{"id":49049,"date":"2023-06-30T12:00:05","date_gmt":"2023-06-30T12:00:05","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=49049"},"modified":"2023-07-18T11:22:49","modified_gmt":"2023-07-18T11:22:49","slug":"renoprotective-effects-of-anthocyanins-against-uric-acid-instigated-injury-mini-review-with-a-special-emphasis-on-purple-sweet-potato-ipomoea-batatas-l-anthocyanins","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol16no2\/renoprotective-effects-of-anthocyanins-against-uric-acid-instigated-injury-mini-review-with-a-special-emphasis-on-purple-sweet-potato-ipomoea-batatas-l-anthocyanins\/","title":{"rendered":"Renoprotective Effects of Anthocyanins Against Uric Acid-Instigated Injury: Mini Review with a Special Emphasis on Purple Sweet Potato (Ipomoea batatas L.) Anthocyanins"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

Anthocyanins are recognized as widely available-bioactive agents in\nvarious natural products. Purple sweet potato (abbreviated as PSP in this\nmanuscript), taxonomically known as Ipomoea\nbatatas<\/em> L., is an important source of anthocyanins. The tuber of this crop\nhas special niche in human civilizations, by serving as both energy source and\nalso regarded as highly nutritious, thus becoming natural product with\nimportant pharmaco-nutritional values. PSP tuber contains significant amount of\nanthocyanins, a group of flavonoid compounds with an array of medicinal\nbenefits (1\u20134). One of such potential benefits is their effects in\nmitigating negative effects of uric acid (UA) on health, especially on kidneys (5). <\/p>\n\n\n\n

Nowadays, acute kidney injury (AKI) and chronic kidney disease (CKD)\npose as significant challenges in the field of medicine, which are associated\nwith metabolic dysfunction such as elevated serum level of UA (hyperuricemia). This\nelevated SUA level promotes the precipitation of UA (6), which can be regarded as a culprit in kidney\ndiseases. This is supported by the fact that AKI risk could be enhanced by the\noccurrence of hyperuricemia (7), and chronic hyperuricemia might both trigger\nalterations resulting in CKD and also act as CKD progression-promoting factor (8). <\/p>\n\n\n\n

Since kidney is important organ in UA metabolism and handling, and hyperuricemia\nis associated with renal disease involving various mechanisms (9), this review will be focused on re-appraising the\nrole of anthocyanins in general, and especially those found in PSP as\nrenoprotectors against UA adverse effects. Specifically, we propose gut\ndysbiosis, Nox4, Nrf2, endoplasmic reticulum stress, and the NLRP3 inflammasome\nas potential targets of PSP anthocyanins renoprotection against UA-induced\ninjury. Future directions regarding the development of anthocyanins as\nprotective agents against UA-instigated kidney injuries are also discussed. <\/p>\n\n\n\n

The Use of Purple Sweet Potato as Folk Remedies<\/strong><\/p>\n\n\n\n

The highly nutritious PSP belongs to family of Convolvulaceae (1), also known as morning glory family. Besides its use\nas energy source, food colorant and edible food packaging (10), PSP is regarded as a promising source of\nbiotherapeutics and as a natural product with diverse array of medicinal values,\nas reviewed elsewhere (11). PSP is known to be traditionally used as\nantiasthmatic agent, antipyretic agent, maintaining oral health, treatment of\ndermatological issues (bugbites, burns) and gastrointestinal issues (nausea,\nconstipation), as well as aphrodisiac, to name a few (1). This natural product had been also classified as folk\nremedy for gynaecological health in Gilgit area, Pakistan (12). Closely related with the focus of this review, is\nthe ethnomedicinal use of Ipomoea batatas\n<\/em>L. leafy stems macerate as oral preparation to treat urinary signs and\nsymptoms such as hematuria, and difficult and painful micturition in Cameroon (13). Up to date, we are lacking data on the effect of PSP\nparts handling during their preparation as these aforementioned folk remedies\non anthocyanins composition and clinical outcomes (regarding safety and\nefficacy). Data on clinical outcomes of pharmacokinetic and pharmacodynamic\ninteraction between phytochemicals contained in PSP and other natural\ningredients are also not available currently. Since PSP has been used\ntraditionally as folk remedies, the fulfilment of this research gaps will\nbroadens our understanding on the potentials and development of PSP as source\nof drugs.  <\/p>\n\n\n\n

Extraction of Purple Sweet Potato Anthocyanins<\/strong><\/p>\n\n\n\n

To facilitate the establishment of its therapeutic effects in more\npredictive and measureable manners, extraction of Ipomoea batatas<\/em> L. tuber is essential. Wide techniques are\navailable in extracting the tubers, one of such is solvent extraction. This\nextraction method is still regarded as the most convenient way (if not easy) in\nthe production of crude extract of natural products. One of the important\npotentially-renoprotective compounds group isolated after the extraction\nprocess is anthocyanins. In a study using two local Javanese PSP varieties,\nsolvent extraction using repeated maceration technique for as long as 24 hours was\nreported to yield anthocyanins for as much as 5 mg\/100 g and 10 mg\/100g from\nthe investigated cultivars (4). Although regarded as a simple extraction method,\nsolvent extraction is time-consuming and lead to the accumulation of solvent\nwaste over time (14). <\/p>\n\n\n\n

Anthocyanins Structure and General Functions: Unity of\nRole in a Chemical Diversity<\/strong><\/p>\n\n\n\n

As flavonoids, anthocyanins retain C6-C3-C6 carbon skeleton pattern.\nThese bioactives occurs more frequently in plants as anthocyanidins (cyanidin,\ndelphinidin, malvidin, pelargonidin, peonidin, petunidin), while also present\nas glycone forms (sugar conjugates of anthocyanidins)  (15). Anthocyanins are structurally-diverse flavonoids,\nbut in whatever chemical structure does the individual anthocyanin exist, as\nsecondary metabolites they perform ultimate role, i.e, stress protectants. Anthocyanins\nconfers photoprotection to plant against excessive light exposure as a form of\nprotective capacity against abiotic stressor (16). Abiotic stressors trigger ROS biogenesis in plant\nwhich in turns upregulates anthocyanins synthesis to confers tolerance against\nthe aforementioned stressors (17). In PSP, the tuber roots are the dominant organs in\nanthocyanins synthesis, which is regulated under specific transcriptional\nregulatory mechanism (18). This spatial distribution of anthocyanins presumably\nprotect the tubers as food storage and reproductive components against wide\narray of abiotic stressors, thus promoting evolutionary fitness. <\/p>\n\n\n\n

Anthocyanins Identified in Purple Sweet Potato<\/strong><\/p>\n\n\n\n

As mentioned before, two Javanese cultivars of PSP, namely Lawang and\nKawi Mountain, had been revealed to contain 10 mg of C3G\/100 g and 5 mg of\nC3G\/100 g, respectively. Interestingly, the antioxidant activity of these\ncultivars was similar, which was presumably contributed by the presence of\nother antioxidants (4). PSP of 5 varieties from Korea (Sinjami, Jami,\nDanjami, Yeonjami, and Borami) was shown to be predominantly rich in peonidin.\nOther anthocyanins such as cyanidin and pelargonidin were also identified in\nthese varieties (19). In a study conducted in China, hot air-dried PSP was\nrevealed to contain cyanidin\n3-sophoroside-5-glucoside, peonidin 3-sophoroside-5-glucoside, cyanidin\n3-p-hydroxybenzoylsophoroside-5-glucoside and peonidin\n3-p-hydroxybenzoylsophoroside-5-glucoside, with total anthocyanin contents\nranging from 82,75 to 609,08 mg\/100 g dry weight (20). These findings provide clues that\nbiogeographical factors determine the composition of anthocyanins in PSP\ntubers. <\/p>\n\n\n\n

Pharmacokinetic Overview of Anthocyanins<\/strong><\/p>\n\n\n\n

In order to integrate anthocyanins into daily diets using oral formulation to prevent disease establishment and progression via appropriate dosing, elucidation of anthocyanins pharmacokinetics after oral administration is mandatory. Stomach and intestines were reported as the major sites of anthocyanins absorption. Uptake of anthocyanins from stomach and kidney was known to be facilitated by special transporter. Anthocyanins were found both as parent compounds and metabolites, with the later existed in much higher level in the systemic circulation. Gut microbiota were also observed to facilitate in decomposing a relatively large portion of anthocyanins reaching the colon (21). In a recently conducted study using a human small intestinal epithelial line INT-407, PSP acylated anthocyanins were not found intracellularly, meaning that acylation impede the cellular uptake of anthocyanins (22), In line with the result, acylated cyanidin-based anthocyanins from purple carrots exhibited lower absorption efficiencies, shorter half-life and higher elimination rate compared to their non-acylated counterparts (23). Using Caco-2 cells as other in vitro <\/em>model for intestinal absorption, anthocyanin absorption efficiency were demonstrated to be determined by several factors (as presented in Table 1). \u201cStructure determines fate\u201d thus can be consolidated as a universal regulatory principle in anthocyanin pharmacokinetics. <\/p>\n\n\n\n

Table 1: Determinants of Transport Efficiency of Anthocyanins across Caco-2 Cells<\/strong>.<\/p>\n\n\n\n\n\n\n\n\n\n
\n

Determining Factors<\/strong><\/p>\n<\/td>\n

\n

Descriptions<\/strong><\/p>\n<\/td>\n

\n

References<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Aglycone structure<\/p>\n<\/td>\n

\n

Higher hydroxyl group number \u00e0 higher lipophobicity \u00e0 lesser transport efficiency<\/p>\n<\/td>\n

\n

(24)<\/p>\n<\/td>\n<\/tr>\n

\n

Sugar conjugates<\/p>\n<\/td>\n

\n

Reported to exert minor effects on transport efficiency due to conflicting results whether simpler sugar conjugates positively associated with higher transport efficiency<\/p>\n<\/td>\n

\n

(24,25)<\/p>\n<\/td>\n<\/tr>\n

\n

Dimerism vs. monomerism<\/p>\n<\/td>\n

\n

Higher structural complexity contributes to lesser transport efficiency<\/p>\n<\/td>\n

\n

(26)<\/p>\n<\/td>\n<\/tr>\n

\n

Other food components<\/p>\n<\/td>\n

\n

Ethanol \u00e0 conflicting results; citric acid enhance transport efficiency across the basolateral plasmalemma; phospholipids and terpenes promotes higher transport efficiency of a\u00e7a\u00ed anthocyanins<\/p>\n<\/td>\n

\n

(27\u201331)<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

The Roles of Anthocyanins as Antihyperuricemic Agents<\/strong><\/p>\n\n\n\n

Hyperuricemia can be potentially controlled via several targets, i.e., classical target such as xanthine oxidase (XO) inhibition and urate transporters, and novel target such as management of gut dysbiosis. PSP highly acylated anthocyanins has been revealed to act synergistically with xanthine oxidase inhibitor (XOI) allopurinol in reducing serum UA level (2). As a modulator of urate transporters, anthocyanins administration facilitate the establishment of UA homeostasis in animal model of hyperuricemia (32), as summarized in Table 2. Intestines are also gaining increasing attention, as important organs in both UA handling and also xenobiotics metabolism. Intriguingly, patients with gout in a study were revealed to exhibit gut microbiota composition with attenuated potential of purine metabolism, which can be reversed using febuxostat, an UA-lowering medication (33). On the other hand, PSP anthocyanins and its peonidin-based individual monomers were reported to enhance the population of probiotic gut microbiota while also suppressed the population of pathogenic microbiota. The gut microbiota modulating effects of PSP anthocyanins points out that these natural pigments also act as prebiotics (34). The role of gut microbiota in UA handling (i.e., maintaining UA homeostasis) and its interactions with pro- and prebiotics had been discussed elegantly elsewhere (35). Based on the aforementioned results regarding gut microbiota modulating actions, it can be predicted that the ultimate result of anthocyanins-gut microbiota interactions is the establishment of antihyperuricemic and anti-inflammatory milieus. <\/p>\n\n\n\n

Table 2<\/strong>: Anthocyanin effects on urate transporters mRNA of murine kidney<\/strong> (32).<\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Urate transporters<\/strong><\/p>\n<\/td>\n

\n

Effect<\/strong><\/p>\n<\/td>\n

\n

Expected Outcomes<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

ABCG2<\/p>\n<\/td>\n

\n

Upregulation<\/p>\n<\/td>\n

\n

 <\/p>\n

Urate reabsorption attenuation<\/p>\n

 <\/p>\n

Enhanced urate elimination<\/p>\n<\/td>\n<\/tr>\n

\n

GLUT9<\/p>\n<\/td>\n

\n

Downregulation<\/p>\n<\/td>\n<\/tr>\n

\n

OAT1<\/p>\n<\/td>\n

\n

Upregulation<\/p>\n<\/td>\n<\/tr>\n

\n

OAT3<\/p>\n<\/td>\n

\n

Upregulation<\/p>\n<\/td>\n<\/tr>\n

\n

OCT1<\/p>\n<\/td>\n

\n

Upregulation<\/p>\n<\/td>\n<\/tr>\n

\n

OCT2<\/p>\n<\/td>\n

\n

Upregulation<\/p>\n<\/td>\n<\/tr>\n

\n

OCTN1<\/p>\n<\/td>\n

\n

Upregulation<\/p>\n<\/td>\n<\/tr>\n

\n

OCTN2<\/p>\n<\/td>\n

\n

Upregulation<\/p>\n<\/td>\n<\/tr>\n

\n

URAT1<\/p>\n<\/td>\n

\n

Downregulation<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

The Roles of Anthocyanins as Antioxidants in Kidney<\/strong><\/p>\n\n\n\n

As antioxidant, anthocyanins exert their effects via multiple\nmechanisms, involving diverse array of targets. Hyperuricemia-hyperglycemia\nassociation is a potential therapeutic target of renoprotection conferred by\nanthocyanins. This notion is supported by findings from in vitro<\/em>, in vivo<\/em> and\nclinical endocrinology studies. By causing oxidative stress in vitro<\/em>, diminishing glucose tolerance,\nand blocking insulin signaling (via inhibition of phosphor-Akt [Ser473] and\nelevation of phosphor-IRS1 [Ser307]) in\nvivo<\/em>, hyperuricemia directly promotes insulin resistance (36). In line with these findings, hyperuricemia had been\nshown to directly affect pancreatic \u03b2 cells. High UA was shown to promote\ninsulin resistance and curtail insulin secretion via promotion of pro-oxidative\nstate and modulation of IRS2\/Akt pathway (phospho-Ser731-IRS2 activation and\nphospho-S473-Akt inhibition) (37). In clinical setting, hyperglycemic states (prediabetes\nand type 2 DM) was observed to show significant linkage to hyperuricemia (38). <\/p>\n\n\n\n

Anthocyanins from PSP tuber are recognized as antioxidants that can\npotentially prevent and ameliorate the progression of hyperglycemia-associated\noxidative damage in tissues and organs. Anthocyanins-rich ethanol extract of\nPSP cultivated in the island of Bali, Indonesia, was observed to attenuate\nblood glucose and MDA levels, while also enhancing antioxidant capacity under\ndose-dependent manner in a rat model of hyperglycemia (39). The extract of PSP harvested from Yogyakarta,\nIndonesia, has been revealed to attenuate renal MDA, and improve renal function\nin a rodent model of hyperglycemia (40). These findings can be partially attributed to the\nROS scavenging activity of PSP anthocyanins as direct antioxidants (19,20). <\/p>\n\n\n\n

Other oxidative stress-related potential therapeutic target of\nrenoprotection against hyperuricemia is renal NADPH oxidase 4 (Nox4) and\nnuclear factor erythroid 2-related factor 2 (Nrf2). This oxidase is a ROS-producing\nenzyme in ER, an important redox-regulating organelle (41).  As the main\nrenal NADPH isoform, Nox4 mediates ROS (H2<\/sub>O2<\/sub>) biogenesis.\nUnder certain conditions such as uremic toxins accumulation, Nox4 predisposes\ntubular epithelial cell to oxidative stress and apoptosis while also inducing\nthe establishment of pro-fibrotic milieu (42). Pathogenesis of tubulointerstitial renal damage has\nbeen associated with hyperuricemia, even in mild degree. In line with the\naforementioned findings, UA was reported to induce proximal tubular cell\napoptosis via Nox4 upregulation (43). Anthocyanins-containing PSP tuber was shown to\nexhibit attenuative effect on renal Nox4 protein expression in a murine model\nof hyperuricemia treated with high-purine diet (5). Based on these findings, it can be assumed that PSP\nanthocyanins may also serve as indirect antioxidant to protect renal tubulointerstitial\nhomeostasis from the adverse effects of UA by modulating Nox4 expression. Of\nnote, obstructive stimulus (modelled using unilateral ureteral obstruction)\nupregulates Nox4 but does not exert structural alteration of kidney (44). This finding points out that renal damaging effect\nof Nox4 upregulation is stimulus-specific, and should be keep as an important\nreminder in studying Nox4 biology. In addition to Nox4 inhibition, activation\nof Nrf2 could mitigate the harmful effects of oxidative stress on kidney, while\nalso attenuating anemia, a common manifestation of CKD complications. These\nbeneficial effects had been documented in\nvivo<\/em>, while clinical trials using Nrf2 activators with positive results are\nongoing (45). <\/p>\n\n\n\n

Endoplasmic Reticulum Stress: Other Potential Target\nof Anthocyanins Renoprotective Action<\/strong><\/p>\n\n\n\n

We propose endoplasmic reticulum (ER) stress as another potential target\nof renoprotection against UA-triggered renal injury. Induction of\nintra-endothelial ROS production was associated with ER stress activation due\nto UA exposure in vitro <\/em>(46). In addition with this fact, endothelial dysfunction\nwas shown to play important role in kidney impairment, especially CKD. Of note,\nlow nitric oxide (NO) bioavailability (as an interactive result of multiple\nfactors, including oxidative stress) had been observed as a near-universal\ncellular event in the most advanced state of CKD. Diminished NO bioavailability\nwas known to impair endothelial functions, and recognized as important player\nin not only renal diseases, but also cardiovascular diseases (47). Of note, aged kidney is relatively prone to acute\ninjury due to diminished capacity in adapting to stressors, such as\nperturbation of proteostasis (i.e., ER stress), which can be partially caused\nby oxidative stress. As a scientific support of this issue, a murine model of\naged kidney had been shown to reveal specific dysfunctional unfolded protein\nresponse (UPR), which can be restored by antioxidant treatment (48). These observed phenomena support the hypothesis that\nER stress is a promising target of renoprotection by anthocyanins to abolish or\nat least to mitigate harmful effects of UA. <\/p>\n\n\n\n

Mechanisms of Anthocyanins in Preventing Renal Cell\nDeath and Combatting Renal Inflammation<\/strong><\/p>\n\n\n\n

In murine model of hyperuricemia induced using potassium oxonate, purple\nsweet potato anthocyanins in highly acylated form has been proven to mitigate\nrenal damage. The renoprotective effect of highly acylated anthocyanins against\nadverse effect of UA-rich internal milieu is established via downregulation of\npro-inflammatory cytokines such as TNF-\u03b1, IL-6 and IL-1\u03b2 (2). Since IL-1 \u03b2 is synthesized by inflammasomes in the\nsite of inflammation (49), the effect of PSP highly-acylated anthocyanins may\nbe facilitated via silencing of inflammasome activity as a possible anti-inflammatory\nmechanism. Further studies are warranted to investigate this prediction of\naction mechanism. <\/p>\n\n\n\n

As mentioned previously, inflammasome (specifically, NLRP3 inflammasome)\nis involved in the pathogenesis of UA-induced renal injury. Soluble form of UA\nplays a detrimental role in activating NLRP3 inflammasome, which also correlate\nwith mitochondrial ROS biogenesis and fibrosis (50). In line with these experimental results, UA could\ninduce pyroptosis, a type of cell death which results in inflammation, in renal\ntubular epithelial cells. In vitro<\/em>\nand in vivo<\/em> studies pointed out that\nUA upregulated caspase-1, gasdermin D (GSDMD), IL-1\u03b2 and\nIL-18, via the induction of NLRP3 inflammasome by involving ROS. These findings\nshow that even though UA is not yet present in crystallized form, it is capable\nof triggering deterioration of renal homeostasis. Favorably, the upregulation\nof pyroptosis-associated biomarkers could be controlled by the administration\nof synthetic antioxidants. These synthetic antioxidants could also normalize\nmitochondrial transmembrane potential, pointing out the crucial role of\nmitochondria in UA-triggered pyroptosis of renal tubular epithelial cells (51).\n  <\/p>\n\n\n\n

Excessive and prolonged\noxidative stress, ER stress and the concomitant inflammation of the kidney will\nultimately induced cell death. This notion is supported by the findings in a\nstudy using human umbilical vein endothelial cells (HUVECs) exposed to UA.\nHUVECs may undergo ER stress and apoptosis under UA exposure, which can be\nsalvaged using direct ROS scavenger and ER stress inhibitor (46). This UA-induced apoptosis had been shown to be\nfacilitated by ROS biogenesis and NLRP3 inflammasome activation, specifically\nvia NEK7-NLRP3 pathway (52). Again, this support the notion that NLRP3\ninflammasome plays an integral role in mediating harmful effects of UA to the\nkidney, via ROS production and pro-inflammatory responses, which are potential\ntargets of antioxidants such as anthocyanins. <\/p>\n\n\n\n

Future Directions<\/strong><\/p>\n\n\n\n

Several challenging issues are still open as interesting area of\nresearch regarding the development of anthocyanins as biotherapeutics to combat\nthe negative effect of UA on kidney. We propose to classify these challenges as\npharmacokinetic and pharmacodynamics challenges. Limited bioavailability of\ndietary anthocyanins (22) poses as an important pharmacokinetic challenge in\napplying them as biotherapeutics, especially in the aspects of oral drug\nformulation and dosing (to optimize absorption and delivery to their targets).\nThe pharmacodynamic challenges comprise of elucidating the complex \u201clandscape\u201d\nof UA pathobiology based on comparative medicine paradigm and the exact action\nmechanism of individual anthocyanins as potential renoprotectors, at molecular\nand systemic level. <\/p>\n\n\n\n

Mitochondria is\ncrucial in facilitating pyroptosis in UA-triggered renal epithelial cells.  Structurally and functionally, mitochondria\nis known to be associated with ER via mitochondrial-associated membrane (MAM).\nOther important organelle in redox communication is peroxisome, partially due\nto its XO content. Mitochondria, ER and peroxisomes forms a \u201credox triad\u201d,\nregulates the redox homeostasis by putting together redoxomes (41).\nThe role of inter-organelles crosstalk via MAM and the role as peroxisome as\ncomponent of the aforementioned \u201credox triad\u201d in renal cells under the exposure\nof UA need to be revealed, and can be potentially exploited as therapeutic\ntarget to alleviate renal injury. The effect of anthocyanins in modulating this\ninter-organelles communication are interesting area of future studies regarding\nthe development of anthocyanins (specifically, PSP anthocyanins) as\nrenoprotectors, based on studies on renal Nox4 protein expression (5)\nand mitochondrial ROS . <\/p>\n\n\n\n

Gut dysbiosis is also an intriguing target in hyperuricemia management (33). The gout-specific altered composition of gut\nmicrobiota may serve as theranostic target for gout and urate nephropathy management.\nThe biology of this specific phenotype of gut dysbiosis in UA-triggered renal\ninjury warrants further investigations. Probiotics and agents with prebiotic\nactivity such as purple sweet potato need to be studied as modulator of gut\ndysbiosis, with the expectation of correcting gut dysbiosis by enhancing\npotential for purine metabolism, while also establishing anti-inflammatory\ncondition to protect kidneys from UA adverse impacts. Since XO inhibitors are\nnot usually indicated in asymptomatic hyperuricemia management and has becoming\nan area of controversy since about the last 4 decades (53), anthocyanins from PSP are potential to be integrated\nin human diet on a daily basis, especially to maintain general health\nconditions and specifically to prevent the establishment of UA-instigated renal\ndiseases. <\/p>\n\n\n\n

Conclusion<\/strong><\/p>\n\n\n\n

Anthocyanins, especially from Ipomoea\nbatatas <\/em>L., are promising protective phytoconstituents in preventing or\nmitigating UA-instigated renal injury. In general, this renoprotection may be\npotentially achieved via several action mechanisms, i.e., antioxidants, ER\nstress modulation, anti-inflammation, anti-fibrosis, anti-apoptosis and\nrestoration of gut dysbiosis. Further investigations are essential to be\nconducted to reveal the pharmacological profile of these anthocyanins as\npotential renoprotectors against the detrimental effects of UA. <\/p>\n\n\n\n

Acknowledgment<\/strong><\/p>\n\n\n\n

We would like to acknowledge dr. Nur Arfian, PhD (researcher of\nmolecular medicine, translational study, and clinically applied anatomy, Department\nof Anatomy, FK-KMK UGM, Yogyakarta, Indonesia) for his valuable expert\ncommentaries on this manuscript regarding the molecular pathobiology of UA in\ntriggering renal dysfunction. <\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

The authors\ndeclare no potential conflicts of interest. <\/p>\n\n\n\n

Funding Sources<\/strong><\/p>\n\n\n\n

The authors\nhave received no specific financial support from any funding agency or\ninstitution.<\/p>\n\n\n\n

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