Punica granatum as Anticandidal and Anti-HIV Agent: Comparison
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The oral cavity is crucial from diagnosis to adherence to HAART therapy in the HIV/AIDS population; consequently, drugs that can maintain healthy conditions in the oral cavity are necessary for patients with HIV/AIDS. Punica granatum (pomegranate) is a tree that has been employed extensively for centuries in the traditional medicine of ancient cultures for the treatment of a wide range of diseases, including oral and dental diseases. Its potent anticandidal properties have been shown, especially on Candida albicans, the cause of the most common clinical manifestation in HIV patients. 

  • Punica granatum
  • pomegranate
  • HIV
  • Candida

1. Introduction

Oral–dental diseases comprise a major public health problem due to their high prevalence and incidence throughout the world, where the unprivileged population bears the greatest burden. It has been calculated that over 3.5 billion people experience oral diseases through childhood to adolescence, adulthood, and until old age [1,2][1][2]. Close to 90% of the world’s population experiences dental and/or oral disease during their lifetime. Dental and oral mucosa diseases significantly impact socioeconomic aspects in terms of healthcare costs, academic time, and work time [3]. In this manner, the role of oral health in the everyday life of people is crucial for general health and well-being [1], due to the profound effect of pain, problems with eating, chewing, smiling, and missing or damaged teeth. Moreover, poor oral health has been related to chronic diseases such as cancer and diabetes, and particularly to HIV/AIDS [4,5][4][5].
Candida species form part of the normal oral microbiota, however, under conditions of immunosuppression, and especially in HIV/AIDS, an exponential increase in colonization causes oral candidiasis (OC). OC is the most common clinical manifestation in HIV patients, furthering the AIDS transition in both patients treated with Highly Active AntiRetroviral Therapy (HAART) and in untreated patients [6,7][6][7]. Thus, candidiasis is considered an important marker of immune suppression (CD4+ counts < 200/mm3) and also a predictor of progression to AIDS [8,9][8][9]. OC also implies discomfort during eating, limitation in chewing, and consequently a reduction in food intake. Thus, malnutrition can be developed, which is a relevant mortality risk factor in patients with HIV, especially children, because of the weakened immune state [6].
C. albicans is the most common species isolated in oral mucosa, while in oropharyngeal candidiasis, it is C. glabrata followed by C. dubliniensis. C. albicans and C. glabrata are known for their development of resistance to azole antifungals; therefore, the management of OC remains difficult in HIV/AIDS [8]. While a number of antifungal agents are available for the treatment of candidiasis, Fluconazole continues to be the first-line therapy. In consequence, the emergence of antifungal resistance in patients with continual OC or long-term use of antifungals demands alternative and effective antifungal agents [10].
Particularly in HIV/AIDS, the oral cavity represents a baseline in the diagnosis of the disease, in which, as wresearchers previously mentioned, candidiasis is the most important infection; however, another aspect of HIV-related illness comprises the ulcerative and periodontal disorders that are involved in the staging of HIV infection [11]. Furthermore, it is noteworthy that severely compromised oral health in patients with HIV/AIDS showed difficulty in chewing, swallowing, in maintenance of the salivary flow, and in tasting foods. All of these aspects are not only involved in general health and well-being, but also impact negatively the adherence to HAART therapy, since the majority of schemes for HIV treatment involve the oral administration of drugs [11,12][11][12]. Therefore, oral health in HIV/AIDS patients remains fundamental and an integral hallmark of the disease, and drugs that can maintain healthy conditions in the oral cavity are necessary for the HIV/AIDS population.
Despite that HAART therapy has improved the length and quality of life for patients with HIV/AIDS through the reduction in the number of cases of AIDS progression and a diminution in AIDS-related morbidity and mortality, positioning it as a chronic manageable disease [13], recent reports indicate that exposure to HAART therapy may have adverse effects, independent of the HIV stage [14]. These adverse effects cause diseases such as neurological (peripheral neuropathy, dementia), hematological (anemia), metabolic (hyperlipidemia, lipodystrophy), gastrointestinal (gastritis, anorexia, diarrhea), hepatic, and cutaneous [14,15][14][15]. Therefore, the population living with HIV/AIDS requires lifelong treatment with sustained potency, limited or absent toxicity, and reduced cost [15], but also drugs that can exhibit more than one mechanism of action and facilitate adherence to the antiretroviral (ARV) treatment. In this regard, natural products have been providing chemical identities with promising anti-HIV properties for the development of novel drugs during the last decades. Natural-compound-based anti-HIV therapies have become more efficient than HAART, with notoriously fewer or the absence of secondary effects [16] and, in addition, with more than one site of action. Even more so, a dual effect such an anti-HIV and anticandidal would be highly valuable, in that it would also impact adherence to pharmacological treatment.

2. Brief Overview of HIV and Candida spp.

Worldwide, more than 38 million people live with HIV. This fact reveals that the HIV-infection pandemic is far from being controlled and eventually eradicated. Therefore, developing a cure for HIV remains a major global health priority. Globally, HIV infection represents a significant health burden, in which the current anti-HIV treatments are not curative, even though their principal goal is to suppress viral replication until reaching undetectable levels. Other treatment targets block the viral–lymphocyte fusion [21][17]. The target of ART drugs is the structural and enzymatic components of both the virus and the CD4 lymphocyte cells. The first anti-HIV-approved drug was Zidovudine in 1987. From that moment to date, over 39 antiretroviral drugs have been classified based on their pharmacological action and resistance outline in six different categories, as follows: (1) nucleoside analogue reverse transcriptase inhibitors; (2) non-nucleoside reverse transcriptase inhibitors; (3) integrase strand transferase inhibitors; (4) protease inhibitors; (5) fusion inhibitors; and (6) co-receptor antagonists [22][18]. For example, the three replicative HIV enzymes, that is, reverse transcriptase (RT), integrase (IN), and protease (PR), are druggable targets; moreover, RT and IN have been suggested for dual novel inhibitors. Some new approaches such as Designed Multifunctional Ligand (DML) recruits several targets that are the site of action of only one substance or compound. One of the most notorious advantages of these multifunctional ligands as antiretrovirals is based on the viral replication cycle, which can be affected in two or more phases [23][19]. HAART, a multi-target drug scheme, has proven effective in treatment for AIDS. However, despite their efficacy and efficiency, ART drugs face challenges, e.g., toxicity, the development of drug-resistant HIV-1 strains, the expensiveness of the drugs, and the failure to eliminate the provirus in infected cells. Consequently, to achieve pharmacological success, many factors are involved, including the following: correct patient adherence to antiretroviral (ART) treatment; the availability of antiretroviral drugs; distribution of antiretrovirals; the development of HIV-resistant genotypes, among others. Thus, novel anti-HIV-1 drugs that can be effective in treating acquired immunodeficiency syndrome (AIDS) progression are needed [24][20]. In this case, the metabolites of certain plants could be a possible alternative. The oral lesions related to HIV have been widely recognized since the start of the epidemic, and they are considered early clinical signs that may predict the disease progression of patients with AIDS. More than one-third of people living with HIV worldwide present oral manifestations. In developing countries, where the majority of HIV-positive patients reside, oral lesions, specifically oral candidiasis, acquire greater significance. Oral candidiasis is the most frequently found oral manifestation of HIV in several world regions, including in patients with HIV/AIDS undergoing HAART [25][21]. The most frequent oral mucosa disease in people living with AIDS (PLWA) is oral candidiasis, specifically the pseudomembranous clinical variety [26][22]. Therefore, Candida spp. arises as a highly potential pathogenic fungus in patients with HIV and bronchopulmonary diseases [27][23].

3. P. granatum Products That Are Relevant for Oral Diseases

In recent years, an increasing number of reports have recognized that oral health exerts an important effect on the general quality of life. Some chronic and systemic diseases are related to poor oral health, which often worsens these diseases [82][24]. The microorganisms detected in the oral cavity include bacteria, virus, fungi, and protozoa, among which many species of bacteria are innocuous. However, a few of the most common oral diseases that affect humans are caused by these microorganisms, that is, dental caries and periodontitis. In consequence, oral hygiene has relevance in the prevention and treatment of oral infections through the daily use of chemical agents in toothpastes and mouth rinses [83][25]. Nevertheless, oral microbes have developed a considerable increase in clinical resistance to drugs such as antibiotics and antifungals, which have been advantageous through the indiscriminate use of antibiotics and azole drugs. Thus, failure to respond in the current scenario of bacteria and fungus diseases calls for the search for novel antimicrobial and antifungal substances that also have no side effects for oral disease pathogens [84,85][26][27]. As wresearchers noted previously, P. granatum has been widely reported in traditional use for the treatment of dental diseases, and a number of studies concerning the effects on different oral diseases have been published in recent decades, during which a variety of mechanisms of action on bacteria, viruses, and fungi were found. However, P. granatum is different from other plants, not only due its effectiveness and lack of side effects, but also because all parts of the plant can be used for pharmacological effects in oral diseases [86][28].

4. Anti-HIV and Anticandidal Properties of P. granatum

In the current HAART therapy utilized for the treatment of HIV, the initial schemes include a combination of three or more ARV drugs from at least two different HIV drug classes that target different structures and steps of the HIV life cycle [12]. The goal of combination ARV is to contain the HIV viral load in plasma under the limit of detection, and also to re-establish the immune function, mainly by elevation in the number of CD4+ T cells [108][29]. Thus, bioactives that possess more than one target of action or their effects involve the decrease or inhibition of viral replication or the restoration of the immune system, an attractive result because of their potential as anti-HIV drugs. Therefore, P. granatum emerges as an interesting candidate for the future development of anti-HIV drugs due its anti-HIV and anticandidal properties reported in recent years [109][30]. In this manner, the anti-HIV activities of pomegranate have been reported for all organs of the plant and in different steps of the viral cycle of replication. The juice of the pomegranate exhibited inhibitory activity against HIV-1 in experiments that employed CD4+ T cells and CXCR4 as cell receptors. Pomegranate juice was able to block HIV-1 binding to CD4+ T and the CXCR4/CCR5 receptor. In the same investigation, one or more components of pomegranate juice bound strongly or irreversibly to the CD4+ T binding site on HIV-1 envelope glycoprotein gp120 [110][31]. The same reseauthorchers also proposed that a topical microbicide applied vaginally (and possibly rectally) may be used for HIV prevention and that it could potentially be manufactured from pomegranate juice, in that HIV-1 entry inhibitors from pomegranate juice form a complex that successfully adsorbs onto a cornstarch base [111][32]. On the other hand, a screening of hydrolyzed peptides extracted from 111 Asian medicinal plants were tested against the HIV-1 RT. Only three species exhibited a potent anti-HIV-1 RT percentage of inhibition, and among these, in the third highest percentage, peptides extracted from the fruit peel of P. granatum showed 96.48% [112][33]. Another study evaluated the inhibition of the HIV-1 RT and HIV-1-IN enzymes of the ethanolic extract obtained from areas of the non-edible parts (leaves, bark, and fruit peels) of P. granatum. The IC50 values exhibited by all the pomegranate extracts revealed a strong inhibitory activity on HIV-1 RT and HIV-1 IN, with ranges of 0.22–0.85 µg/mL and 0.12–0.5 µg/mL, respectively. The bark extract exerted the highest inhibitory activity on HIV-1 RT, while the highest leaf extract inhibitory activity was exerted on HIV-1-IN. In this same investigation, the compounds detected in the pomegranate extracts were isolated and tested individually against the HIV-1 RT and HIV-1-IN enzymes. In the leaf extract, ellagic acid, flavones, and triterpenoids were identified, while hydrolyzable tannins, such as punicalagin, in addition to ellagic acid, were isolated from the bark and the peel extracts. Punicalagin and ellagic acid exhibited potent inhibition on both HIV-1 replicative enzymes: IC50 values ranged from 0.12–1.4 µM and from 0.065–0.09 µM for the RT and IN inhibition, respectively. In the case of luteolin and apigenin (flavonoids), inhibitory activity was demonstrated on both HIV-1 replicative enzymes (IC50 values ranged from 3.7–22 µM), while luteolin 7-O-glucoside selectively inhibited HIV-1 IN. In the case of betulinic acid, ursolic acid, and oleanolic acid, the inhibitory effect observed was selective for HIV-1 RT [113][34]. The aqueous and methanolic extracts of the pericarp of pomegranate were tested against HIV-1 PR, where they exhibited percentages of inhibition of 25.9 ± 4.2 and 18.0 ± 1.4, respectively [114][35]. However, the aqueous root bark of pomegranate showed 88% of inhibition on HIV-1 PR in a concentration of 250 µg/mL, which can be considered active (>70%) [115][36]. On the other hand, recent investigations established the relationship between antioxidant/phytochemical levels and immunomodulation in animals as well as in humans. Thus, the management of immune diseases such as HIV through targeting oxidative stress or boosting the endogenous levels of antioxidants could represent a benefit to general health and the immune system. In this respect, ellagic acid extracted from P. granatum as one of the major compounds has exhibited to be immunostimulatory in HIV [116][37]. Concerning the anticandidal properties of pomegranate, a number of investigations have demonstrated the effect of pomegranate on different strains of Candida spp., but mainly on C. albicans species. Among these investigations, as follows, wresearchers highlight some examples. The hydroalcoholic extract of the fruit peel of pomegranate exhibited high activity against C. albicans and C. parapsilosis, both exhibiting MICs of 3.9 µg/mL. By bio-guided fractionation, punicalagin was isolated as the majority compound and was tested as a pure compound against C. albicans and C. parapsilosis with the MICs obtained being 3.9 and 1.9 µg/mL, respectively. Moreover, the potent synergistic effect between punicalagin and Fluconazole against C. albicans was shown by the two-fold decrease in MIC values when they were combined. Combinations of punicalagin and other commercial drugs such as Amphotericin B, Nystatin, and Ketoconazole were also tested against C. albicans; however, synergism was observed only with Ketoconazole. In the same study, remarkable morphological alterations caused by punicalagin on Candida were observed by electron microscopy, including an irregular budding pattern and pseudohyphae, while certain ultrastructure alterations were also detected, such as a thickened cell wall, changes in the space between the plasma membrane and the cell wall, changes in vacuoles, and a reduction in cytoplasmic content [117][38]. Another investigation reported that the chitin-binding lectin (PgTeL) isolated from the fruit of pomegranate possesses anticandidal activity against C. albicans and C. krusei, due to that the observed values for the MIC were 25 and 12.5 µg/mL, respectively. The mechanisms involved in this anticandidal action comprise oxidative stress, energetic collapse, and damage to fungal cell walls. Indeed, PgTeL caused ultrastructural damage in both strains, but more prominent effects were observed in C. krusei, due to the alterations in the integrity of the fungal cell wall. Additionally, treatment of the yeast cells with PgTeL induced a decrease in intracellular ATP content and in lipid peroxidation. Even in lower concentrations (0.195 and 0.39 µg/mL), PgTeL exhibited significant antibiofilm activity on C. albicans [118][39]. An interesting report of the antimicrobial activity of the fruit peel ash extract of P. granatum was published in the year 2011. One half of the fresh fruit peels obtained in Turkey were combusted at 400 °C, and the other half was pulverized by using a mortar. Both were extracted by using a mix of solvents (dH2O:ethanol:methanol:acetone:CH2Cl2 (1:2.5:2.5:2:2)). The extract revealed anticandidal activity against C. albicans ATCC 26555 at the doses of 10, 20, and 30 µL [119][40]. The anticandidal activity of the extracts prepared with methanol, ethanol, water, acetone, chloroform, ethyl acetate, and methyl acetate of the fruit peels of P. granatum were evaluated in three C. albicans strains, C. albicans H from a human source, C. albicans V from chicken, and C. albicans N (NRRL YB-3464), by agar diffusion assay and broth microdilution susceptibility test. Although the extracts demonstrated anticandidal activity, the methanol, ethanol, and aqueous extracts exerted the best inhibitory effect on C. albicans growth. Additionally, the methanolic, ethanolic, and aqueous extracts were also employed in the preparation of an aerosol useful for completing the sanitization of semi-closed places against the growth of C. albicans [120][41]. In the year 2006, Vasconcelos et al. [121][42] evaluated the anticandidal properties of a gel prepared with the fruit of pomegranate against C. albicans, but also against the bacteria S. mutans, S. mitis, and S. sanguis. In the MIC adherence values of the pomegranate gel, C. albicans exhibited higher values than the bacteria. However, when C. albicans was associated with bacteria, the pomegranate gel exhibited stronger inhibition, particularly in the S. mutans + S. mitis + S. sanguis + C. albicans association. When compared with Miconazole, the pomegranate gel exhibited greater efficiency in inhibiting microbial adherence. Previously, these same reseauthorsrchers  reported an investigation of the in vivo evaluation of the gel prepared with the fruit of pomegranate against C. albicans associated with denture stomatitis. Thus, groups of 30 patients received the pomegranate gel 3 times per day for 15 days. The clinical results demonstrated a medium to good response in 21 subjects who received the pomegranate gel; in addition to that, a negativity for yeasts was observed in 23 subjects in whom pomegranate gel was administered. These results were very similar to those of the administration of the Miconazole gel, and perhaps the extract of pomegranate would be useful as a topical agent in the treatment of candidiasis associated with denture stomatitis [122][43]. A study on the evaluation against Enterococcus faecalis and C. albicans in isolation and in mono- and polymicrobial biofilms of the leaf hydroalcoholic extract of pomegranate, in combination with calcium hydroxide (Ca(OH)2) or alone, was carried out by Sousa et al. [123][44]. The persistent infections observed after endodontic procedures have rendered it possible to identify E. faecalis and C. albicans as the cause of these infections, in that they are frequently present in the root canal system. In order to disinfect the root canal, Ca(OH)2 has been widely used to delay dressing in the treatment of the canal systems. Therefore, novel substances that present antimicrobial actions against E. faecalis and C. albicans, and that additionally can be employed in combination with Ca(OH)2, represent an alternative of high value for endodontic treatments. The results showed that the pomegranate extract alone or in combination with Ca(OH)2 exhibited significant antimicrobial activity against planktonic cells and mono- and polymicrobial biofilms. Thus, pomegranate extract + Ca(OH)2 may be useful in endodontic treatments, due to the efficacy shown in disinfecting root canal systems. The dichloromethane and methanol extracts of P. granatum were tested against several Candida strains, such as C. albicans CBS-562, C. dubliniensis CBS-7987, C. parapsilosis CBS-604, C. tropicalis CBS-94, C. guilliermondii CBS-566, C. utilis CBS-5609, C. krusei CBS-573, C. lusitaniae B-06, C. glabrata B-07, and C. rugosa B-12. While both extracts exhibited activity on all of the Candida species, the strongest effect was observed in the dichloromethane P. granatum extract. MIC values for both extracts ranged from 0.03–0.001 mg/mL [124][45]. The methanolic extracts of different organs of P. granatum, such as peel, flower, leaf, and stem, collected in Iran, were evaluated against C. albicans NCPF 3153 by well diffusion. The MIC and Minimum Fungicidal Concentration (MFC) values obtained revealed that the methanolic extract of leaf was the most active: 15.62 and 7.81 mg/mL, respectively. In the case of the maximal inhibition zones of the antifungal effect, the flower extract showed activity in the 200 μL concentration [125][46]. The aqueous and methanolic extracts of fruit skin of P. granatum were tested against Pseudomonas aeruginosa, Staphylococcus aureus, and C. albicans clinical isolates. The methanolic extract exhibited a potent antifungal effect on C. albicans, while both extracts exerted antibacterial activity [126][47]. The aqueous leaf and pericarp extracts of P. granatum were tested against the following Candida species: C. albicans, C. glabrata, C. parapsilosis, and C. tropicalis. The aqueous pericarp extract exerted an effect on C. glabrata and C. albicans with a zone of growth inhibition between 24 mm and 37 mm, respectively [127][48].

References

  1. Petersen, P.E. The World Oral Health Report 2003: Continuous improvement of oral health in the 21st century–The approach of the WHO Global Oral Health Program. Community Dent Oral Epidemiol. 2003, 31, 3–24.
  2. Peres, M.A.; Macpherson, L.M.; Weyant, R.J.; Daly, B.; Venturelli, R.; Mathur, M.R.; Listl, S.; Keller Celeste, R.; Guarnizo-Herreño, C.C.; Kearns, C.C.; et al. Oral diseases: A global public health challenge. Lancet 2019, 394, 249–260.
  3. Jin, L.J.; Lamster, I.B.; Greenspan, J.S.; Pitts, N.B.; Scully, C.; Warnakulasuriya, S. Global burden of oral diseases: Emerging concepts, management and interplay with systemic health. Oral Dis. 2016, 22, 609–619.
  4. Petersen, P.E.; Bourgeois, D.; Ogawa, H.; Estupinan-Day, S.; Ndiaye, C. The global burden of oral diseases and risks to oral health. Bull. World Health Organ. 2005, 83, 661–669.
  5. Villanueva-Vilchis, M.D.; López-Ríos, P.; García, I.M.; Gaitán-Cepeda, L.A. Impact of oral mucosa lesions on the quality of life related to oral health. An etiopathogenic study. Med. Oral Patol. Oral Cir. Bucal 2016, 21, e178–e184.
  6. Rafat, Z.; Sasani, E.; Salimi, Y.; Hajimohammadi, S.; Shenagari, M.; Roostaei, D. The prevalence, etiological agents, clinical features, treatment, and diagnosis of HIV-associated oral Candidiasis in pediatrics across the world: A systematic review and meta-analysis. Front. Pediatr. 2021, 9, 805527.
  7. Gaitán-Cepeda, L.A.; Sánchez-Vargas, O.; Castillo, N. Prevalence of oral candidiasis in HIV/AIDS children in highly active antiretroviral therapy era. A literature analysis. Int. J. STD AIDS 2015, 26, 625–632.
  8. Patel, P.K.; Erlandsen, J.E.; Kirkpatrick, W.R.; Berg, D.K.; Westbrook, S.D.; Louden, C.; Cornell, J.E.; Thompson, G.R.; Vallor, A.C.; Wickes, B.L.; et al. The changing epidemiology of oropharyngeal candidiasis in patients with HIV/AIDS in the era of antiretroviral therapy. AIDS Res. Treat. 2012, 2012, 262471.
  9. Delgado, A.C.D.; de Jesus Pedro, R.; Aoki, F.H.; Resende, M.R.; Trabasso, P.; Colombo, A.L.; de Oliveira, M.S.M.; Mikami, Y.; Moretti, M.L. Clinical and microbiological assessment of patients with a long-term diagnosis of human immunodeficiency virus infection and Candida oral colonization. Clin. Microbiol. Infect. 2009, 15, 364–371.
  10. Thompson III, G.R.; Patel, P.K.; Kirkpatrick, W.R.; Westbrook, S.D.; Berg, D.; Erdlandsen, J.; Redding, S.W.; Patterson, T.F. Oropharyngeal candidiasis in the era of antiretroviral therapy. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 2010, 109, 488–495.
  11. Cherry-Peppers, G.; Daniels, C.O.; Meeks, V.; Sanders, C.F.; Reznik, D. Oral manifestations in the era of HAART. J. Natl. Med. Assoc. 2003, 95, 21S–32S.
  12. FDA-Approved HIV Medicines. Available online: https://hivinfo.nih.gov/understanding-hiv/fact-sheets/fda-approved-hiv-medicines (accessed on 27 June 2022).
  13. Hawkins, T. Understanding and managing the adverse effects of antiretroviral therapy. Antivir. Res. 2010, 85, 201–209.
  14. Hima Bindu, A.; Naga Anusha, P. Adverse effects of highly active anti-retroviral therapy (HAART). J. Antivir. Antiretrovir. 2011, 3, 60–64.
  15. Sharma, A.; Vora, R.; Modi, M.; Sharma, A.; Marfatia, Y. Adverse effects of antiretroviral treatment. Indian J. Dermatol. Venereol. Leprol. 2008, 74, 234–237.
  16. Popović-Djordjević, J.; Quispe, C.; Giordo, R.; Kostić, A.; Katanić Stanković, J.S.; Tsouh Fokou, P.V.; Carbone, K.; Martorell, M.; Kumar, M.; Pintus, G.; et al. Natural products and synthetic analogues against HIV: A perspective to develop new potential anti-HIV drugs. Eur. J. Med. Chem. 2022, 233, 114217.
  17. Lichterfeld, M.; Gao, C.; Yu, X.G. An ordeal that does not heal: Understanding barriers to a cure for HIV-1 infection. Trends Immunol. 2022, 43, 608–616.
  18. Shin, Y.H.; Park, C.M.; Yoon, C.H. An overview of Human Immunodeficiency Virus-1 antiretroviral drugs: General Principles and Current Status. Infect Chemother. 2021, 53, 29–45.
  19. Mahboubi-Rabbani, M.; Abbasi, M.; Hajimahdi, Z.; Zarghi, A. HIV-1 Reverse Transcriptase/Integrase dual inhibitors: A review of recent advances and structure-activity relationship studies. Iran. J. Pharm. Res. 2021, 20, 333–369.
  20. Mohamed, H.; Gurrola, T.; Berman, R.; Collins, M.; Sariyer, I.K.; Nonnemacher, M.R.; Wigdahl, B. Targeting CCR5 as a component of an HIV-1 therapeutic strategy. Front. Immunol. 2022, 12, 816515.
  21. Tappuni, A.R. The global changing pattern of the oral manifestations of HIV. Oral Dis. 2020, 26 (Suppl. S1), 22–27.
  22. Moosazadeh, M.; Shafaroudi, A.M.; Gorji, N.E.; Barzegari, S.; Nasiri, P. Prevalence of oral lesions in patients with AIDS: A systematic review and meta-analysis. Evid. Based Dent. 2021, 1–10.
  23. Peña, D.E.R.; Innocentini, L.M.A.R.; Saraiva, M.C.P.; Lourenço, A.G.; Motta, A.C.F. Oral candidiasis prevalence in human immunodeficiency virus-1 and pulmonary tuberculosis coinfection: A systematic review and meta-analysis. Microb. Pathog. 2021, 150, 104720.
  24. Irani, S. Herbal medicine and oral health: A review. J. Int. Oral Health 2016, 8, 989–994.
  25. Chinsembu, K.C. Plants and other natural products used in the management of oral infections and improvement of oral health. Acta Trop. 2016, 154, 6–18.
  26. Gowhar, O.; Singh, N.; Sultan, S.; Ain, T.; Mewara, A.; Shah, I. Natural herbs as alternative to synthetic antifungal drugs-the future challenging therapy. Br. Biomed. Bull. 2015, 3, 440–452.
  27. Ostrosky-Zeichner, L.; Casadevall, A.; Galgiani, J.N.; Odds, F.C.; Rex, J.H. An insight into the antifungal pipeline: Selected new molecules and beyond. Nat. Rev. Drug Discov. 2010, 9, 719–727.
  28. Rajan, S.; Ravi, J.; Suresh, A.; Guru, S. Hidden secrets of Punica granatum use and its effects on oral health: A short review. J. Orofac. Res. 2013, 3, 38–41.
  29. Chen, L.F.; Hoy, J.; Lewin, S.R. Ten years of highly active antiretroviral therapy for HIV infection. Med. J. Aust. 2007, 186, 146–151.
  30. Bakır, S.; Yazgan, Ü.C.; İbiloğlu, İ.; Elbey, B.; Kızıl, M.; Kelle, M. The protective effect of pomegranate extract against cisplatin toxicity in rat liver and kidney tissue. Arch. Physiol. Biochem. 2015, 121, 152–156.
  31. Neurath, A.R.; Strick, N.; LI, Y.Y.; Debnath, A.K. Punica granatum (Pomegranate) juice provides an HIV-1 entry inhibitor and candidate topical microbicide. Ann. N. Y. Acad. Sci. 2005, 1056, 311–327.
  32. Neurath, A.R.; Strick, N.; Li, Y.Y.; Debnath, A.K. Punica granatum (Pomegranate) juice provides an HIV-1 entry inhibitor and candidate topical microbicide. BMC Infect. Dis. 2004, 4, 1–12.
  33. Seetaha, S.; Hannongbua, S.; Rattanasrisomporn, J.; Choowongkomon, K. Novel peptides with HIV-1 reverse transcriptase inhibitory activity derived from the fruits of Quercus infectoria. Chem. Biol. Drug Des. 2021, 97, 157–166.
  34. Sanna, C.; Marengo, A.; Acquadro, S.; Caredda, A.; Lai, R.; Corona, A.; Tramontano, E.; Rubiolo, P.; Esposito, F. In vitro anti-HIV-1 Reverse Transcriptase and Integrase properties of Punica granatum L. leaves, bark, and peel extracts and their main compounds. Plants 2021, 10, 2124.
  35. Kusumoto, I.T.; Nakabayashi, T.; Kida, H.; Miyashiro, H.; Hattori, M.; Namba, T.; Shimotohno, K. Screening of various plant extracts used in ayurvedic medicine for inhibitory effects on human immunodeficiency virus type 1 (HIV-1) protease. Phytother. Res. 1995, 9, 180–184.
  36. Xu, H.X.; Wan, M.; Loh, B.N.; Kon, O.L.; Chow, P.W.; Sim, K.Y. Screening of traditional medicines for their inhibitory activity against HIV-1 protease. Phytother. Res. 1996, 10, 207–210.
  37. Venkatalakshmi, P.; Vadivel, V.; Brindha, P. Role of phytochemicals as immunomodulatory agents: A review. Int. J. Green Pharm. 2016, 10, 1–18.
  38. Endo, E.H.; Cortez, D.A.G.; Ueda-Nakamura, T.; Nakamura, C.V.; Dias Filho, B.P. Potent antifungal activity of extracts and pure compound isolated from pomegranate peels and synergism with fluconazole against Candida albicans. Res. Microbiol. 2010, 161, 534–540.
  39. Da Silva, P.M.; de Moura, M.C.; Gomes, F.S.; da Silva Trentin, D.; de Oliveira, A.P.S.; de Mello, G.S.V.; da Rocha Pitta, M.G.; Barreto de Melo, M.J.R.; Breitenbach, L.C.; Macedoc, A.J.; et al. PgTeL, the lectin found in Punica granatum juice, is an antifungal agent against Candida albicans and Candida krusei. Int. J. Biol. Macromol. 2018, 108, 391–400.
  40. Ergin, M.A. Investigation of antimicrobial activity of Punica granatum L. fruit peel ash used for protection against skin infections as folk remedies especially after male circumcision. Afr. J. Microbiol. Res. 2011, 5, 3339–3342.
  41. Tayel, A.A.; El-Tras, W.F. Anticandidal activity of pomegranate peel extract aerosol as an applicable sanitizing method. Mycoses 2010, 53, 117–122.
  42. Vasconcelos, L.C.D.S.; Sampaio, F.C.; Sampaio, M.C.C.; Pereira, M.D.S.V.; Higino, J.S.; Peixoto, M.H.P. Minimum inhibitory concentration of adherence of Punica granatum Linn (pomegranate) gel against S. mutans, S. mitis and C. albicans. Braz. Dent. J. 2006, 17, 223–227.
  43. Vasconcelos, L.C.D.S.; Sampaio, M.C.C.; Sampaio, F.C.; Higino, J.S. Use of Punica granatum as an antifungal agent against candidosis associated with denture stomatitis. Mycoses 2003, 46, 192–196.
  44. Sousa, M.N.; Macedo, A.T.; Ferreira, G.F.; Furtado, H.L.A.; Pinheiro, A.J.M.C.R.; Lima-Neto, L.G.; Fontes, V.C.; Ferreira, R.L.P.S.; Monteiro, C.A.; Falcai, A.; et al. Hydroalcoholic leaf extract of Punica granatum, alone and in combination with calcium hydroxide, is effective against mono-and polymicrobial biofilms of Enterococcus faecalis and Candida albicans. Antibiotics 2022, 11, 584.
  45. Höfling, J.F.; Anibal, P.C.; Obando-Pereda, G.A.; Peixoto, I.A.T.; Furletti, V.F.; Foglio, M.A.; Gonçalves, R.B. Antimicrobial potential of some plant extracts against Candida species. Braz. J. Biol. 2010, 70, 1065–1068.
  46. Shafighi, M.; Amjad, L.; Madani, M. In vitro antifungal activity of methanolic extract of various parts of Punica granatum L. Int. J Sci. Eng. Res. 2012, 3, 2229–5518.
  47. Sadeghian, A.; Ghorbani, A.; Mohamadi-Nejad, A.; Rakhshandeh, H. Antimicrobial activity of aqueous and methanolic extracts of pomegranate fruit skin. Avicenna J. Phytomed. 2011, 1, 67–73.
  48. Jain, P.; Nafis, G. Antifungal activity and phytochemical analysis of aqueous extracts of Ricinus communis and Punica granatum. J. Pharm. Res. 2011, 4, 128–129.
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