{"id":51149,"date":"2023-09-30T11:54:13","date_gmt":"2023-09-30T11:54:13","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=51149"},"modified":"2023-10-07T08:28:09","modified_gmt":"2023-10-07T08:28:09","slug":"miana-coleus-scutellariodes-inhibits-nuclear-factor-kappa-b-nf-kb-activity-and-its-antibacterial-and-anti-inflammatory-benefits-in-infectious-diseases-review-article","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol16no3\/miana-coleus-scutellariodes-inhibits-nuclear-factor-kappa-b-nf-kb-activity-and-its-antibacterial-and-anti-inflammatory-benefits-in-infectious-diseases-review-article\/","title":{"rendered":"Miana (Coleus scutellariodes) Inhibits Nuclear Factor-kappa B (NF-kB) Activity and its Antibacterial and Anti-inflammatory Benefits in Infectious Diseases: Review Article"},"content":{"rendered":"\n

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

Herbal and its products including\nMiana (Coleus scutellariodes<\/em>) widely used as supplements and treatment\nin traditional medicine in several tropical countries such as Indonesia for\nboth infectious and non-infectious diseases. Several studies have demonstrated\nthe efficacy of herbal medicine, such as virgin coconut oil for Alzheimer’s\ndisease1<\/sup>, Valerian extract for antidepressant2<\/sup>, Moringa\nOleifera Lam for neuroprotective and hepatoprotective3<\/sup> and Maina\nfor  antibacterial against Aggregatibacter\nactinomycetemcomitans<\/em>4<\/sup> and Porphyromonas gingivalis.<\/em>5\n<\/sup><\/p>\n\n\n\n

Previous studies revealed that in\nrats with traumatic brain injury, caffeic acid phenethyl ester (CAPE), one of\nthe bioactive components of propolis extract, is shown to reduce cerebral\nvasospasm6 <\/sup>and neuroprotective.7<\/sup> Another study on\npropolis showed antibacterial effects against Klebsiella pneumoniae<\/em>10\n<\/sup>and Salmonella typhi.<\/em>8,9 <\/sup> Another study revealed that banana components\nhave an anti-inflammatory effects.10<\/sup> and is strongly associated with\nthe treatment of Alzheimer’s disease.11<\/sup> Furthermore, curcumin\nexhibits an antimicrobial effect against Salmonella typhi<\/em>12<\/sup>\nand Toxoplasma gondii<\/em>.13<\/sup> Other studies showed that MLC901 is\na traditional Chinese medicine for protects the ischemia of the brain14<\/sup><\/p>\n\n\n\n

The study by Korbecki, et al, showed\nthat the hypoxic cycle in infection causes an increase in systemic Reactive\nOxygen Species (ROS) which has the effect of inducing HIF-I and activating NF-kB.15<\/sup>\nMiana and Quercetin’s anti-inflammatory properties may be mediated by the\nsuppression of NF-kB activation and cytokine release.16,17<\/sup> Besides\nthat, a study conducted by Wahyuni, et al, stated that using Miana orally\nshowed a significant increase in levels of Natural Resistance Associated\nMacrophage Protein1 (NRAMP-1) as a macrophage activator in Klebsiella\npneumonia<\/em> infection.18<\/sup> <\/p>\n\n\n\n

A study to more fully comprehend the\neffects of Miana (Coleus scutellariodes<\/em>) as an anti-inflammation and\nantibacterial on alterations in Nuclear factor-kappa B (NF-kB), which may be a\nmechanism for infectious diseases, would be urgently required based on the\nbackground and previous findings.<\/p>\n\n\n\n

Methods <\/strong><\/p>\n\n\n\n

Using keyword combinations of the\nmedical subject headings (MeSH) of “Miana,” “Coleus\nscutellariodes<\/em>\u201d, “NF-kB\u201d, “antibacterial, “anti-inflammation\u201d,\nand “Infectious disease” an in-depth review of the literature was\ncarried out in the PubMed (NIH), Scopus, EMBASE, and Google Scholar databases.\nRelevant reference lists were also manually searched. This review article\nincluded and narratively discussed any relevant publications from the database\nabove.<\/p>\n\n\n\n

Preferred Reporting Items for Systematic Reviews and\nMeta-Analyses Protocols (PRISMA) guidelines were also followed.19<\/sup>\nAll relevant publications of any research design published in the previous data\nset in either the English or Indonesian language were included and narratively\nevaluated.<\/p>\n\n\n\n

Results<\/strong><\/p>\n\n\n\n

Miana (Coleus scutellariodes<\/em>) <\/strong><\/p>\n\n\n\n

Miana (Coleus scutellariodes<\/em>) is a plant for many years, the plant height is between 15-30 cm with a very wide variety of plant colors or leaf colors. People in Indonesia commonly use Miana as traditional medicine.20<\/sup> The composition of Miana useful chemical compounds, namely essential oils, tannins, flavonoids, saponins, thymol, carvacrol, and eugenol, and the content of active substances such as essential oils, alkaloids, flavonoids, and phenolic derivatives (polyphenols) can be antibacterial.21,22<\/sup><\/p>\n\n\n\n

Miana is a plant that grows in the tropics and is a\nshrub with a height of up to 1.5 m. The leaves are efficacious as a remedy for\nhemorrhoids, acne vulgaris, puerperal fever, ear inflammation, and irregular\nmenstruation.<\/p>\n\n\n\n

Miana’s taxonomy is Kingdom : Plantae; Division : Spermatophyta; Sub Division : Angiosperms; Class : Dicotyledonae; Order: Solanales; Family: Lamiaceae; Genus: Coleus<\/p>\n\n\n\n

Species : Coleus scutellariodes<\/em> (L) Benth.23<\/sup><\/p>\n\n\n\n

This plant has other names, namely Bulunangko\n(Toraja), Jawek Kotok (Sunda), Serewung (Minahasa), Ati-ati (Bugis),  Sigresing (Batak),  Iler (Central Java), and Adong-adong\n(Palembang). Miana (Coleus scutellarioides<\/em> (L) Benth) is originally from\nThailand and India.<\/p>\n\n\n\n

Miana also has a different Latin name, such as Solenostemon\nscutellariodes<\/em> Codd , Plectranthus scutellariodes<\/em>, (Linn), C.\ningrates<\/em>. Benth, Coleus atropurpureus<\/em>. Bent, , Coleus laciniatus<\/em>.\nBenth, Coleus hybridus<\/em> Hort, Coleus blunei<\/em>.24,25<\/sup> <\/p>\n\n\n\n

The morphology of the Miana root is in the form of a taproot, which is indicated by the presence of 1 enlarged root stem. Miana plants include herb plants, where the stems are soft and easily broken. The structure of the stem is upright or lying at the base. Grows up to 1.5 m tall.<\/p>\n\n\n\n

Miana leaves include single leaves, heart-shaped, rounded, or curved bases to resemble the shape of a heart. Each edge of the leaf has continuous thin grooves and long stalks measuring 3-4 cm with various colors. The tip of the leaf is tapered and the veins are pinnate. Miana flowers are shaped like a strand of flowers in layers and are red and purple in color. It has a distinctive aroma and a slightly bitter taste. (Figure 1)<\/p>\n\n\n\n\n\n
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Figure 1: Miana Tree (Coleus scutellariodes<\/em>).<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Based on the literature and\npublications that have been done before, it can be concluded that until now the\nlevel of resistance tends to increase and it is likely that many patients\ninfected with microorganisms have not been successful with antibiotics.26<\/sup>\nAccording to these conditions, they began to be directed to look for additional\ntherapies that have almost the same effect as antibiotic therapy, one of which\nis by administering herbal medicines that have useful phytochemicals to\nsuppress the inflammatory process that occurs. There are 32 plants that have\nbeen tested and have a similar antimicrobial effect as antibiotics, but in\nIndonesia, the mechanism of action of these herbal plants has not been studied\nin depth both molecularly and immunologically.9<\/sup><\/p>\n\n\n\n

One of the plants that are\ncommonly found in Indonesia is Miana leaves (Coleus scutellariodes<\/em>),\nwhich based on a study assessing the ethnopharmacology of Miana in West\nHalmahera assessed that in this area the use of Miana leaves varies widely from\ncultivation to being mixed to be used as medicine for several diseases\nincluding low back pain, coughs, ulcers, and hemorrhoids, but no one has\nreported direct consumption in typhoid sufferers. Miana’s effectiveness in\ntreating the disease is thought to be due to the phytochemical content in\nMiana, including flavonoids, tannins, saponins, phytol, rosmanic acid,\nstroptozocin, steroids, eugenol, essential oils, quercetin.25 <\/sup>The\nphytochemical content in Miana leaves such as flavonoids as anti-inflammatories\nwas also assessed to be able to have an effect on the expression of the HMGB-1\ngene as a pro-inflammatory cytokine, especially in S. typhi<\/em> infection.\nAmong these phytochemicals, which have antibacterial activity are flavonoids,\nsteroids, tannins, saponins, and alkaloids. Apart from being antibacterial, the\nflavonoid content in Miana plants is considered to have an effect as an\nanti-inflammatory.21,22,26<\/sup> Miana leaves from the purple plant are\nknown to have antioxidant properties. This antioxidant property is due to the\npresence of secondary metabolites of the phenolic group. Flavonoids are the\nlargest group of phenolic compounds found in nature. The purple color of purple\nleaves shows that antioxidant properties come from compounds belonging to the\nflavonoid group.27<\/sup> <\/p>\n\n\n\n

The chemical structure of the\nflavonoid derivatives contained in Miana (Figure 2) where Flavonoids can be\ndivided into several classes include anthocyanins, aurones, biflavones,\nchalcones, dihydrochalcones, dihydroflavonols, flavans and proanthocyanidins,\nflavanones, flavones, flavonols, isoflavonoids.28<\/sup> The basic\nstructure of Anthocyanins is a flavilium salt (Fig. 2; no.1). Flavones have\nsubstitutions at rings A and B but lack oxygenation at position 3 of ring C\n(Fig. 2; no. 2). Although flavones are generally present in cell vacuoles as O-\nand\/or C glycosides (C-glycosyl flavone), some compounds, especially simple and\npolymethoxylated flavone, are present in heartwood and as farinose exudate, bud\nwax, and so on. Flavonols are flavone attached to the hydroxyl group at\nposition 3 (Figure 2; no.3). The chalcone is a double bond between the and\npositions, but not the dihydrochalcone. So that the color of many chalcones\nbecomes yellow (Fig. 2; no. 4).<\/p>\n\n\n\n

Auron glycosides act as a water-soluble yellow\npigment in Mina flowers (Fig. 2; no. 5)<\/p>\n\n\n\n

Dihydroflavonol,\nnamely 3-hydroxy-flavanone is an intermediate required in the pathway to\nflavonols via one pathway and to anthocyanins via flavan 3,4-diol via another\npathway (Fig. 2; no. 6). Isoflavonoids differ from other classes of flavonoids\nin that they have the basic structural feature of binding to C-3 but not C-2,\nand are divided into several classes, e.g. isoflavones, coumestans,\ncoumaronochromones, pterocarpans, and rotenoids (Fig. 2; no. 7)  <\/p>\n\n\n\n\n\n
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Figure 2: Chemical structure of Flavonoid derivatives28<\/sup><\/strong><\/p>\n

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Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

A previous study has been carried out by\nassessing the potential of Miana leaves content flavonoid as an immunomodulator\nin cases of Klebsiella pneumonia<\/em> infection and the results demonstrate\nthat NRAMP-1 (Natural Resistance Associated Macrophage Protein-1) expression\ncan be elevated by Miana leaf extract (Coleus scutellariodes<\/em>).18<\/sup><\/p>\n\n\n\n

Effects of flavonoid in Miana<\/strong><\/p>\n\n\n\n

A study by Vezza, et al, showed that flavonoid derivatives have very varied effects (Table 1). By inhibiting enzymatic activity and suppressing inflammatory processes both in vivo and in vitro, the biological action of flavonoids including their antioxidant properties can reduce the severity of inflammatory diseases related to the digestive system.29<\/sup><\/p>\n\n\n\n

Table 1: Effects of flavonoid derivate as anti-inflammation in infectious diseases.29<\/sup> <\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

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

\n

Chemical compound<\/strong><\/p>\n<\/td>\n

\n

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

\n

 <\/strong><\/p>\n<\/td>\n

\n

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

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

Hibiscus sabdariffa<\/em><\/p>\n<\/td>\n

\n

Cyanidin-3-glucoside<\/p>\n<\/td>\n

\n

Decrease in the generation of inflammatory mediators<\/p>\n

Blocking the STAT pathway<\/p>\n

Reducing PGE-2 production by controlling COX-2 activity<\/p>\n<\/td>\n<\/tr>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

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

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

Alfinia katsumadai<\/em><\/p>\n

Alfinia conchigera<\/em><\/p>\n<\/td>\n

\n

Cardamomin<\/p>\n<\/td>\n

\n

Suppression of NF-kB activity<\/p>\n

Leukocyte migration restriction<\/p>\n

Preventing the production of reactive nitrogen species<\/p>\n

Pro-inflammatory mediators reduced<\/p>\n<\/td>\n<\/tr>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

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

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

Grapefruit<\/p>\n

(Citnes paradise)<\/em><\/p>\n

 <\/p>\n<\/td>\n

\n

Naringenin<\/p>\n<\/td>\n

\n

Suppression of NF-kB activity<\/p>\n

Reduction of the production of pro-inflammatory mediators<\/p>\n

Enhanced epithelial barrier performance<\/p>\n

Suppression of leukocyte migration<\/p>\n

Modulation of the gut microbiota and the antimicrobial action<\/p>\n

Suppressing COX-2 activity<\/p>\n

Suppression of the generation of reactive nitrogen species<\/p>\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

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

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

Picea crassifolia<\/em><\/p>\n<\/td>\n

\n

Chrysin<\/p>\n<\/td>\n

\n

Reduction of NF-KB activity<\/p>\n

Preventing the production of reactive nitrogen species<\/p>\n

Pro-inflammatory mediators are reduced<\/p>\n

Leukocyte migration restriction<\/p>\n<\/td>\n<\/tr>\n

\n

Scutellaria baicalensis<\/em><\/p>\n<\/td>\n

\n

Baicalin<\/p>\n<\/td>\n

\n

Suppression of NF-KB activity<\/p>\n

Modulation T cell activities<\/p>\n<\/td>\n<\/tr>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

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

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

Disosma reitchii<\/p>\n<\/td>\n

\n

Quercetin<\/p>\n<\/td>\n

\n

Suppression of NF-kB activity<\/p>\n

Decrease in the production of inflammatory mediators<\/p>\n

Preventing the generation of reactive nitrogen species<\/p>\n<\/td>\n<\/tr>\n

\n

Ruta graviolens<\/p>\n<\/td>\n

\n

Rutin<\/p>\n<\/td>\n

\n

Reduction of NF-kB activity<\/p>\n

Enhanced epithelial barrier performance<\/p>\n

Leukocyte migration restriction<\/p>\n

Reduction of COX-2 activity<\/p>\n

Reduction of pro-inflammatory mediators<\/p>\n<\/td>\n<\/tr>\n

\n

Tartaryy buckwheat<\/p>\n

(Fagopyrum tataricumm)<\/em><\/p>\n

Oaks species<\/p>\n

(Quercus sp.)<\/em><\/p>\n

 <\/p>\n<\/td>\n

\n

Quercitrin<\/p>\n<\/td>\n

\n

Reduction of NF-kB activity<\/p>\n

Decrease in the generation of inflammatory mediators<\/p>\n

Enhanced epithelial barrier performance<\/p>\n

Leukocyte migration restriction<\/p>\n

Preventing the production of reactive nitrogen species<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

The Toll-like receptors (TLRs) pathway, a protein that is crucial in triggering the body’s immune response, especially for infections carried on by the S. typhi bacteria, maybe the mechanism through which Miana leaves have an antibacterial impact.30<\/sup> <\/p>\n\n\n\n

Previous studies using the UV-V spectrophotometer qualitative\nmethod revealed that the total flavonoid component of the 96% ethanol extract\nof Miana leaves (Coleus atropurpereus<\/em>) was 8.59 mg RE\/gram of extract.\nThis compound can be used as an immunostimulator in the prevention and\ntreatment of various diseases.21,31<\/sup><\/p>\n\n\n\n

By decreasing the NF-kB signal transduction pathway, the flavonoid concentration in Miana may reduce NF-kB activity (Figure 3). After the NF-kB receptor is induced by the components of microorganisms, the NF-kB protein complex (p65-p50) will bind to each other and be inhibited by the IK-kB protein. The IKK complex (IKK, IKK, and IKK) is activated by pro-inflammatory cytokines such LPS from S. typhi<\/em>, which phosphorylates the IK-B protein. IB is phosphorylated, which results in proteasomal breakdown and the release of NF-kB. The active NF-kB protein is then activated by post-translational modifications (phosphorylation, acetylation, glycosylation), and it is translocated to the nucleus where it induces the expression of its target genes and regulates a number of biological processes, including innate and adaptive immunity, inflammation, stress response, cell development, and lymphoid organogenesis. Thus, the inhibition of the NF-kB signal transduction pathway may be responsible for some flavonoid derivatives’ ability to reduce inflammation.29<\/sup><\/p>\n\n\n\n

The results above support the hypothesis that administering Miana leaf extract can inhibit the expression of proinflammatory cytokines including MCP-1-1, IL-6, TNF-\u03b1 , and IL-1 through the NF-kB pathway.<\/p>\n\n\n\n\n\n
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Figure 3: Mechanism of inhibition of the inflammatory process through suppression of the NF-kB signaling pathway by Flavonoids.29<\/sup><\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Previous research on Mycobacterium\ntuberculosis-infected Balb\/c mice has demonstrated that Miana has\nanti-inflammatory properties by suppressing the mRNA expression of vascular\nendothelial growth factor (VEGF), hypoxia-inducible factor-1 (HIF-1), and\nintercellular adhesion molecule-1 (ICAM-1).17,32<\/sup> A previous study\nhas demonstrated that Miana can stimulate the expression of IL-37 mRNA in\nBalb\/c mice that have been injected with Candida albicans.33,34<\/sup> <\/p>\n\n\n\n

By inducing the transcription of\nproinflammatory genes, NF-kB transcriptional activation, which results from\ninfection with the translocation core complex in the cytoplasm, is a key factor\nin the inflammatory process. When cells are appropriately stimulated, most\nfrequently by signals from pathogenic or hypoxic microorganisms, these pathways\nbecome activated.35,36<\/sup><\/p>\n\n\n\n

Through the innate immune response, NF-kB is\ncrucial to the host’s defense against microbial infection. NF-kB is activated\nby multiple signaling pathways originating from many different cellular\nreceptors and sensors. Most pathogenic microorganisms are the most capable of\nregulating NF-kB activation and will then induce signals for various types of\nproinflammatory cytokines. 37<\/sup>Despite differences in signaling\nprocesses, NF-kB activation involves two major signaling mechanisms: canonical\nand noncanonical (or alternative) pathways. Both of these pathways are crucial\nto regulate immunological and inflammatory responses. After being activated by\nmicrobial or product, NF-kB will be stimulated from upstream, for example IKK\nupstream signaling factors to downstream, for example transforming growth\nfactor-\u03b2-activated kinase 1 (TAK1).36 <\/sup><\/p>\n\n\n\n

Transcriptional regulator immune system\nfunction, apoptosis, differentiation, and stress response are all crucially\nregulated through NF-kB. Multiple stimuli, such as microbial infection or its\nproducts, interact to activate NF-kB, which in turn can mediate alternative\ntranscriptional programs. As a result, both positive and negative regulatory\nmechanisms tightly regulate and closely coordinate NF-kB-dependent\ntranscription with other signaling pathways. In order to optimize the numerous\nbiological roles of NF-kB for certain responses, this complex crosstalk is\nrequired.38<\/sup><\/p>\n\n\n\n

According to Martin et al. (2016) and Lin et\nal. (2016), activation of NF-kB signaling results in the production of a\nvariety of inflammatory cytokines, chemokines, and transcription factors that\nstart and modulate inflammatory reactions as well as control the host response\nto tissue damage. In addition, NF-kB is crucial for controlling the survival,\nactivation, and differentiation of innate immune cells and inflammatory T\ncells.39,40<\/sup> Based in large part on the activation of NF-kB by\nproinflammatory cytokines like interleukin-1 (IL-1) and tumor necrosis factor\n(TNF), nuclear factor-kappa (NF-kB) has long been thought of as an archetypal\nproinflammatory signaling pathway.40<\/sup> One of the most significant\nmolecules connecting chronic inflammation to infection is nuclear factor-k (NF-kB),\na transcription factor required for the inflammatory response. The activity of NF-kB\nis closely controlled by a number of mechanisms.42<\/sup><\/p>\n\n\n\n

Bacterial endotoxins such lipopolysaccharides\nand pro-inflammatory cytokines like IL-1 and TNF-\u03b1  are the major mediators of NF-kB activation.\nMost solid tumors and hematological malignancies exhibit NF-kB activation in\ncancer cells as well as in the tumor microenvironment.43<\/sup>\nAdditionally, systemic lidocaine administration affects TNF-\u03b1  and NF-kB gene expression on musculoskeletal injury.44<\/sup>\nas well as VEGF, HIF-I, and HMGB1 as a crucial regulator in DOX-induced\ncardiomyocyte damage through NF-kB pathway.45<\/sup> <\/p>\n\n\n\n

The molecular mechanisms of Miana through Nuclear factor-kappa B (NF-kB)\n activities on infectious diseases<\/strong><\/p>\n\n\n\n

By preventing the synthesis of\nnucleic acids and affecting the permeability of bacterial cell walls,\nmicrosomes, and lysosomes, the flavonoids and quercetin found in Miana are\nknown to directly inhibit the growth of microorganisms (both in vitro and in\nvivo). According to Taufik et al. and Yanto et al, the mechanism involves\ninteractions between flavonoids and bacterial DNA, the formation of complex\ncompounds with external proteins, the destruction of the latter through\ndissolution in bacterial cell membranes, and mixing with intracellular\nchemicals.8,34<\/sup> <\/p>\n\n\n\n

In a state of infection, apart from\ncausing PAMP and DAMP events caused by microorganisms, it will also increase\nROS and NF-kB activity, where proinflammatory cytokines including TNF-\u03b1, MCP-1,\nIL-8, and IL-6, and IL-1 are produced more frequently as a result of\ninflammation stimulation.<\/p>\n\n\n\n

 This increase in proinflammatory cytokines\nwill have an impact in the form of biological effects such as symptoms of\ninflammation, bacterial growth, endothelial activation, cell migration, tissue\ndamage, and sepsis. Besides that, the increase in ROS activity due to infection\nwill induce NF-kB activity and also end up with an increase in the production\nof proinflammatory cytokines. ROS will also induce HIF-I and can affect NF-kB\nactivity. In addition, hypoxia and increased HIF-I activity are closely related\nto inflammation, bacterial growth, endothelial activation, cell migration,\ntissue damage, and sepsis.<\/p>\n\n\n\n

Microorganism antigens can bind to\nTLR-4 ligands and then TLR-4 will induce NF-kB which will produce inflammatory\nstimulation and end with increased production of proinflammatory cytokines.<\/p>\n\n\n\n

Miana’s active components such as\nflavonoids and quercetin as strong antioxidants can inhibit the inflammatory\nprocess through the ROS pathway thereby preventing hypoxia. Also, Miana can\ninhibit inflammatory processes through the NF-kB, TLR-4, and HIF-1 alpha\npathways and the production of proinflammatory cytokines. Thus, the effect of\nMiana (Coleus scutellariodes<\/em>) to inhibit NF-kB via several pathways\nwhile NF-kB has a pivotal regulator of proinflammatory cytokines in infectious\ndiseases. In addition,  the increase of\nvarious angiogenic factors in infectious disease, both in vitro and in vivo,\nmay be caused by Miana’s inhibition of HIF-1 expression and TLR-4 function.<\/p>\n\n\n\n

Downstream of the body’s defense system against infection, Miana’s effect can inhibit proinflammatory cytokines such as TNF-\u03b1 , MCP-1-1, IL-8, IL-6, and IL-1. Thus, it can be concluded that the effect of Miana (Coleus scutellariodes<\/em>) to inhibit NF-kB via several pathways such as PAMP and DAMP. The summary of molecular mechanisms of Miana through Nuclear factor-kappa B (NF-kB) activities on infectious diseases could be shown in Figure 4. <\/strong><\/p>\n\n\n\n\n\n
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Figure 4: Pathomechanisms of Miana (Coleus scutellariodes)<\/em> via Nuclear factor-kappa B (NF-kB) activities on Infectious Diseases<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

In cases of\nbacterial infection, including S. typhi<\/em>, extracellular HMGB1,\npathogen-associated molecular patterns (PAMPs), and damage-associated molecular\npatterns (DAMPs) are known to interact with a variety of receptors and\nimmunological sensors.46,47<\/sup> In order to produce pro-inflammatory cytokines like\ntumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1-1),\nIL-6, and IL1, HMGB1 must bind to the TLR-4 receptor, which activates the\nnuclear factor kappa- (NF-kB) signaling pathway through the IKK kinase complex\n(I-kB)\nbinding.48<\/sup> Similar to quercetin, a flavonoid derivative, NF-kB is suppressed in its transcriptional activity by\nquercetin, which inhibits the NF-kB pathway.49.50,51<\/sup> <\/p>\n\n\n\n

Inflammatory stressors triggered by infection by S.typhi<\/em>\ncan cause an exaggerated immune response and sepsis which will cause damage to\norgans.36<\/sup> The mechanism of anti-inflammatory action of Miana and\nQuercetin is related to their ability to inhibit signals from several Toll-like\nreceptors (TLRs) which mediate the inflammatory response. Miana which contains\nflavonaoids and quercetin as anti-inflammatories, works to stabilize cell\nmembranes by reducing the release of proteases from neutrophils or macrophages.\nMiana and quercetin are able to inhibit the release of inflammatory cytokines\nsuch as interleukin-37, IL-1, and VEGF. Miana and parenteral quercetin also\nshow the ability to inhibit neutrophil adhesion, migration and accumulation,\nmacrophage activity and enzyme release.34,52,53,33<\/sup> <\/p>\n\n\n\n

According to a study by Canton et al. from 2021, NF-kB is engaged in hypoxic circumstances, and there is increasing evidence that HIF-1 and NF-kB interact to cause HIF-1 to be upregulated in situations when NADPH oxidase-mediated ROS are present.54<\/sup> By inhibiting NF-kB activation and altering the expression of HIF-1 and ICAM-1 and cytokine release, Miana contain flavonoid and Quercetin may be able to reduce inflammation.55,16,17<\/sup> Additionally, a study by Wahyuni et al. in 2021 found that administering Miana orally caused induced Balb\/c mice with Klebsiella pneumonia<\/em> to have significantly higher plasma levels of NRAMP-1, which is responsible for activating macrophage cells.18<\/sup> <\/p>\n\n\n\n

Table 2 provides an overview of Miana’s prior publications in a number of infectious disorders, including vulvoginal candidiasis, TB, typhoid fever, A. actinomycetemcomitans<\/em>, and Klebsiella pneumoniae<\/em> infections.<\/p>\n\n\n\n

Table 2: Effects of Miana extract as anti-inflammation and antimicrobial in infectious diseases<\/strong>. <\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

 <\/strong><\/p>\n

Disease\/<\/strong><\/p>\n

Microrganisms  <\/strong><\/p>\n

 <\/strong><\/p>\n<\/td>\n

\n

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

\n

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

\n

Typhoid fever\/<\/p>\n

Salmonella typhi<\/em><\/p>\n<\/td>\n

\n

Inhibition TLR-4 activity<\/p>\n

Antimicrobial effect<\/p>\n<\/td>\n

\n[30]\n<\/td>\n<\/tr>\n
\n

Typhoid fever\/<\/p>\n

S.typhi<\/em><\/p>\n<\/td>\n

\n

Inhibition NF-kB activity<\/p>\n

Antimicrobial effect<\/p>\n<\/td>\n

\n

This study<\/p>\n<\/td>\n<\/tr>\n

\n

Pneumonia\/<\/p>\n

Klebsiella pneumoniae<\/em><\/p>\n<\/td>\n

\n

Increase Natural Resistance Associated Macrophage Protein 1 (NRAMP-1)<\/p>\n

Antimicrobial effect<\/p>\n<\/td>\n

\n

[18]\n<\/td>\n<\/tr>\n

\n

Vulvovaginal candidiasis\/<\/p>\n

Candida albicans<\/em><\/p>\n<\/td>\n

\n

Induce mRNA IL-37 expression<\/p>\n

Antioxidant<\/p>\n

Antimicrobial effect<\/p>\n

Decrease IgM<\/p>\n<\/td>\n

\n

[33]\n

[20]\n

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

\n

Tuberculosis\/<\/p>\n

Mycobacterium tuberculosis<\/em><\/p>\n<\/td>\n

\n

Inhibition TLR-4 activity<\/p>\n

Alterations in HIF-1 and ICAM-1 Expression<\/p>\n

Inhibition VEGF<\/p>\n

Antimicrobial effect<\/p>\n<\/td>\n

\n

[56]\n

 [17]\n

 [32]\n<\/td>\n<\/tr>\n

\n

Periodontitis\/<\/p>\n

A. actinomycetemcomitans<\/em><\/p>\n<\/td>\n

\n

Increase IL-10<\/p>\n

Antimicrobial effect<\/p>\n<\/td>\n

\n

[4]\n<\/td>\n<\/tr>\n

\n

Pseudomonas aeruginosa<\/em><\/p>\n

Escherichia coli<\/em>\/<\/p>\n

Streptococcus<\/em> sp.\/<\/p>\n

Staphylococcus<\/em> sp.\/<\/p>\n<\/td>\n

\n

Inhibition HIF-I<\/p>\n

Antimicrobial effect<\/p>\n<\/td>\n

\n

[34]\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

The interaction between LPS S.\ntyphi<\/em> and TLR-4 that activates MyD88 is crucial in regulating bacterial\nexponential development. Inducible NO synthase (iNOs), NF-KB, and TNF-cytokines\nwill all turn into nuclear translocated as a result of LPS stimulation of TLR-4\nand the effect of Miana significantly reduced the TLR-4 mRNA expression.30<\/sup>\nMeanwhile, Miana’s molecular pathomechanisms can suppress NF-kB activity in\ninfectious conditions. <\/p>\n\n\n\n

According to Wahyuni’s study, the\nadministration of Miana will result in an increase in NRAMP-1 protein levels,\nand clinical impact has shown a comparable effect on inhibiting Klebsiella\npneumoniae<\/em>. A metal ion transporter called NRAMP-1 can export iron and\nmanganese from the macrophage phagosome in order to reduce the number of metals\nthat an intracellular pathogen can access. The expression of NRAMP-1 (cytosolic\niron transport) and iron-carrying protein is induced by microbial infection in\nmacrophages. These alterations in iron homeostasis improve iron\nbioavailability, which makes it easier to obtain iron and boosts intracellular\nmicrobe survival. The regulation of NRAMP-1 during microbial infection shows\nthat NRAMP-1 helps phagocytes fight off infections and, in mammalian hosts,\nisolates iron, zinc, and manganese ions to restrict microbial development\nthrough a mechanism known as nutritional immunity.18<\/sup> <\/p>\n\n\n\n

 Miana may act as an anti-inflammatory through\nits role as an antioxidant, so it could potentially be used as an alternative\ntreatment in humans, particularly patients with vulvovaginal candidiasis.\nAccording to another study, Miana has fungistatic effects on the expression of\nmRNA IL-37 in vulvovaginal candidiasis. The body needs antioxidants to stop and\nget eliminated pathogen invasion and produce an appropriate and effective\nimmune response. Flavonoids, one type of antioxidant found in Miana, have been\nshown to elevate levels of IFN-\u03b3 and CD4+ T-cells with decreasing microbe\nnumbers.<\/p>\n\n\n\n

Miana are herbal medicines that at\nthe molecular level exhibit anti-inflammatory properties in patients with\nvulvovaginal candidiasis caused by Candida albicans<\/em>, as well as the\npotential to inhibit the production of prostaglandin, pro-inflammatory\nsignaling molecules. It has been identified over the years the significance of\ntraditional remedies for treating vulvovaginal candidiasis and how the cytokine\nIL-37, an IL-1 derivative that has been shown to naturally inhibit the\nnon-specific immune system, has a similar effect as an immune mediator with\nanti-inflammatory properties. Although the mechanisms of cytokine IL-37 action\nare still unknown, lipopolysaccharide induction has been shown to be the basis\nof its pro-inflammatory features.33<\/sup> \n<\/p>\n\n\n\n

Currently, azoles, polyenes,\nechinocandins, allylamines, and fluoropyrimidines are utilized as antifungals\nto treat fungal infections. However, the restricted use of these antifungals\nfor C. albicans<\/em> infection has increased patient toxicity and drug\nresistance. It has been demonstrated that the Miana is safe and effective in\npharmacological activities, such as antifungal activity, and that it has the\npotential to create new antifungals to treat Candida infection. The metabolites\nof allicin, diterpene, coumarin, terpenoids, curcumin, xanthorrhizol, thymol,\nessential oils, eugenol, and [6]-shogaol may show the mechanism of action of\nMiana against C. albicans<\/em>. T The antifungal mechanisms of medicinal\nplant metabolites include disruption of hyphal production by allicin, filament\nand biofilm formation by [6]-shogaol, curcumin, and xanthorhizol, envelope by\neugenol, membrane permeabilization by essential oils, thymol, and diterpene,\nand cell wall by terpenoids, thymol, and coumarin.  Metabolite primarily exerts its antifungal\neffects through the cell wall, membrane, and growth inhibition active\nmechanisms.20<\/sup><\/p>\n\n\n\n

According to Amsyah et al., Miana\ntreatment against A. actinomycetemcomitans<\/em> had a substantial impact on\nthe expression of IL-10 mRNA, and Miana administration will increase the\nexpression of IL-10 mRNA in periodontitis caused by A. actinomycetemcomitans<\/em>.\nLipopolysaccharides (LPS), cytolethal distending toxin (cdtABC), leukotoxins,\nand A.actinomycetemcomitans<\/em> all have virulence factors that can affect\nthe host immune system and contribute to periodontal disease. CdtB entrance\ninto the cell is facilitated by interactions between CdtA and CdtC and the host\nmembrane. When CdtB enters the cell, an active mechanism that requires amino\nacid residues in its N terminus transports it into the nucleus. Through its\nDNAse activity, CdtB induces apoptosis and damages DNA in the nucleus. Aa Cdt\nhas the ability to increase the production of receptor activator of nuclear\nfactor-KB ligand in human gingival fibroblast, which is involved in\npathological bone resorption that is a hallmark of localized aggressive\nperiodontitis. Lipopolysaccharides (LPS) activate macrophages to create\ninterleukin-1, tumor necrosis factor, mRNA, and protein that are implicated in\npotent inhibitors of fibroblast proliferation, bone resorption, and tissue\ninflammation, among other immunological and endotoxic actions.4<\/sup> <\/p>\n\n\n\n

By altering the ratio of pro- and\nanti-inflammatory cytokines as well as the strength and quantity of the immune\nsystem’s reaction to T cells, B cells, and cytokines, Miana can improve\nimmunity. Miana administration influenced the expression of IL 10 mRNA, which\nthus impacted host immunity. The specific genotypes with low IL-10 expression\nmay exacerbate the inflammatory response and lead to the expansion of the\ngingival. IL-10 is a significant anti-inflammatory cytokine that was involved\nin the development of periodontal disease. By producing reactive oxygen species\n(ROS) and nitrogen intermediates, IL-10 suppresses the activity of\nproinflammatory cytokines and prevents phagocytosis and microbial death.\nBecause proinflammatory cytokines have not been regulated by anti-inflammatory\ncytokines when IL-10 levels are low, their activity can increase.4<\/sup>  <\/p>\n\n\n\n

Based on a previous study, quercetin,\nand flavonoid extracted from herbals and their derivatives, including Miana,\nhave been proven to strongly inhibit the activities of NF-kB and HIF-1. In\naddition, it has been revealed that the transcriptional regulator NF-kB has a\ncritical role in controlling the immune system, apoptosis, differentiation, and\nstress response. Flavonoids such as rutin and quercetin activated Sirtuin1.\nSirtuin1 is essential in the NF-kB regulation and the immune system, apoptosis,\nand oxidative stress transcriptional regulation of a variety of transcription\nfactors. Sirtuin1’s role in infectious diseases makes it possible to explore\nthe pathomechanisms of Miana.57-61<\/sup> \n<\/p>\n\n\n\n

Furthermore,\nNF-kB has a key role in activating the pro-inflammatory genes that produce\ncyclooxygenase-2, IL12, IL6, and TNF-\u03b1 . TLR-4 assists NF-kB in mediating the\ndifferentiation of macrophages towards the M1 phenotype. M1 stimulates the\nrelease of cytokines that cause inflammation and the proliferation of T cells\nthat cause inflammation. Several studies have reported that herbals and their\nderivatives including Miana contain flavonoid and quercetin which is effective\nin strongly inhibiting NF-kB  and HIF-1\nactivities.62,34,63,64.<\/sup> <\/p>\n\n\n\n

Conclusions<\/strong><\/p>\n\n\n\n

Miana\n(Coleus scutellariodes<\/em>) is a commonly used supplement agent for\ninfectious diseases and it is unclear exactly how the mechanisms of Miana are\nagainst bacteria and inflammation. Nuclear factor-kappa B (NF-kB) strongly\ninduces proinflammatory cytokines through I-kB by interacting with the NF-kB\nreceptor, which affects cytokine release and angiogenesis. Because VEGF is an\nangiogenic factor and activates the NF-kB pathway, it can drive cellular\nresponses on the surface of endothelial cells, where HIF-1 plays a significant\nrole in the cellular response to systemic oxygen levels of cells.<\/p>\n\n\n\n

Under\nconditions of Miana used to treat infectious diseases, NF-kB plays a crucial\nrole as a regulator and mainly functions through multiple pathways. Miana’s\ntreatment of infectious diseases could inhibit NF-kB activity leading to the\nconclusion that NF-kB is a stimulator of several proinflammatory cytokines. The\nproduction of HIF-1, which is also responsible for the elevation of various\nangiogenic factors in infectious disease both in vitro and in vivo, can be\ndecreased by Miana treatment through reduced NF-kB.<\/p>\n\n\n\n

Because\nMiana contains active components of flavonoid, which have broad and complex\nabilities, both in inflammatory and non-inflammatory processes that involve\nNF-kB, research is urgently needed to link upstream, for example, IKK upstream\nsignaling factors to downstream, for example transforming growth factor-\u03b2\n-activated kinase 1 (TAK1) of the mechanisms of canonical and non-canonical of\nNF-kB pathway.<\/p>\n\n\n\n

Besides\nthat, studies are needed to be related to the intricate crosstalk in the\ninflammatory process due to microorganism infection through NF-kB activity in\nMiana interventions containing flavonoid active substances.<\/p>\n\n\n\n

Acknowledgement<\/strong><\/p>\n\n\n\n

Authors would like to thank Romi Usman, Mus Jubaru, Wani, and Markus of Molecular Biology and Immunology Laboratory for Infection Diseases, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia who helped in the search of journals.<\/p>\n\n\n\n

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

The authors declare no conflict of interest, financial or otherwise. <\/p>\n\n\n\n

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

No specific funding are available. <\/p>\n\n\n\n

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

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    Abbreviation<\/strong><\/p>\n\n\n\n

    DAMP            =\nDamage-associated molecular pattern<\/p>\n\n\n\n

    HIF-I               = Hypoxia-inducible factor-1 <\/p>\n\n\n\n

    HMGB1          =\nHigh mobility group box protein 1<\/p>\n\n\n\n

    IL                    =\nInterleukin <\/p>\n\n\n\n

    TNF-\u03b1            = Tumor Necrosis Factor alpha<\/p>\n\n\n\n

    MCP-1            =\nMonocyte Chemoattractant Protein-1<\/p>\n\n\n\n

    MMP               =\nMatrix metalloproteinase<\/p>\n\n\n\n

    NF-kB             =\nNuclear factor kappa beta<\/p>\n\n\n\n

    NRAMP-1       =\nNatural resistance associated macrophage protein-1<\/p>\n\n\n\n

    PAMPs            =\nPathogen-associated molecular patterns<\/p>\n\n\n\n

    RAGE             =\nReceptor for advanced glycation end-product<\/p>\n\n\n\n

    ROS                =\nReactive oxygen species<\/p>\n\n\n\n

    STAT              =\nSignal transducer and activator of transcription<\/p>\n\n\n\n

    TLR-4             =\nToll like receptor-4<\/p>\n\n\n\n

    TNF-\u03b1            =\nTumor Necrosis Factor Alpha<\/p>\n\n\n\n

    VEGF              =\nVascular endothelial growth factor <\/p>\n","protected":false},"excerpt":{"rendered":"

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