August 30, 2018

Newsletter • 2018 • vol.2 • 52-62

PHYTOCHEMICAL AND PHARMACOLOGICAL IMPORTANCE OF NEGLECTA: AN UPDATED REVIEW Sana Khalid1* and Uzma Saleem1 11Faculty of Pharmaceutical sciences, Government College University, Faisalabad-

[email protected]

Abstract Traditional herbal mediciene is known to mankind from decades and still widely practiced throughout the globe. employed in traditional applications are the potential sources of cheap herbal medicines. Malva neglecta from family is used to treat several serious ailments. Numerous phytoconstituents identified in different parts of Malva neglecta exhibit strong therapeutic effects. Phytochemical studies on this have revealed the presence of phenolic acids, flavonoids, lipids and anthocyanins. Malva neglecta showed a wide range of pharmacological activites including antioxidant, anti-arthritic, anti-microbial, anti-urolithiac, anti-cholinesterase, anti aging and few others. This review article summarizes all the essential information on the phytochemical and pharmacological importance of Malva neglecta and will be a valueable addition to the pharmacology of plants as there is no previously reported review present on this topic.

Keywords: Traditional medicine, Malva neglecta, Phytochemicals, Pharmacological activities.

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Introduction tolık by local people in [10]. Its local name Hmamchoorieh and Panirak in [11, 12]. Bioactive compounds from natural sources Malva is comprised of 25–30 species are gaining consumer attention owing to increased of annual, biennial, and perennial plants. The genus cost and potentially damaging side effects of is prevalent throughout the temperate, subtropical conventional medicines. Plant-based medicines are and tropical regions of Europe, Asia and Africa[13, promising for drug development because they are 14]. Malva neglecta is native to almost all of Europe, significant sources of phytochemical constituents. from northern Europe (e.g., , , These constituents obtained from traditional plants , , ), middle Europe are the potential raw material for the production of (e.g., , ), Southeastern Europe (e.g., new medicines. By the mid of 19th century, the , , , etc.), to Southwestern origin of almost 80% of the medicines was herbs. It is Europe (e.g., , , ). It is also generally recognized that folk medical uses of plants found in Western Asia, the Arabian Peninsula, specify the existence of biologically active Northwestern Asia (e.g., , , constituents in a plant. In a broader sense, , ) and also in China and the traditional medicines represent a shortcut method Indian subcontinent. In Africa, it is found mostly in to discover contemporary medicines [1, 2]. Herbal North Africa, Such as and [15]. medicines have also been known as botanical Morphological characteristics medicines or phytomedicines. The medicinal The leaves are stipulate, shallowly lobed, properties of the traditional plants are attributed to long-stalked crenate, pilose and blade-kidney their parts like stem, roots, bark, fruit, flowers and shaped. Its flowers are actinomorphic, 1.5-2.5 cm leaves to support general health and treatment. wide. Petals are of 8-15mm and white, pinkish or Such herbal constituents may be utilized as a red-veined with notched tips [16]. are formulation or may be incorporated into different triangular and 2-4.5mm in size. Mericarps are products [3]. smooth and epicalyx is linear. Flowers are borne in Malva neglecta is an annual herbaceous plant leaf axils. Stem is erect and pilose with simple setae of the genus Malva and family Malvaceae [17]. traditionally eaten fresh as a leafy vegetable or used Traditional uses as decoctions. It is also used to treat several medical Malva neglecta had been used as herbal conditions such as abdominal pain, asthma, colds, medicine in the treatment of different diseases in digestive and urinary tract infections [4]. Scientific Iran. All parts of the plant exhibit diuretic, studies have reported antioxidant, antibacterial and demulcent, laxative and anti-phologistic properties. anti-ulcerogenic properties for this plant [5]. The leaves and flowers have been used mainly as a Plant profile poultice, for inflammation, bruise and insect bites or Taxonomic classification internally for respiratory and urinary tract infections Kingdom: Plantae; Subkingdom: [18]. The stem and root of this plant is abortifacient Tracheobionta; Superdivision: Spermatophyta; and aerial parts have been used to treat Division: Magnoliophyta; Class: Magnoliopsida; hemorrhoids, kidney stones and diarrhea. The leaf Subclass: Dilleniidae; Order: ; Family: bears the therapeutic potential against Malvaceae ; Genus: Malva L.; Species: Malva neglecta stomachache, gynecological disorders, cough and Wallr. [6]. diabetes. Its poultice has been used widely for Common names and distribution maturation of abscess and wound healing [10]. The It is known by various common names such plant is used for the treatment of acne, burns, as Common mallow, dwarf mallow, cheese plant, broken bones, dermatitis and throat infection [19]. cheese weed, button weed and round leaf mallow Malva tea helps to lessen inflammation and [7]. Malva neglecta is locally known as Sonchal [8], mouth irritation due to its high mucilage content. and Banerak [9] in Pakistan. In Turkey, it is called as Malva neglecta is a valuable plant to treat cough ebegümeci, develik, gömeç, kömeç, ebegömeci and because of its expectorant and cough-suppressing action. Additionally, leaves of

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this plant contain tannins, which alleviate prevent oxidative stress and delay the oxidative stomachache and diminish intestinal spasms [7]. processes [23]. Natural antioxidant compounds, Phytochemical investigation derived from plant sources, have been identified as The methanol extracts of Malva neglecta active oxygen scavengers [24]. Nowadays, interest have been screened by using a liquid has been increased considerably in the discovery of chromatography-mass spectrometry (LCMS) to natural antioxidants for use in medicine to replace qualify and quantify different compounds including the synthetic antioxidants, which are being several phenolic acids, flavonoids and some non- restricted due to their harmful effects [25]. phenolic compounds shown in Table 1. Malva Hydroalcoholic extract of Malva neglecta neglecta was rich in terms of phenolic acids [20]. have shown strong antioxidant capacity, hydrogen Regarding the amount of total phenolics in Malva peroxide scavenging, free radical scavenging, neglecta, leaf contained the highest concentration, superoxide anion radical scavenging, and metal which directly coincides with high antioxidant chelating activities in comparison with natural and capacity of the plant [21]. Among the phenolics, the synthetic standard antioxidants such as BHA, BHT largest contribution was from flavonoids. and α-tocopherol [26]. Phenolic compounds and Flavonoids made up the largest group by the flavonoids have also been reported to show potent contribution of both subgroups: flavonols and in vitro antioxidant properties and their potential anthocyanins. Very low levels of anthocyanin is in the prevention of various diseases caused by present in the different parts of Malva neglecta [10]. oxidative stress [27]. Anti-oxidant capacities of M. Malvidin was the main flavonoid compound of Malva neglecta fruit have been measured using Folin– cells followed by catechin, delphinidin, and apigenin Ciocalteu method, ferric reducing assay and oxygen [22]. 4-Hydroxycinnamic acids made the second radical absorbance capacity assays [10], which are largest group of phenolic compounds contributing based on mechanisms of electron transfer and approximately 10–18% of total phenolics. The quantify the total concentration of redox-active distribution pattern of total phenolics total species [28]. flavonoids and 4-hydroxycinnamic acids was same in Anti-inflammatory activity the parts of plant i.e. root < stem < fruit < flower < Malva neglecta extract reduces the leaf [10]. production of pro-inflammatory cytokines in The composition of the lipids obtained from synoviocytes. It reduces TNF-α gene expression in the petroleum ether extract has been identified as both LPS-induced human monocytic cell lines (THP-1 palmitic acid (36.8%), linoleic acid (17.8%), and cells) and synoviocytes. Moreover, it can reduce IL- linolenic acid (13.2%). The chief constituents of the 1β, COX-2, IL-18 and iNOS genes expression in essential oil have been identified as cineole (18.8%), synoviocyte cells. This shows that the Malva neglecta hexatriacontane (7.8%), tetratetracontane (7.8%) is effective in the reduction of pain and and α-selinene (4.2%). When compared the essential inflammation in osteoarthritis [11]. oil composition of Malvaceae family, M. neglecta is TNF-α is the main inflammation causing seemed to have richer content than others [20]. agent among the inflammatory cytokines involved in Malva neglecta has considerable amounts of 4- the pathogenesis of osteoarthritis. Previous anti- hydroxy benzoic, salicylic acids and malic acid inflammatory studies performed on medicinal plants content [10]. have shown that the consumption of these plants Pharmacological activities reduces the expression of inflammatory cytokines Anti-oxidant activity TNF-α, IL-1B, PGE2 and induced NO [18]. The Excess generation of reactive oxygen reduction in expression of TNF-α and IL-1B cytokines . species (ROS) and other free radicals (O2.-), (HO ), by Malva extract, that slows down the process of 1 H2O2, ( O2) during metabolism results in oxidative cartilage weakening and reduction in the production stress which is related to inflammation, cancer, of prostaglandin and nitric oxide is reported in the ageing and various chronic diseases responsible for pain relief and inflammation [30]. Malva’s potential increase in death rate. Exogenous antioxidants to reduce the pro-inflammatory factors has been namely Vitamin E, carotenoids and flavonoids studied in various tissue cell types, and its role as an

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alternative and supplement method to The crude extracts of Malva neglecta have traditional NSAIDs used in the treatment of shown to be effective against fungal strains. osteoarthritis was confirmed [31]. Chloroform and Ethyl acetate fractions were active The reduction in expression or production of in fungal strains mentioned in table 3. The water and inflammatory agents has been found to be less with n-butanol fractions of plant extract have the best ibuprofen and betamethasone as compare to Malva Antifungal activity [36]. The reason behind the anti- neglecta extract. This extract has been reported to bacterial and anti-fungal activity might be the be effective in preventing and treating other presence of certain phytochemicals such as diseases associated with inflammation and tissue alkaloids, glucosinoltes, flavonoids, rhamnose, damage [28]. Anti-inflammatory effect of Malva tannins, phenolic acids and volatile oils [19]. neglecta extract may be due to saponin content Anti-cholinesterase activity present in this plant [32]. Inhibition of acetylcholinesterase is a Anti-microbial activity promising treatment strategy in case of neurological Various researches have been documented disorders such as myasthenia gravis; senile on the anti-microbial properties of Malva neglecta dementia, glaucoma, Parkinson’s disease and ataxia extracts. Previous studies have demonstrated [39]. Polyphenols are biologically active compounds bactericidal [33] , antifungal [13], and embedded in plant parts and are known to prevent immunomodulatory [34] properties of this plant. degenerative diseases [40]. All of the extracts of Suitable efficacy of chloroform, water and ethanol Malva neglecta exhibit moderate activity against extracts on some bacterial and fungal contaminants acetyl-and butyryl-cholinesterase enzymes. have been confirmed [35]. All extracts of this plant Especially, the Malva neglecta methanolic extract were active against S. aureus, P. aeruginosa, and P. have the highest activity against acetyl-and butyryl- vulgaris which have been reported to be cholinesterase enzymes. There are only few studies troublesome bacteria in wound infections, about Malva and Malvella genus anticholinesterase especially in the case of antibiotic resistant activity in literature. Therefore, Malva neglecta may microorganisms. Anthocyanin can be responsible for be useful as good anticholinesterase inhibitor. acceptable antibacterial effects of aqueous extracts However, further evaluations, particularly in vivo of this plant [36]. tests, are needed to understand the activity in The anti-bacterial activity has been biological systems [20]. quantitatively determined by the presence of In addition to that there are two studies inhibition zone around the discs containing the about anticholinesterase activity of Thespesia extract. Malva neglecta can depress S. aureus and S. populnea (Malvaceae). In these researches, it has epidermidis bacterial growth and this anti-bacterial been reported that T. populnea bark is important for paralleled to increasing of concentration. The improving memory and in the management of highest activity was against S. epidermidis .These Alzheimer disease [41]. strains were more susceptible to the extract of Anti-urolithiac activity Malva neglecta as compared to standard antibiotics Malva neglecta is extensively used in folk [37]. Organic extracts have been found to yield medicine for urolithiasis. This palnt had a preventive more consistent results regarding antimicrobial and treatment effect on calcium oxalate (CaOx) activity. A report by Parekh et al. [38], illustrated calculus formation and tubulointerstitial damage that most of the identified antimicrobial with a dosage dependent manner. Administration of phytochemicals were water insoluble, a possible ethylene glycol and ammonium chloride can induce reason why extracts by organic solvents were more renal CaOx deposition in rats [42, 43] as a model to effective. Malva neglecta organic solvent extract mimic the kidney stone formation in humans. There was more effective against the growth of bacterial has been a traditional use of Malva neglecta in strains mentioned in Table 3. A study reported by kidney stones, and it has been evaluated by its Jasim (2006), reported that the petroleum ether aqueous extracts on ethylene glycol and ammonium extract inhibited the growth of S. aureus, S. chloride induced kidney stones in male rats. pneumoniae, H. influenzae and M. catarrhalis [16]. Microscopic examinations of kidney sections have

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shown extensive renal damage and CaOx beneficial for use in topical compositions for deposits in calculi induced rats. In prophylactic and application to the skin and provide significant and curative treatment groups, low and high dosages of unexpected benefits for skin, include enhancing skin extract reduced the number of CaOx calculi and barrier protection and skin moisturization, tubulointerstitial damage whereas high dosages of improving, reducing, inhibiting, or delaying the extract seemed to be more effective. The exact appearance of aging in skin [15]. mechanisms involved in the effect of M. neglecta on Conclusion CaOx calculi remain unclear. To conclude, Malva neglecta is a widely It has been speculated that Malva neglecta distributed plant with significant pharmacological prevents the formation of CaOx calculi and effects. The presence of phytochemicals in all parts tubulointerstitial damage due to its antioxidant and of the plant makes it highly beneficial to be used in anti-inflammatory effects. Saponins have been various diseases. However, these wide range of reported to exhibit antioxidant, antiviral and phytoconstituents need to be explored more. cholesterol lowering properties [31]. Previous Acknowledgement studies have indicated that plants rich in saponin I am thankful to Dr. Uzma Saleem, Assistant content have protective effects on the renal Professor, GC University Faisalabad-Pakistan for oxidative stress and renal interstitial fibrosis in rat guidance and encouragement in preparing this models [42]. They play a vital role in prevention of manuscript. ethylene glycol induced urolithiasis [44]. References In traditional medicine, Malva neglecta is 1. Gilani, H., 2005. Atta-ur-Rahman. Trends in used for the treatment kidney stones and urinary ethnopharmacology. 100(1-2):43-49. disorders. The anti-urolithiatic activity of this plant 2. Alves, R. m. R., Rosa, I.M., 2007. Biodiversity, might be attributed to its components such as traditional medicine and public health: saponins, flavonoids, mucilage, and phenolic where do they meet? Journal of compounds [45]. Ethnobiology and Ethnomedicine. 3(1):14. Anti-ageing 3. Tang, S.Y, Halliwell, B., 2010. Medicinal Traditional art describes use of Malva plants and antioxidants: what do we learn neglecta in forms such as a water decoction, after from cell culture and Caenorhabditis elegans removing insoluble parts of the plant taken orally, as studies? Biochemisty and Biophysics a poultice, or an infusion applied to wounds and Research Communications. 394(1):1-5. tumors. Malva neglecta in the form of decoctions 4. Türker, M., Dalar, A., 2013. In vitro have been used for treating abscesses, boils, burns, antioxidant and enzyme inhibitory eczema, and insect bites Using water typically properties and phenolic composition of M. extract only the most polar constituents, e.g., neglecta Wallr. (Malvaceae) fruit: A tannins [15]. traditional medicinal fruit from Eastern (Rogers et al., 1996) demonstrated Anatolia. Industrial Crops and Products. significant decreased levels of major skin lipid 51:376-380. species, in particular ceramides with increasing age. 5. Pinela, J., Barros, L., Antonio, A.L., Carvalho, (Jensen et al., 2005) demonstrated reduced A.M, Oliveira, M., Ferreira, I.C., 2016. Quality activities of ceramide-generating enzymes in the control of gamma irradiated dwarf mallow inner epidermis of aged Skin. It is highly desirable to (Malva neglecta Wallr.) based on color, increase skin lipid levels, e.g., ceramide levels, to organic acids, total phenolics and achieve significant improvements in skin barrier antioxidant parameters. Molecules. structure and function specifically improving on the 21(4):467. appearance of aging [46, 47]. 6. USDA N. 2013. The PLANTS Database Extracts of Malva neglecta provide a (http://plants. usda. gov). National Plant significant increase in ceramide levels in human skin Data Team, Greensboro. North cells, which is indicative of improved skin barrier Carolina.27401-24901. function. Certain extracts of Malva neglecta are

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ethanol and water extracts of medicinal 34. Ghaoui, W. B. J. E., Ghanem, E. B., Chedid, L. plants, Malva sylvestris and Malva neglecta A., Abdelnoor, A. M., 2008. The effects of on some bacterial and fungal contaminants Alcea rosea L., Malva sylvestris L. and Salvia of wound infections. Journal of Medicinal libanotica L. water extracts on the Plants Research. 6(29):4550-4552. production of anti―egg albumin 24. Tanagho, E., McAninch, J., 2000. Smith's antibodies, interleukin―4, gamma General Urology (LANGE Clinical Science). interferon and interleukin―12 in BALB/c New York: McGraw-Hill. mice. Phytotherapy Research. 22(12):1599- 25. Brighente, I., Dias, M., Verdi, L., Pizzolatti, 1604. M., 2007. Antioxidant activity and total 35. Grierson, D., Afolayan, A., 1999. Antibacterial phenolic content of some Brazilian species. activity of some indigenous plants used for Pharmaceutical Biology. 45(2):156-161. the treatment of wounds in the Eastern 26. Güder, A., Korkmaz, H., 2012. Evaluation of Cape, South Africa. Journal of in-vitro antioxidant properties of Ethnopharmacology. 66(1):103-106. hydroalcoholic solution extracts Urtica 36. Magro, A., Carolino, M., Bastos, M., Mexia, dioica L., Malva neglecta Wallr. and their A.n., 2006. Efficacy of plant extracts against mixture. Iranian Journal of Pharmaceutical stored products fungi. Revista Research: IJPR. 11(3):913. Iberoamericana de Micologea. 23(3):176-178. 27. Dai, J., Mumper, R. J., 2010. Plant phenolics: 37. Sonboli, A., Mojarrad, M., Ebrahimi, S.N., extraction, analysis and their antioxidant Enayat, S., 2010. Free radical scavenging and anticancer properties. Molecules. activity and total phenolic content of 15(10):7313-7352. methanolic extracts from male inflorescence 28. Saremi, J., Kargar-Jahromi, H., Pourahmadi, of Salix aegyptiaca grown in Iran. Iranian M., 2015. Effect of Malva Neglecta Wallr on Journal of Pharmaceutical Research: IJPR. ethylene glycol induced kidney stones. 9(3):293. Urology Journal. 12(6):2387-2390. 38. Parekh, J., Jadeja, D., Chanda, S., 2006. 29. Mirghiasi, S., Akhzari, M., Vassaf, M., Akbari, Efficacy of aqueous and methanol extracts A., Baghi, S., 2015. The Effect of Malva of some medicinal plants for potential neglecta on the Reduction of Inflammatory antibacterial activity. Turkish Journal of Agents in Patients with Osteoarthritis. Mol Biology. 29(4):203-210. Biol. 4(4):135. 39. Neves, J.M., Matos, C., Moutinho, C., 30. Chaipinyo, K., Oakes, B. W., van Damme, M. Queiroz, G.r., Gomes, L. g. R., 2009. P. I., 2002. Effects of growth factors on cell Ethnopharmacological notes about ancient proliferation and matrix synthesis of low- uses of medicinal plants in Trás-os-Montes density, primary bovine chondrocytes (northern of Portugal). Journal of cultured in collagen I gels. Journal of Ethnopharmacology. 124(2):270-283. Orthopaedic Research. 20(5):1070-1078. 40. Abbas, M., Saeed, F., Anjum, F. M., Afzaal, 31. Mojab, F., Kamalinejad, M., Ghaderi, N., M., Tufail, T., Bashir, M. S. (2017). Natural Vahidipour, H. R., 2010. Phytochemical polyphenols: An overview. International screening of some species of Iranian plants. Journal of Food Properties, 20(8), 1689- Iranian Journal of Pharmaceutical 1699. Research.77-82. 41. Xie, X. s, Liu, H. c., Yang, M., Zuo, C., Deng, 32. Francis, G., Kerem, Z., Makkar, H.P., Becker, Y., Fan, J. m., 2009. Ginsenoside Rb1, a K., 2002. The biological action of saponins in panoxadiol saponin against oxidative animal systems: a review. British journal of damage and renal interstitial fibrosis in rats Nutrition. 88(6):587-605. with unilateral ureteral obstruction. Chinese 33. Cheng, C.l., Wang, Z. y., 2006. Bacteriostasic Journal of Integrative Medicine. 15(2):133- activity of anthocyanin of Malva sylvestris. 140. Journal of Forestry Research. 17(1):83-85.

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42. Divakar, K., Pawar, A., Chandrasekhar, S., clinical symptoms of osteoarthritis. Nature Dighe, S., Divakar, G., 2010. Protective effect Reviews Rheumatology. 6(11):625. of the hydro-alcoholic extract of Rubia 46. Rogers, J., Harding, C., Mayo, A., Banks, J., cordifolia roots against ethylene glycol Rawlings, A., 1996. Stratum corneum lipids: induced urolithiasis in rats. Food and the effect of ageing and the seasons. chemical Toxicology. 48(4):1013-1018. Archives of Dermatological Research. 43. Khalili, M., Jalali, M. R, Mirzaei-Azandaryani, 288(12):765-770. M., 2012. Effect of hydroalcoholic extract of 47. Jensen, J. M, Förl, M., Winoto, S., Seite, S., Hypericum perforatum L. leaves on ethylene Schunck, M., Proksch, E., SchÃtze, S., 2005. glycol-induced kidney calculi in rats. Urology Acid and neutral sphingomyelinase, Journal. 9(2):472. ceramide synthase, and acid ceramidase 44. Prior, R. L., Wu, X., Schaich, K., 2005. activities in cutaneous aging. Experimental Standardized methods for the Dermatology. 14(8):609-618. determination of antioxidant capacity and phenolics in foods and dietary supplements. Journal of agricultural and food chemistry. 53(10):4290-4302. 45. Sellam, J. r. m., Berenbaum, F., 2010. The role of synovitis in pathophysiology and

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Table 1: List of some reported chemical compounds in Malva neglecta.

Sr. No. Compound Chemical type 1. Gallic acid Phenolic acid 2. Chlorogenic acid Phenolic acid 3. Protocatechuic acid Phenolic acid 4. Tannic acid Phenolic acid 5. tr- caffeic acid Phenolic acid 6. p-Coumaric acid Phenolic acid 7. Rosmarinic acid Phenolic acid 8. Rutin Flavonoid 9. Hesperidin Flavonoid 10. Salicylic acid Phenolic acid 11. Myricetin Flavonoid 12. Fisetin Flavonoid 13. Chrysin Flavonoid 14. Rhamnetin Flavonoid 15. Apigenin Flavonoid 16. Kaempferol Flavonoid 17. Luteolin Flavonoid 18. Hesperetin Flavonoid 19. Naringenin Flavonoid 20. Quercetin Flavonoid 21. Lauric acid Lipid 22. 10-Undecenoic acid Lipid 23. Myristic acid Lipid 24. Palmitic acid Lipid 25. Phytol Alcohol 26. Linoleic acid Lipid 27. Oleic acid Lipid 28. Stearic acid Lipid 29. Arachidic acid Lipid 30. 6-Hexadecenoic acid Lipid 31. Behenic acid Lipid

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Table 2: Summary of effective extracts and plant parts of Malva neglecta for specific pharmacological activity.

Pharmacological activity Effective extract Plant parts References

Anti-oxidant Hydroalcohalic extract Flowers and leaves [26]

Anti-inflammatory/ anti Aqueous extract Whole plant [29] arthritic

Anti-microbial/anti-bacterial Ethanolic extract Aerial parts [18]

Anti-cholinesterase Methanolic extract Aerial parts [20]

Anti-urolithiac Aqueous extract Leaves [28]

Anti-hypertensive N/A Whole plant [9]

Anti-tussive N/A Seed, flower, fruit [11,12] N/A= Not available

Table 3: Bacterial and fungal strains active against Malva neglecta [19].

Bacterial Strains Fungal Strains

Escherichia coli Aspergillus fumigatus

Klebsiella pneumonia Aspergillus flavus

Salmonella typhi Aspergillus niger

Bacillus subtilis Fusarium solani

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Figure 1: Malva neglecta (plant parts, phytochemicals and respective traditional uses).

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