Psidium guajava L.: A Systematic Review of the Multifaceted Health Benefits and Economic Importance

ABSTRACT The lifestyle changes observed in recent years are related to the increase in the chronic diseases that have become the main causes of mortality and increased expenditure on systems worldwide. Psidium guajava L. (guava) has several medicinal properties, e.g., antioxidant, anti-inflammatory, and antimicrobial activities, which could be useful for the prevention and treatment of diabetes, cardiovascular diseases, and cancer. This study aimed to review the effects of P. guajava on human health and evaluate the commercial importance of the fruit. PubMed, EMBASE, and COCHRANE databases were searched, and PRISMA guidelines were followed. Studies have reported that the bioactive phytochemicals of P. guajava can treat respiratory disorders, gastroenteritis, diarrhea and dysentery, wounds, ulcers, rheumatic pain, toothache, anorexia, cholera, laryngitis, and skin disorders. Therefore, the use of P. guajava contributes to reducing the risk of or treati3ng several chronic diseases. It is also important for the economy of several countries that produce the fruit. It is noteworthy that this plant is safe for consumption since in vivo tests did not show toxicity, and mutagenicity, in addition to the low potential for drug interactions. The by-products of the fruit (seeds and skin) show future application in the food and cosmetic industries.


Introduction
Ultra-processed foods have been gaining popularity in recent decades, as they are ready-toeat, affordable and hyperpalatable food products, in addition to being energy-dense, rich in refined carbohydrates, saturated fats, salt, low in dietary fiber and vitamins, and go through various industrial processes. However, consuming these foods may lead to an increase in noncommunicable chronic diseases (dyslipidemia, obesity, hypertension, metabolic syndrome, insulin resistance, and cancer), which are the main causes of mortality in the world and are related to increased costs in health care system. [1][2][3] In addition to this type of food quality, other lifestyle factors, such as smoking, physical inactivity, alcohol intake, and increased body weight, also directly influence human life expectancy and the incidence of chronic diseases. [4,5]

Focused question
The focused question that was used for this review was: what are the effects of P. guajava on human health?

Language
We used only studies in English.

Databases
For this review, we consulted the following databases: PubMed, EMBASE, and COCHRANE. The mesh terms were P. guajava or guava and health or glycemia or diabetes or hypertension or dyslipidemia or obesity or cardiovascular diseases. These mesh terms helped the identification of randomized clinical trials (RCTs) that reported the use of P. guajava on human health. The search followed Preferred Reporting Items for a Systematic Review and Meta-Analysis (PRISMA) guidelines [18] (Fig. 2).

Study selection
In this systematic review, we used Randomized Clinical Trials (RCTs) that investigated the effects of P. guajava or its derivatives on human health. The inclusion criteria were double-blind, RCTs, and placebo-controlled studies. Only full texts were included. The exclusion criteria were in vitro or animal  [18] model studies, clinical trials that used associations of different herb formulations, reviews, studies performed in other languages than English, case reports, editorials, and posters. Reviews were used only for the discussion section.

Data extraction
We do not restrict the time period for searching RCTs. The included clinical trials are shown in Table 2.

Quality assessment
The evaluation of the presence of risk of bias in the RCTs (detection, selection of the study, and reporting biases) was evaluated according to The Cochrane Handbook for Systematic Reviews of Interventions was used to perform this quality assessment. [28] Results and discussion The results of this systematic review ( Table 2) showed that nine clinical trials met the inclusion criteria. Table 3 shows the evaluation of the presence of bias in the included studies. These clinical trials used P. guajava in the form of extracts or formulations administered orally. Altogether, the studies included 478 volunteers (224 men and 192 women), whose age ranged (between 18 and 70 years, only two studies were carried out with children aged 8 to 10 years) [24] and aged 6 to 9 years. [26] The included studies were carried out in India (two studies), [19,24] Thailand (two studies), [21,25] Mexico (two studies), [26,27] Indonesia (one study), [22] Austria (one study) [20] and in Japan (one study). [23] The included studies were performed according to the design: double-blind, randomized, placebo-controlled; parallelized, randomized clinical study; randomized, single-blind placebo-controlled; parallel-group, randomized, double-blind, and placebo-controlled trial and open-label. Three studies used P. guajava-based mouthwash. [19,22,24] Three studies used P. guajava juice [20,25,26] for the prevention of insulin resistance (IR) (increased postprandial glucose response), as well as favoring cardiovascular health and treating anemia.
A study was conducted with P. guajava-based toners [21] to treat acne and, consequently, the minimization of pores due to the pharmacological profiles of the tannins present in the fruit (reduces the oiliness of the forehead and nose). Finally, two studies were performed with capsules- [23,27] containing P. guajava leaf extract to investigate the preventive effect on the symptoms of osteoarthritis (relief of pain in the knees due to the inhibition of cartilage degeneration and inflammation), and reduction of abdominal pain and cramps in patients with gastrointestinal problems.
Among the nine clinical trials included, none reported serious adverse effects regarding using the plant P. guajava.
Bioactive constituents of P. guajava P. guajava, popularly known as guava, is also called "the apple of the tropics" or "poor man's fruit", as it thrives in various soils, propagates easily, and bears fruit relatively quickly. Guava is the only fruit of the Myrtaceae family with significant commercial relevance and is native to tropical America (southern Mexico to South America, tropical and subtropical regions). It is a small tree that, in addition to being a food source, is also an alternative to medicine due to its various herbal properties. Various studies have shown that guava possesses excellent antioxidant activity due to its high content of ascorbic acid, in addition to having the highest natural concentrations of folic acid, niacin, pyridoxine, and dietary fiber. [8,29]  Guava leaf extract mouthwash showed a reduction in gingival inflammation, reduction in GI and CFU scores, and, consequently, improvement in gingival health. [19] Salzburgo, Áustria Double-blind, parallelized, randomized clinical study with 31 young, healthy adults (20 ♀ and 11 ♂), aged between 19-29y.
Volunteers performed OGTT, in which the control group received a glucose solution (75 g), and the intervention group received a glucose solution with guava juice extract (2.5 mL) prepared by supercritical CO2 extraction. Blood was collected before and up to two hours after glucose consumption to quantify blood glucose and insulin levels.
Consumption of guava fruit extract resulted in a significantly reduced increase in postprandial glucose response over the basal fasting plasma glucose levels after 30 min and 90 min. Besides that, the inhibiting intestinal glucose resorption, possibly in combination with reduced insulin secretion. [20] Thailand Randomized single-blind placebo-controlled. 21 Thai volunteers (17 ♀ and 4 ♂) aged between 20-35y.
The volunteers were requested to apply 5 drops of the guava or base toners twice (morning and evening) onto either side of their faces. This split-face procedure was undertaken for intraindividual comparative trials. The volunteers were asked to clean their faces following the same cleansing practice using the assigned product/28 days (monitoring on days 7, 14, and 28).
The toners were stable with none of the skin irritation. Guava toner significantly reduced the oiliness of the forehead and nose better than the base toner. [21] Bandung, West Java, Indonesia Single-blind, randomized controlled trial. It contains 48 participants (29 ♀ and 19 ♂) aged between 18-22y.
Participants were distributed to one of 3 groups (n = 16): supplemented daily with either 200 g guava, 200 mg synthetic vitamin C, or water (control-group). The study included a 14-day preexperimental period with oral hygiene instructions, scaling, prophylaxis, and supplementation. At baseline, Day 7 and Day 14 of experimental gingivitis, PII, and GI were surveyed.
The group supplemented with guava developed significantly less plaque compared to the control group. In addition, the increase in GI in the guava and vitamin C groups was significantly lower than the increase in the control group. [22] (Continued) 45-70y and the main inclusion criterion was a high score on the JKOM.
The subjects were assigned to guava group (1 g of guava leaves capsules) or placebo/ 3xd/ 12 w. Blood samples were evaluated at weeks 0 and 12. Adherence to the treatment was evaluated based on the intake recorded in the diary.
The consumption of guava leaf alleviated pain in the knees through its joint effect (inhibition of cartilage degeneration and inflammation), that is, the "pain and stiffness" score and VAS in the guava group were significantly lower compared tp the group placebo. [23] India The study was randomized, contains 40 participants (14 ♀ and 26 ♂); 8-10y.
After 48 hours and at 7 days, the mean CFU/mL in Distilled Water was significantly higher than Guava mouthwash followed by Pomegranate mouthwash and Grape mouthwash. A significant reduction in the CFU/mL was seen with the use of Psidium guajava mouthwash at the end of 7-day use. [24] Thailand Open-label, randomized block design with 30 healthy volunteers (20 ♀ and 10 ♂); 20 -45y, BMI of 18-27 kg/ m2, and signed informed consent.
Three groups were assigned (n = 10), in which they ingested 500 mL of YBR juice, guava fruit juice (GF) and water. Participants were instructed to stop taking certain medications or food supplements for 14 days before the study. The participants were fasted overnight or at least 12 hours before the studying day.
After ingestion of YBR and GF juices, collagen-induced in vitro platelet aggregation was significantly attenuated compared to the control group; there was a decrease in blood pressure. GF juice affected all cardiovascular variables measured (heart rate, systolic and diastolic blood pressure). [25] Tarahumara
The children were allocated to receive 300 mL of natural guava juice (n = 50), with 200 mg of AA or placebo (n = 45) (guava-flavored juice free of AA) with the main meal (5 d/w)/10 w Information about dietary intake was collected at weeks 3, 5, and 7.
The guava juice group, used as a source of AA, presented better and higher results for Hb and PF than the placebo group among children with iron deficiency. [26] Mexico Randomized, double-blinded study performed with 100 adult patients (61 ♀ and 39 ♂); 20-59y suffering from a non-complicated acute diarrhea disease (AAD).
Capsules with 500 mg of QG-5 † were administered every 8 h/ 3 d to the experimental group (n = 50), and control (n = 50) received placebo capsules. Oral rehydration therapy was indicated in all patients according to conventional procedures followed in the medical institution for treatment of ADD.
The use of HQ-5 † in patients with ADD had a decrease in abdominal pain and cramps. [27] AA: ascorbic acid; ADD: acute diarrheic disease BMI: body mass index; CHX: Chlorhexidine; GI: gingival index; GF: guava fruit; Hb: hemoglobin; ICDSs: Integrated Child Development Services; JKOM: Japanese Knee Osteoarthritis Measure; OGTT: oral glucose tolerance test; PF: plasmatic ferritin; PII: plaque index; CFU: colony forming unit; VAS: visual analogue scale; YBR: Yam bean root.  [19] yes no yes yes yes yes yes no yes yes [20] yes yes yes yes yes yes yes yes yes no [21] yes no yes no NR yes yes yes NR no [22] yes no no no yes yes yes yes no no [23] yes no yes yes yes yes yes yes NR yes [24] yes no yes no yes yes yes yes NR no [25] yes no no no yes yes yes yes NR no [26] yes no yes no yes yes yes no yes yes [27] yes no yes yes NR yes yes yes nr no NR: Not reported.

Effects of P. guajava on human health
Guava exerts antioxidant properties, principally due to its abundance of bioactive compounds. It is known that the presence of reactive oxygen species (ROS) and free radicals causes damage to the cells characterized by oxidative injury, which represents oxidative stress. The production of oxidative molecules, such as free radicals, occurs all-time in the human organism. Moreover, metabolism of drugs and other endogenous chemicals (adrenalin and noradrenalin) can contribute to the production of oxidation-related molecules. Furthermore, it is also known that oxidative stress is an essential component of various diseases, such as neurodegenerative and metabolic diseases (such as diabetes), in addition to contributing to inflammatory and autoimmune pathologies (e.g., rheumatoid arthritis, atherosclerosis, and cancer). The oxidative stress that causes cell deaths and tissue injuries is also related to the aging process. The guava bioactive compounds that exert antioxidant activities are kaempferol, ferulic acid, caffeic acid, quercetin, guavin B, epicatechin, ascorbic acid, and β-carotene (Table 1). Antioxidants exhibit health effects principally by protecting the organism against the ROS and reactive nitrogen species that trigger lipid peroxidation, protein damage, and DNA alterations characterized by strand breaking. In the P. guajava leaves, there are large amounts of different natural phenolic bioactive antioxidant compounds. Besides that, the guava fruit also contains antioxidant phytoconstituents, such as vitamin C and polyphenols that diminish the emergence of degenerative inflammatory diseases, brain dysfunctions, diabetes, cancer, and heart diseases. The antioxidant activity of guava fruit is known to delay the aging process. [10,34,39,[62][63][64][65] Fig. 3 summarizes the antioxidant effects of guava.
P. guajava has several pharmacological properties. The fruit can produce six times more ascorbic acid than strawberries and five times more than kiwi fruit or oranges, making it one of the few foods that contain this vitamin C with high content and at a low cost. As mentioned above, the benefits of this plant are varied (dietary fiber, vitamins A and B2, and minerals). Guava has great economic and commercial relevance, as it is a cheap fruit and can be easily consumed in meals as flaky or dried fruit, jelly, antioxidant additives, and juice. [8,26,29] Several studies report the use of the fruit in gastrointestinal and respiratory disorders as promoting anti-inflammatory actions, in gastroenteritis, diarrhea, and dysentery. In contrast, the leaves are used in wounds, ulcers, rheumatic pain, and chewed for toothache relief. In addition, the leaves and fruit are also used for anorexia, cholera, gastric failure, inflamed mucous membranes, laryngitis, skin problems, sore throat, ulcers, and vaginal discharge. [10,34] Cancer is a human complex and progressive disease that is caused principally by the accumulation of multiple genetic mutations. The use of P. guajava can be a natural alternative to prevent growth and metastasis of the cancerous cells, principally due to its antioxidant activities, such as free radical scavenging. Its antioxidant and anti-inflammatory properties have been associated with much more anticancer properties, such as regulations of gene expressions and modulations of DNA damage repairments, apoptosis, and cell proliferation, mainly by the modulations of cellular signaling pathways. Guava leaves showed anticancer activity against nine human cancer lines: K562 (leukemia), MCF7 (breast), NCI/ADR-RES (resistant ovarian cancer), NCI-H460 (lung), UACC-62 (melanoma), PC-3 (prostate), HT-29 (colon), OCARV-3 (ovarian) and 786-0 (kidney). The active compounds of the plant, in which there are physicochemical properties similar to estradiol and tamoxifen. Guajadial (meroterpenoid) also has shown anticancer potential. It has a mechanism of action similar to tamoxifen, that has antiproliferative and antiestrogenic activities. [10,16,34,39,[75][76][77][78]  Guava is widely used to treat diabetes, obesity, and hypertension. Because it has high levels of triterpenoids in the plant leaves, it is possible to reduce the appearance of diabetic peripheral neuropathy in rats, improving insulin resistance (IR) in adipocytes. Corosolic acid (higher leaf triterpenoid) is a potent inhibitor of α-glucosidase, which delays the breakdown of carbohydrates and reduces the postprandial blood glucose surge (beneficial for the treatment of Diabetes mellitus (DM). Ethanol leaf extract also has an antidiabetic and protective effect on altered glucose metabolism, in which it reduces blood glucose levels of HbA1c and increases plasma insulin levels. [79,80] The use of aqueous extract from the leaf of this plant has cardioprotective effects against myocardial ischemia/reperfusion injury. Quercetin maintains the effective functioning of the immune system due to its antioxidant properties. The leaf extract can significantly prevent lipolysis (LPS) induced by nitric oxide and prostaglandin E2. [10,19] In addition to the effects described above, P. guajava can help clean teeth through the use of guava sticks, as it has the presence of bioactive compounds (saponins, tannins, flavonoids, and alkaloids). For swelling, it is recommended to use the guava root/peel as a mouthwash. A decoction of the leaves as a gargle is suggested for swollen gums, ulceration, and bleeding problems. [24,40] Nayak et al., [19] Amaliya et al., [22] and Singla et al. [24] showed that the use of guava leaf mouthwash could be an herbal alternative to maintain a healthy gum (antimicrobial property) and the ingestion of 200 g of guava/day has a preventive effect on the development of experimental gingivitis, as well as the fruit extract (mouthwash), showed anti-streptococcal results, being, in pediatrics, a good alternative to combat antimicrobial activities (in contrast to the conventional use of ethanol extract).
König et al. [20] showed that the development of food supplements or functional foods containing fruit extract seems promising for patients with diabetes and the prevention of resistance to insulin action. For acne treatment, Pongsakornpaisan et al. [21] encourage the use of guava toner due to the pharmacological profiles of tannins. A study performed by Kakuo et al. [23] showed that continuous ingestion of P. guajava leaf extract is effective for knee pain, suggesting a preventive effect against symptoms of osteoarthritis.
Thaptimthong et al. [25] demonstrated that the fruit juice promotes cardiovascular health, in which it reduces systolic blood pressure, diastolic blood pressure, and heart rate by inhibiting platelets and lowering blood pressure. Monárrez-Espino et al. [26] obtained an improvement in plasma hemoglobin and ferritin results among children with iron deficiency, in which the juice helps in the treatment of anemia. Furthermore, Lozoya et al. [27] obtained a reduction of abdominal pain and cramps in patients with gastrointestinal problems, consuming capsules with 500 mg of HQ-5.
Recently, Dewa et al. [81] evaluated the effects of red guava fruit extract on the damaged pulmonary tissue of rats that were exposed to cigarette smoke. The results showed that the extract restored the damaged alveolar pulmonary tissue of the rats. These all are new conclusions of using the guava plant that can prospect new research in human health, which opens new areas of study for guava in human life.
In summary, the use of P. guajava is beneficial to human health in several aspects due to its vast availability of bioactive compounds.

Effects on diabetes
Diabetes corresponds to a metabolic state of hyperglycemia being defined by two different forms, type 1 and type 2 diabetes mellitus (T1DM and T2DM, respectively). It is estimated that 1 in every 11 adults globally has DM, a number that corresponds in 90% to the T2DM presence. The number of individuals affected by T2DM in the world is increasing every day, confirming that this metabolic disorder is one of the most common. T2DM represents a combination of primary factors, such as insulin resistance and insulin deficiency, leading to hyperglycemia. The risk factors for developing T2DM are represented by overweight, obesity, sedentarism, unhealthy diet, genetic predisposition, gut microbiome dysbiosis, epigenetic factors, and mitochondrial dysregulations, insofar as obesity plays the major role. T2DM associates with increased atherosclerosis development and other CVD and cardiovascular outcomes. Diet and lifestyle interventions are effective attitudes to prevent this metabolic disease.
Added to that, not only the T2DM but the pre-diabetes state are all features that compose the diagnosis of metabolic syndrome (MS), which is a complex condition that associates with high blood glucose. People affected by MS are at higher risk of developing cardiovascular diseases. [82][83][84][85][86] P. guajava can be used to treat diabetic patients essentially due to its properties in reducing blood glucose levels. This plant has several bioactive compounds that present antidiabetic effects, such as quercetin (which is encountered principally in the fruit and leaf flowers), epicatechin (encountered in the fruit), and kaempferol (encountered in the leaves, leaf flowers, and in the fruit). The regular consumption of guava fruit positively affects the regulations of blood glucose, improving the insulin sensitivity of the tissues and, therefore, reducing insulin resistance. A study of Jayachandran et al. [87] evaluated the effects of P. guajava leaves extract on the diabetes status of streptozotocin-induced rats and showed that the treatment decreased the plasma and skeletal muscle lipids peroxidation markers, increased the antioxidant properties, and improved insulin signaling by regulating the insulin genes of the skeletal muscles, leading to maintenance of the blood homeostasis principally due to the guava properties on alleviating oxidative stress, in addition to certainly regulating the insulin genes. Another study of Jiao et al. [88] demonstrated that guava fruit polysaccharides can protect the pancreas and the liver of diabetic rats, in addition to having antihyperglycemic and antihyperlipidemic effects. These guava fruit polysaccharides named GP-1, GP-2, GP-3, and GP-4 were related to upregulations of various genes expressions, showing actions on fighting against T2DM. In another study, Jayachandran et al. [87] demonstrated that the use of guava leaf extract in streptozotocin-induced diabetic rats was related to diminishes hyperglycemia, and prevent pancreatic β-cells death, could inhibit inflammation (principally due to the regulation of NF-kB expression), and could control oxidative stress. Yang et al. [89] used guava leaf extract to attenuate the insulin resistance of diabetic rats models principally due to the actions of the extract on activating phosphoinositide 3-kinase/protein kinse B (PI3K)/Akt) signaling pathway. It is known that insulin resistance strongly associates with the progression of the metabolic disease characterized by T2DM and the effects of guava leaf extract on attenuating insulin resistance can correspond to an important antidiabetic effect of the plant. Farinazzi et al. [90] demonstrated that the use of guava pulp juice and food supplemented with guava seeds decreased glycemia of Wistar rats. Vinayagam et al. [91] also showed the effects of guava leaf extracts on diabetic rats to improve the glucose metabolism and the lipid profile, inhibiting hepatic gluconeogenesis and increasing glycogen synthesis principally due to the guava's actions on activating PI3K/Akt signaling pathway of AMPK phosphorylation in the liver cells.
One parallelized, randomized, double-blind clinical study conducted by König et al. [20] with 31 young and healthy subjects from nineteen to twenty-nine years old (twenty women and eleven men) in Austria demonstrated that the consumption of the extract of guava fruit associates with significant reductions in the increase of postprandial glucose response. Added to that, the authors suggested that the guava fruit extract used in the trial, which was prepared by supercritical CO 2 extraction, could inhibit the intestinal glucose resorption, combining with reduced insulin secretion. [20] Fig. 4 shows various effects of guava on diabetes.

Effects on hypertension, hyperlipidemia, and cardiovascular diseases
Cardiovascular diseases (CVD) are disorders of the heart and the blood vessels. These are the main cause of deaths in western countries, principally due to the increase in life expectance and the difficulty of making governments and populations adhere to the prevention actions. CVD cause elevated morbidity and mortality among patients and is an important cause of disabilities and loss of productivity. CVD associate with risk factors, such as age, gender, genetic factors, family history, smoking status, hypertension, sedentarism, unhealthy diet, obesity, psychological stress, and dyslipidemia. Frequently asymptomatic for a long time, the CVD are chronic and related to gradual evolvement. The first symptoms of the CVD affections can emerge only when the advanced cardiovascular condition is installed and can be directly death. [92,93] Hypertension is considered to be the most important modifiable risk factor to diminish morbidity and mortality among the world's individuals, principally when these people are affected by CVD. P. guajava and its extracts exert hypotensive effects and diminish the risk of CVD and cardiovascular outcomes, in addition to cerebrovascular outcomes, such as heart attacks, strokes, and dementia. Hypertension is also a component of the MS diagnosis. Leaf extracts of guava were used in many different animal models to evaluate the natural actions of guava on decreasing blood pressure. Guava fruit has great amounts of potassium, ions that decrease the influences of sodium in regulating blood pressure. It is known that aqueous and ethanolic extracts of guava leaves can also have effects on inhibiting intracellular calcium release, which can contribute to hypotensive actions. Other studies suggested that a polyphenolic-rich extract of guava leaves could effectively work inhibiting the activities of the angiotensin-converting enzyme (ACE) while acting to attenuate the oxidative stress associated with the hypertensive organism. Dahl salt-sensitive rats were used to investigate the hypotensive effects of an aqueous leaf extract of P. guajava. The results showed that the acute intravenous administration of the extract decreased the systemic arterial blood pressure and heart rates of the animals significantly in a dose-dependent manner. [10,34,39,[94][95][96][97][98][99][100][101][102] Dyslipidemia has a relevant function in deteriorating cardiovascular health, principally when atherosclerosis gets into the equation. The atheroma formation leads to inflammation of the arterial vessels intima layers, and this process increases the accumulation of oxidized lipids in the arterial walls. Atherosclerosis is the basic pathophysiological pathway to coronary artery disease and peripheral artery disease. Low-density lipoproteins cholesterol (LDL-c) and apolipoprotein B (apo-B) are the main transporters of cholesterol and are the principal particles to initiate and progress atheroma formation. P. guajava can exert hypolipidemic effects. Its extracts can also increase the activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase help dimmish oxidative stress and, therefore, lipid peroxidation. Experimentally induced dyslipidemic hamsters were used to evaluate the effects of lycopene-rich extract from red guava on decreasing triglycerides levels in plasma and on improving the presence of oxidative stress biomarkers. Guava fleshes and seeds were related to present fibers as an important nutrient that helps to keep cholesterol, LDL-c, and triglycerides levels at normal levels. In rabbits fed with a high-cholesterol diet, an intervention with an aqueous extract of guava leaf was associated with decreases in plasma-cholesterol levels and LDL-c levels, in addition to an increase in highdensity lipoproteins cholesterol (HDL-c) levels. Farinazzi et al. [90] conducted an animal study to evaluate the effects of P. guajava on the metabolic profile of Wistar rats. In comparison with the placebo group, the biochemical results of the study demonstrated that the treatment supplementations significantly improved the lipidemic variables with guava pulp juice and by the rat food supplemented with guava seeds: these interventions diminished triglycerides and total cholesterol levels, in addition to augmented HDL-c levels. These hypolipidemic effects of guava are associated with cardiovascular protection. [10,34,39,[103][104][105][106][107][108][109][110][111] Besides the cardioprotective effects on reducing hypertension, blood lipids, diabetes, and, principally, oxidative stress, guava can exhibit other effects on cardiovascular system. Its extract was related to the improvement of myocardial ischemia-reperfusion injury in isolated rat hearts. Guava can maintain the levels of endogenous antioxidants and maintain the antioxidant status of the myocardium and the hemodynamic parameters in good standards. The hypoglycemic effects of the guava leaf extracts could be related to improved endothelial function in a mice model with diet-induced obesity. In another study, the administration of an ethyl acetate fraction of guava leaves was related with ameliorations of diabetes-associated myocardial modifications, principally due to its actions on decreasing the concentrations of advanced glycation end products in the heart of diabetes-induced rat models, in addition to protecting the animals' myocardium against tissue alterations. Added to that, budding guava leaves can present anticoagulant activities in plasma, reducing thrombin clotting time and inhibiting antithrombin III actions. [10,34,39,[112][113][114][115][116] Fig. 5 shows some effects of guava on CVD.

Effects against different human cancers
Cancer is one of the most important causes of death worldwide, and this parameter is present in countries of all income levels. This disease comprehends a complex alteration system of cells proliferation and death, which leads to increases in cells multiplication or decreases in cells death, or both. Therefore, it is known that carcinogenic events result from disturbed cell function. The molecular pathology study for cancer cases is growing; however, the incidence of cancer attempts to rise rapidly nowadays. The aging process and the inadequate lifestyle of the population are all factors behind the recent explosion of cancer cases. Research affirms that cancer is a human disease characterized principally by genetic mutations, and these mutations can be inherited, such as in familiar tumor syndromes, or by accumulated somatic genetic alterations. In family tumor syndromes, mutations are considered to be germline, and the other somatic mutations accumulate during the progression of the cancer case in the human body. Genetic instability is the main related cause, and genetic and epigenetic changes can be encountered in human cancer cells. The risk factors involved in the pathogenesis of cancer are mainly lifestyle-associated: tobacco use, sedentarism, obesity, alcohol intake, use of a diet that contains carcinogenic, and many others. Besides that, there are cancer risk factors that are considered physical: exposure to electromagnetic, ultraviolet, and ionizing radiations are these factors involved in the genesis of cancers. According to the World Health Organization, 35% of all global deaths caused by cancer are derived from modifiable risk factors. [117][118][119][120][121] Previous review by Jamieson et al. [16] critically evaluated anticancer potential of P. guajava based on pre-clinical and clinical studies. P. guajava exerts anticancer and antitumor activities principally due to the actions of specific bioactive compounds contained in different parts of the plant (see Table 1 for all these bioactive molecules of guava). Correa et al. [118] evaluated the antiproliferative effects of different guava fruit extracts against MDA-MB-435 and MCF-7 lines of human breast cancer cells. The results suggested that guava pulp exerts antiproliferative effects on the breast adenocarcinoma cells. The viability of the cancer cells was diminished, principally due to the effects of the guava pulp on regulating the cell cycle and on controlling the tumor progression via apoptosis induction. Polinati et al. [122] demonstrated the effects of lycopene derived from guava products against breast cancer MCF-7 cells line. The effects of the lycopene on cytotoxicity, cell cycle, and apoptosis against the MCF-7 cells were analyzed. The results showed that the treatment with lycopene influenced the cells' cycles and increased apoptotic cells ratios compared to the untreated cells of the study. Lin et al. [123] demonstrated the effects of guava seed polysaccharide fraction 3 against MCF-7 breast cancer cells growth. The polysaccharide derived from the guava seeds inhibited the growth of the cells principally by increasing Bax/Bcl-2 (Bcl-2 associated protein X/β-cell lymphoma protein 2) ratio or Fas mRNA expression levels. Therefore, this compound of guava acts directly or indirectly on the modulation of immune cells' cytokine secretion profiles, being denominated a potent anticarcinogenic agent. Lin et al. [124] also demonstrated the pharmacological effects of guava seed polysaccharide fraction 3 against PC-3 prostate cancer cells. The study's results affirmed that the polysaccharide corresponds to decreases in the PC-3 cell growth principally through the induction of apoptosis. Wu et al. [125] discussed the inhibitory effects that kaempferol exerts against the development of cancerous bladder cells. The antiproliferative kaempferol's modulatory actions against these bladder cancer cells are related principally due to induced apoptosis accompanied by S phase arrest. This arrest associates with the activation of p53 signal pathway. The authors also mentioned the antioxidant effects on the bladder cancer cells that the kaempferol exerted. Zhu et al. [126] associated two unnamed compounds of guava (one of them was a benzophenone newly discovered by the researchers) with inhibitions of growth and colony formation of HCT116 cells of human colon cancer line. The results were primarily related to the effects of the compounds on inducing apoptosis of the cells. Additionally, the compounds modulated programmed cells death, in addition to multiple signaling proteins involved in the proliferation's regulation of the cells. Figure 6 shows various effects of guava on cancer.

Effects against different pathological organisms
P. guajava extracts in combination with fluconazole were associated with anticandida effects, principally due to the guava's actions on potentializing the medicament's activities. The antifungal actions of the extracts may be associated with the higher levels of flavonoids and phenolic bioactive compounds that these extracts presented. The results of this study are relevant principally in the fight against the multiple resistance mechanisms that the genus Candida has gained along the time. In another study, a P. guajava alcoholic leaf extract was used to demonstrate the antidiarrheal effects of guava against Escherichia coli induced infectious diarrhea. This study evaluated that quercetin is the most important bioactive compound of the guava extract used in the study to affect infectious diarrhea. Inhibition of intestinal secretion, inflammatory expression (pro-inflammatory IL-1β and TNF-α cytokines expressions), and decreased nitric oxide production (NO) are the related-antidiarrhea activities of the extract. The results also suggest that there was a positive reactivation of the Na + /K-ATPase activity against infectious diarrhea. The extract used in this study also restored altered antioxidant levels. Quercetin isolated from P. guajava was also related in another study to inhibit secreted extracellular protein A (SepA) protease activity in treating infectious diarrhea caused by Shigella flexneri. Guava also associates with anthelmintic effects, principally due to its bioactive hydrosoluble compounds. These compounds were associated with actions of blocking the motility of a levamisole-resistant Caenorhabditis elegans strain. The guava compounds inhibited the motility of the pathogenic organism by a different way of the mechanism of action promoted by the drug levamisole. Different water extracts of P. guajava were associated with antiinfective effects against various types of bacteria, such as Streptococcus aureus and Pseudomonas aeruginosa, principally due to the actions of guava on attenuating the virulence of the bacteria. [127][128][129][130][131] Industrial applications of P. guajava Among 3,500 fleshy fruit plants of the Myrtaceae family, guava is the most economically and commercially important, as it is a cheap fruit to grow and buy. Being widely produced in North and South America (Mexico and Brazil), India, and Thailand (average annual production of 6.8 million tons since 2017), guava is easily consumed in meals as dried or bottled fruit, jelly, antioxidant additives, and juices. Its consumption is diverse, being generally eaten raw (both green and ripe) or cooked (cakes, puddings, sauce, ice cream, butter, marmalade, chutney, and other products and pies). Regarding commercially processed products, it can be used in jellies, jam, cream, cheese, puree, juice, powder, and nectar. [29,132] India is the world's largest producer of guava, followed by Pakistan, but the fruit has a successful economic potential in more than 50 countries. The fruit is widely planted in the Southeast (concentrating around 44.3% of the national production) and Northeast of Brazil (with an annual production of approximately 460 thousand tons), being considered one of the favorite fruits for industrialization for the production of sweet guava, jam, and juice. Guava production is equivalent to more than 11,000 tons annually in Kenya. However, the commercial value is almost non-existent in this location since there is no variety in the industrial processing of pulp. [133,134] The global production of the fruit is around 40 million tons; however, the productivity of guava in India, for example, does not have the same results since, in addition to possible inadequate management, there are many post-harvest losses (physiological and physical processes due to wilting and mechanical lesions and pathological processes resulting from fungi and bacteria). Besides that, there are no available methods for preserving guava to promote a longer shelf life (modified atmospheric packaging or the use of chemicals, such as calcium chloride, calcium nitrate, and salicylic acids). [31,135,136] The plant can grow and start producing fruit from 2 or 3 years onwards, continuing for 40 to 60 years. The ripening process is fast (average of 3 to 8 days), when its climacteric peak is between days 4 and 5 post-harvest (ripe, green, and harvested fruits) and can be stored from 8 to 12 days on 6th to 14°C. [31,134] In addition to the loss of post-harvest fruit, another problem is the disposal of by-products generated in the food industry since the residues cause ecological problems (proliferation of insects and rodents) and economic (transport to the repository). However, guava residues have high antioxidant potential (rich in compounds that delay oxidation). The husks and seeds of the extract are effective in lipid oxidation, slowing down in processed chicken meat, for example. The seeds have also been reported in studies as flour to contain high protein levels, as in pasta, cookies, and yogurt. [137][138][139] During guava processing, approximately 80 kg of waste per metric ton of fresh fruit is produced (by-products are mostly seeds -100 to 500 seeds per fruit -and husks, which total about 30% of the weight of the fresh fruit processed). Proving this fact, in Malaysia, one of the main producing countries of guava puree, there is a disposal of 25% of guava by-products, and, in Brazil, there is a disposal of more than 70 thousand tons. Although it has high levels of dietary fiber (which could be used, for example, for bowel regulation, prevention of diabetes, CVD, and colon cancer) and carbohydrates (supply of nutrients in the food chain), studies on the health-promoting effects of by-products of guava are still scarce. It is noteworthy that the concentration of bioactive compounds in guava is higher than in cereals and pseudo-cereals (oats, barley, rye, quinoa, amaranth, and chia). [140,141] Studies have shown that antioxidants extracted from guava leaves can be used for incorporation into human and animal food. In addition, studies show that seeds contain about 16% oil (a good source of edible oil, palmitic acid, and stearic acid), 61.4% crude fiber, and 7.6% protein. Besides that, guava seed oil contains appreciable amounts of tocopherols and carotenoids. The fatty acid profile of seed oil shows similarity to some consumed edible oils, showing it can be an alternative source of edible oil for consumption. As it is a rich source of linoleic acid, it can be used to supplement food products deficient in omega-6 essential fatty acids. [141,142] However, although the production and consumption of P. guajava are large, the loss of the fruit during post-harvest and as a form of disposal is large. Proper handling is necessary for harvesting, packaging, transport, storage, processing, and more investments in the use of waste as new enriching sources of food, as guava has 100% importance in economic income for several producers. The alternative use of by-products such as food additives, for example, can generate economic gains for industries, reduce nutritional problems, produce beneficial effects on human health and reduce environmental implications (which generate waste). [134,143] For these reasons, investments are needed in this area of disposal, enabling the cultivation of ecologically sustainable guava.

Use of P. guajava in the cosmetic industry
Guava has been used in many different products formulations in the cosmetic and dermatological industries, principally because of the antioxidant activities. Regularly applications of antioxidants on the skin prevent cell damage due to oxidative stress. The use of natural ingredients in this type of industry is optimum since more industries use a commercial appeal to reduce synthetic ingredients in their formulations. It is known that the use of guava leaf extracts is effective against acne, especially when an inflammatory-development ambiance accompanies this condition. The guava leaf extract is associated with antimicrobial actions. Therefore the use against acne corresponds to an opportunity for treatment. Another study confirms that guava fruit extract can improve the UV-protection efficiency of synthetic filters in sun cream formulations. Added to that, the use of the guava fruit extract supplementation was related to reductions in the use of synthetic components in the UVprotection filters, in addition to reductions in the risk of synthetic agent toxicity and to reductions in the cost of these filters productions. [10,34,[144][145][146][147]

Use of P. guajava in food industry
Guava and its bioactive compounds are related to being successfully used in the food industry, principally due to the antioxidant actions. A natural antioxidant extract of guava leaves was applied in fresh pork sausage. The experiment results showed that the guava leaf extract at 4,000 ppm or greater was responsible for effectively preventing oxidation in the sausages. The results demonstrated that the extract slowed the lipid oxidation process of the fresh pork sausage best at 5,000 to 6,000 ppm of guava leaf extract; however, the guava extract at 4,000 ppm was as effective as the extract at higher concentrations. In addition to that, the extract maintained the desired color of the sausages, which only confirms the antioxidant properties. Another study demonstrated the effects of ethanolic guava leaf extracts using different chlorophyll removal processes in the quality of pacific white shrimp during 12 days of refrigerated storage at 4°C. Ethanolic guava leaf extract without chlorophyll removal and ethanolic guava leaf extracts with chlorophyll removal using sedimentation process or dechlorophyllization using chloroform were evaluated. The results showed that changes in microbial and chemical qualities were lower in the ethanolic guava leaf extract with chlorophyll removal using sedimentation process, in addition to the high effects of this extract on reducing melanosis and quality deterioration. Guava powder was also used as an antioxidant dietary fiber in the production of sheep nuggets. The study found that the powder reduced lipid peroxidation in the cooked nuggets and did not change the sensory characteristics of the product. It is known that the use of natural antioxidants is a special manner to reduce the potential harmful effects to human health of synthetic antioxidants. Lots of different food products can be obtained from the guava plant, especially from the guava fruit. Although the industrial processes can be associated with positive or negative modifications in the activities of the bioactive compounds of guava, the processing industrial methods obtain from guava many eating goods like jam, juice, wine, and chocolates. [10,34,135,144,[148][149][150][151][152] One food industry that appears to be enormously benefited from the guava plant is the probiotic field. Casarotti et al. [153] aimed to characterize the impacts that guava by-products perform on a probiotic fermented product from goat milk, in addition to cereal-based fermented products. As known, the agro-industrial field of guava generates residues that are considered waste by many economic areas. These authors suggested that the use of guava waste created in other industrial processes could be important in the formulation of a milk-derived fermented probiotic beverage. The results of the study were positive, and these open doors to the industrial world add value to residues of many other plants, reducing the environmental impact in nature. Araújo et al. [154] studied the effects of guava processing coproducts on the probiotic Lactobacillus strains that are submitted to freezedrying, in addition to storage. The outcomes of the study showed that the guava processing coproducts could demonstrate protective effects to the Lactobacillus. The bacteria were subjected to prolonged storage under refrigeration and the process occurred in freeze-drying conditions. Guava preserved the efflux activity and the membrane potential of the bacteria, in addition to stabilize the bacteria during the freeze-drying and storage processes. The effects of guava on the bacteria can principally associate with protection against membrane lesions.
Guava and its constituents can be also used in the animal industry. The leaf powder of P. guajava was used to evaluate the effects of this constituent of the guava plant on aspects of the eggs of laying hens. The productivity and the quality of the eggs were inspected by the researchers, and characterizations determined that the addition of the leaf powder of guava in the diet of the hens improved mass conversion, production, and the weight of the laid eggs. The shell thickness and the yolk color were also improved, confirming that the supplemented diet with leaf powder not only associates with ameliorations in the productivity, but with quality aspects of the eggs. The guava leaves were also related in the literature with supplementary feed for fish species, principally due to the immune-stimulatory effects of the leaves of the guava plant in many species. Guava wastes were also used in the feeding of broiler chickens. The inclusion of these constituents of guava promoted to chickens similar performances and carcass yield to that obtained with the normal dietary features, such as corn and soybean meals. Guava agroindustrial waste can also be used to feed the goat. Although the use of guava residues was not associated with amelioration in the feed efficiency of the goats, the use of these guava constituents did not change physicochemical compositions and other quality features of the cheese that was produced from the milk of these animals. Guava was also used to feed post-weaning piglets, especially the guava leaf meal and cooked extract. The use of these guava composts in the diet of the piglets improved the production rates and controlled diarrhea's incidence among the animals. Besides that, the use of the guava substances reduced the use on the post-weaning piglets of growth-promoting antibiotics in their feed diets. In addition, the intervention improved the body weight, the average daily feed intake, the average daily gain, and the feed conversion of the treated piglets. [34,[155][156][157][158]

Use of P. guajava in biotechnological industry
The biotechnological industry corresponds principally to alternative use of the agro-industrial waste products of guava, associating economic valuation to compounds of the plant that are not usually used by the regular industries, such as food and cosmetics industries. In the biotechnological industry, guava presents some alternative functions, which can prospect principally use the plant residues to perform different activities. The guava seeds are residues that are produced in large amounts by primarily the food industry of other guava-producing countries. One of the guava seeds waste applications can be summarized by the production of biofuels, such as biodiesel. Iha et al. [159] extracted and characterized guava oils from residual seeds as biodiesel. Although the oils derived from the guava seeds need to be treated to remove oxygenated and light compounds, the biofuel that derives from the guava seed matches the parameters for the biodiesel specifications in Brazil. Another study of Darmasiwi et al. [160] demonstrated that the guava seed waste from a specific group of guava strains can be fermented and can form an edible biofilm. Guava seeds were also used in research as support to produce tannase (an enzyme used in the biotechnological field) in solid-state fermentation. The biotechnological field also goes beyond the use of residues. Wongsanao et al. [161] searched the thermoregulatory effects of guava leaf extract-menthol toner application. The study proposed that the use of the guava-menthol toner application significantly reduced post-exercise perspiration and not influenced heat dissipation or heart mechanisms. Besides that, the use of some different parts of guava was recently associated with bio-remediation, prospecting the use of guava into nature preservation fields. Principally the guava leaves are involved in the generation of different magnetic nanoparticles that are used to remove methylene blue from water. It was evaluated that modified guava seeds can be also used in the bio-remediation processes to remove fluoride and arsenate composts, as proved by Vargas et al. [162] that investigated modified guava seeds by aluminum (AlCl 3 ) in aqueous solutions. [144,163] Guava has other roles in the biotechnological industry. Ravindranath et al. [164] studied the antimicrobial activity of the guava plant extracts to produce incorporated gelatin beads with gelatin extracted from fish wastes. The P. guajava leaves exert high antimicrobial actions, and the incorporation of the plant leaf in the marine fish gelatin used in the study was associated with the production of gelatin beads by an emulsion cross linking-type method. This production is potentially a good opportunity for the use of guava in other industries, like pharmaceutical and medical.

Future perspectives of the use of P. guajava
P. guajava is a plant of multipurpose uses and applications, principally because this plant and its bioactive compounds are frequently well-tolerated and exert tremendous benefits to human health. Besides the activities of guava that were cited in this paper, much more effects and appliques of the plant can be elucidated, such as the immune-booster actions that guava leaves in different formulations can exert in animal models. Although much can be associated with guava on an essential health basis, other areas use guava plants as raw material and as supplements. [10,34,141] Safety profiles of P. guajava As for toxicity, there is no evidence of potential side effects of the plant extract. However, studies have also reported that toxic effects have been observed when phytochemicals are ingested in excessive amounts. As an example, the sum of repeated administration and high dose of crude extract of methanol from guava peel (prolonged treatment of 28 days with doses of 1,000 mg/kg of body weight) can cause toxicity light on the organs. [19,33,165] Morais-Braga et al. [166] published a review on the toxicity studies with several parts and extracts of P. guajava and showed that this plant is safe for consumption.
Tests performed in vivo regarding mutagenicity and cytotoxicity of the aqueous extract of the guava leaves in bone marrow cells of Wistar rats and in human peripheral blood lymphocytes did not present significant modifications in the cell cycle or the number of chromosomes. The guava aqueous extract and tea prepared with the leaves did not induce toxicity, mutagenicity, or interactions with antidiabetic and antihyperlipidemic drugs. The results showed low potential for drug interactions. [9,167,168] In vivo studies performed in mice and Wistar rats showed that the use of respectively 1,534 ± 69 mg/kg (intraperitoneal) of guava leaves aqueous and 100-500 mg/kg body weight are safe. Acute tests of toxicity with ethanolic extract of the leaves did not produce signs of toxicity in Wistar rats that received doses over 2,000 mg/kg. [169][170][171]

Conclusion
Due to the above discussion, it can be concluded that P. guajava is a plant of multipurpose health activities and economic utilizations. Guava and its bioactive compounds are associated with many different and useful behaviors against chronic diseases, such as diabetes, hypertension, and dyslipidemia. Guava also has effects against chronic degenerative diseases, including human cancers. Guava possesses anti-inflammatory, antimicrobial, hepatoprotective, antiobesity, antidiarrheal effects, and antioxidant effects, corresponding to one of the most important effects of the P. guajava plant's different parts. Besides that, guava contains enormous economic relevance, principally in industrial productions' food and cosmetic fields. However, the prospective economic pertinency of P. guajava residues, mainly agro-industrial wastes, can associate with the highest economic importance of the guava plant. Each day more, the whole world seeks green technologies to substitute the old ones, and the components of guava integrate goods in the food industry, animal feed (principally with guava wastes bioproducts), cosmetic preparations, enzyme productions, and biofuel developments.