoprotein [LDL], high-density lipoprotein [HDL], and triglycerides) has shown positive outcomes. Cholesterol is a lipid categorized into LDL and HDL. Elevated serum total cholesterol and LDL levels amplify the risk of cardiovascular disease ^69-71. HDL, conversely, is vital for stabilizing total cholesterol, as it facilitates the transport of cholesterol to the liver, where it is sequestered and eliminated. It also contributes to vascular protection by stimulating nitric oxide release and removing oxidized lipids from LDL ⁶⁹.

Elevated triglyceride levels are identified as a risk factor for cardiovascular disease, HT, and DM. Individuals with hypertri-glyceridemia (high triglyceride levels) are more prone to develop obesity, hepatic steatosis, and ectopic fat deposition ^48,60,72,73. For these clinical markers, the use of A. cordifolia has been shown to decrease serum triglyceride levels ^{24,28,31,32,39}, total cholesterol levels ^{28,31,32,39,43}, and LDL ^31,32,39, in addition to increasing HDL ^31,39. Another clinical marker, uric acid, which is a product of purine metabolism, when elevated, results in hyperuricemia, known as gout ⁷⁴. Gout is a form of inflammatory arthritis, with the most typical clinical presentation being intense acute inflammatory arthritis ⁷⁵. Moreover, there is evidence that uric acid is significantly associated with hypertension, indicating that effective management is crucial in preventing HT ⁷⁴. According to the findings of this scoping review, the plant extract exhibits an anti-hyperuricemic effect and inhibits the enzyme xanthine oxidase ⁴¹, which is responsible for converting xanthine into uric acid and thus directly relates to the quantity and rate of uric acid production ⁷⁶.

Another pathology highlighted in the studies was cataracts, characterized by the opacification of the eye's lens, leading to impaired visual acuity, which can be partial or total. The prevalence of cataracts in diabetic patients is significantly higher-two to five times-compared to the general population ⁷⁷. Additionally, it remains a leading cause of visual impairment among individuals with DM due to increased incidence and progression, as well as earlier occurrence. It is estimated that 20 % of cataract surgeries are conducted on patients with DM ^78,79. Regarding the therapeutic use of A. cordifolia, the plant demonstrated positive effects in an experiment on induced cataracts in goat lenses ²², where the treated lenses exhibited a lesser degree of cataract, along with a reduced concentration of malondialdehyde. Malondialdehyde, a biomarker indicative of oxidative stress, is closely linked to the development of cataracts; the higher its level, the greater the ocular lens turbidity and the cataract severity. The level reduction is presumably due to the extract's high antioxidant content ²².

After reviewing all the articles and learning about the benefits of A. cordifolia and its therapeutic potential, it is evident the plant holds promise for the production of herbal medicine. It is critical to acknowledge that scientific research has been a pivotal factor driving the increased interest in herbal medicine. There remains a need to enhance awareness about the vast biodiversity of medicinal plants in Brazil and how to access them for both the public and professionals who can offer guidance on their use ⁸⁰.

Health professionals, especially nurses, are at the forefront of recognizing PICS and play a significant role in fostering the ex change and development of new knowledge regarding medicinal plants. Nevertheless, the lack of awareness about PICS and the absence of a scientific basis for these practices are barriers to providing safe care ⁸¹. Hence, professionals must possess scientific knowledge about medicinal plants, such as A. cordifolia, and encourage ongoing scientific research into their properties, effects, and safe usage to integrate them into future care practices ⁸⁰.

Conclusions

This scoping review has facilitated the identification and mapping of evidence regarding the therapeutic properties of Anredera cordifolia in treating chronic non-communicable diseases. The compiled studies suggest that the plant may effectively treat DM, HT, CKD, obesity, and cataracts. Additionally, it has demonstrated the potential for controlling triglycerides, cholesterol, and uric acid levels.

The primary attributes identified include its hypoglycemic effects, antihypertensive activities, and ability to lower total cholesterol and triglyceride levels. It is also worth noting that Anredera cordifolia has been found to have healing properties for diabetic wounds, reduce serum creatinine levels, prevent body weight gain, and exhibit positive effects on factors directly influencing CNDs. Therefore, our findings contribute to advancing research on the therapeutic benefits of Anredera cordifolia, particularly highlighted by the urgency for further research in different geographical locations and by various researchers to validate the published research data.

Emphasizing and incorporating traditional knowledge into new research is crucial. Given the significance of medicinal plants and the positive impacts of Anredera cordifolia and its potential as a therapeutic resource in healthcare practice, further investigation in the field of nursing is suggested. This approach aims to provide a scientific foundation and support for the safe use of medicinal plants in healthcare settings.