ANDROGRAPHOLIDE AND HESPERIDIN – A BRIEF OVERVIEW

ANDROGRAPHOLIDE AND HESPERIDIN - A BRIEF OVERVIEW

S. Navenaa ^*, R. Vadivu and R. Radha

Department of Pharmacognosy, College of Pharmacy, Madras Medical College, Chennai - 600003, Tamil Nadu, India.

ABSTRACT: Andrographolide is a labdane diterpenoid isolated from the leaves and roots of Andrographis paniculata Nees (Acanthaceae). Andrographolide is isolated by various processes and the simple method is the maceration process. It is bitter in taste and used as hepatoprotective, cholinergic, antispasmodic, stomachic, anthelmentic, alterative, blood purifier, and febrifuge. It promotes the secretion of bile in the liver and is used in jaundice, torpid liver, cold and upper respiratory tract infection. It is also used in the treatment of snake bites and is found to be more effective than the anti-snake venom generally used. Hesperidin is a flavanone glycoside isolated from the peels of Citrus sinensis (Rutaceae). Hesperidin plays an important role in plant defense mechanisms. Hesperidin is commonly isolated by two laboratory processes maceration and continuous percolation method. The major pharmacological actions of the hesperidin reported are anti-hyperlipidemic, cardioprotective, antihypertensive, antidiabetic, antioxidant, anti-inflammatory, and antiartherogenic activity. However, what is noteworthy about this paper is highlighting the evidence-based overview on the chemical and physical nature of Andrographolide and Hesperidin along with a brief account on the plants from which they are isolated, the extraction and isolation procedures of the above chemical constituents, their physical properties and structure along with their pharmacological properties are also discussed.

Andrographolide, Hesperidin, Andrographis paniculata, Citrus sinensis, Hepatocellular Carcinoma

INTRODUCTION: From the earliest times, herbs have been prized for their pain-relieving and healing abilities, and today we still rely on the curative properties of plants in about 75% of our medicines. Herbal medicine often complements conventional treatments, providing safe, well-tolerated remedies for chronicillness ¹. Andro-grapholide is a Labdane Diterpenoid which is the major chemical constituent of Andrographis paniculata Nees of Acanthaceae family and is called as Maha-Tita literally known as “King of Bitter” in Northeastern India ².

They are also called as Bhumi-Neem, meaning “Neem of the Ground” since it has a strong bitter taste than that of the Neem tree. In Malaysia, it is known as Hempedu Bumi, which means “Bile of Earth” ³. The constituent Andrographolide is used for liver sluggishness and as an antidote for colic dysentery and dyspepsia ⁴.

Andrographis paniculata is also given in the case of snakebite asanti-venom agent ⁵. They show various pharmacological actions such as anti-hyperglycemic, anti-inflammatory, and suppression of various cancer cells ⁶. Hesperidin is a flavanone glycoside isolated from the peels of Citrus sinensis of the Rutaceae family, which is known as Sweet Orange. Hesperidin was first isolated by Chemist Lebreton in 1828 from the peels of the Citrus fruit ⁷. Hesperidin has a wide range of biological activities. It possesses an Inhibitory effect against the development of neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Multiple Sclerosis ⁸. It also has an inhibitory effect against obesity diseases and regulates lipid metabolism and glucose metabolism. Hesperidin enriched dietary supplements can significantly improve symptoms such as postprandial hyperglycemia and hyperlipidemia ⁹. Hesperidin is generally used as antihypertensive, antidiabetic, cardioprotective, anti-inflammatory, and antiartherogenic activity ¹⁰.

Plant Details:

Habitat: Andrographis paniculata Nees is found throughout India from Himachal Pradesh to Assam, Mizoram, and all over Southern India ¹¹. It is also distributed in tropical countries such as USA, Jamaica, Pakistan, Sri Lanka, Thailand, and West Indies. It is found in a variety of habitats such as Hill slopes, Dry and Wetlands, Forest areas, Farms and Wastelands ^12, and also in phytogeographical and edaphic zones of China, America, West Indies, and Christmas Island ¹³.

Citrus sinensis are found throughout Southeast Asia, Southern United States, and Mediterranean Region ¹¹.

Vernacular Names:

Andrographis paniculata: ¹¹

Citrus sinensis: ¹⁴

Plant Description: Andrographis Paniculata is an annual, branched, herbaceous plant. The inflorescence of the plant is terminal and axillary in panicle, 10-30 mm long. The bract is small, and the pedicel is short. Citrus sinensis, commonly known as Orange or Sweet Orange, is a small evergreen tree, and its branch has large spines originally domesticated in Subtropical Asia. The fruit consists of two distinct regions pericarp and endocarp.

TABLE 1: DESCRIPTION OF PLANTS ^15-21

Phytochemistry:

Andrographis paniculata: The main constituent is Andrographolide. The plant leaves possess the highest amount of Andrographolide, while the seeds contain the lowest amount ²². The other chemical constituent generally includes Deoxyandrographolide-19β-D-glucoside and Neo-andrographolide which are bitter constituents. The roots have Andrographan, Andrographosterin, Andrographon, Homoandrographolide, and Stigmasterol ²³. They also contain Flavanoids, Diterpenoids, and Polyphenols ²⁴.

Citrus sinensis: The main constituent present is Hesperidin which is a Flavanone Glycoside, and its Aglycone form is called Hesperetin. They are usually present in higher amounts in the peels of the Citrus Rinds. They are rich in Vitamin C, Fiber, Calcium, and Vitamin D.  Orange juice contains β-cryptoxanthin, a natural Carotenoid Pigment which is converted to Vitamin A (Retinol) and known as Provitamin A ^25-26. They also contain other phytoactive compounds such as Potassium, Carotenoids, Flavanoids, and other volatile Organic compounds like Alcohols, Ketones, Terpenes, and Esters etc. ²⁷. Limonene, Linalool and Citral are the main volatile material present in Citrus sinensis ²⁸.

Extraction:

Plant Material:

Andrographis paniculata: The leaves are air-dried under shade for 15 days and then in a hot air oven below 60°. It is powdered to 40 mesh and stored in an airtight container at 15–20° until further use ²⁹.

Citrus sinensis: The peels of the Citrus fruit are obtained and they are dried and grinded and stored in an airtight container until further use ³⁰.

Procedure:

Andrographis paniculata: Andrographolide is usually extracted by two processes. They are Solid-Liquid Extraction and Ultra Sound Assisted Extraction.

Solid-liquid Extractions: It is extracted with different solvents such as methanol, water, 10% water-methanol, 5% water-methanol.

Cold Extraction: In this process, the sample is dissolved in the solvent in the ratio of 1:20 in round bottom flasks overnight at room temperature. The supernatant obtained is filtered by the Vacuum Filtration process and concentrated at 40° at reduced pressure.

Hot Extraction: In this process, the sample is extracted by using the Soxhlet apparatus on a water bath for 5 hours, and then they are cooled, filtered, and concentrated on getting the extracts which are further tested for their activity ³¹.

Ultrasound-Assisted Extraction: It is done by using a rectangular Branson Ultrasonic cleaning bath device. The working frequency is 40 kHz, and Input Power is 230W and has digital operating control. The sample is transferred to a Screw-capped glass tube which is mixed with different ratio of Ethanol and solvent-to-solid- ratio.

Then they are immersed in water, and the extraction process is carried out with the above-said frequency and power. Replicate Experiments were also carried out at room temperature. Then the extract was filtered by Whatman No.1 filter paper and centrifuged at 6000 rpm for 15 minutes at 4 °. Then the supernatant liquid is further filtered and stored at 4° for further use ₃₂.

Citrus sinensis: The extraction process involves the Supercritical Fluid extraction method and Organic Solvent extraction method, which result in the formation of Crude extract from which further studies are done.

Supercritical Fluid Extraction: The orange peel is dried under hot air, and they are ground to small particles. Extraction is carried out by using an extractor with SC-CO₂ as solvent. Optimization of Super Critical Extraction is determined by Surface Response Methodology ₃₃.

Organic Solvent Extraction method: Organic solvent extraction methods are usually one of the conventional systems of extraction method. They involve extraction with methanol: dimethyl sulphoxide in the ratio 1:1 ³⁴.

Isolation Procedure:

Isolation of Andrographolide: Andrographolide is usually isolated by cold maceration, hot maceration and microwave-assisted extraction.

Cold Maceration: The sample is taken in a round bottom flask and extracted exhaustively with 1:1 ratio of dichloromethane: ethanol. They are filtered, and the solvent is removed by vacuum. A green crystalline mass is obtained, which is separated and washed repeatedly with Toluene to remove the colouring matter present in them. Toluene should be completely removed from the residue ³⁵.

Hot Maceration: Two samples are taken; one is dissolved in Methanol and another in 95% alcohol, and they are macerated overnight. Then the marc obtained is packed in a Soxhlet apparatus and the extraction process is carried out. The extract is obtained separately for both the process and the solvent is removed by Vacuum. A green crystalline mass will be obtained, which are separated and they are washed repeatedly with Toluene to remove the colouring matter present. Then the Toluene should be completely removed from the residue ³⁵.

Crystallization Procedure: The product obtained is dissolved in Hot Methanol and cooled for Crystallization process. The procedure is done several times to obtain the chemical constituents Andrographolide ³⁶.

Purification Process: Purification process involves washing the green mass obtained with Toluene to remove the green colour matter present. The Toluene was completely removed by evaporation. Then the residue is dissolved in Hot Ethanol, and the filtrate was cooled and filtered while hot, and they are cooled in the refrigerator. The process is repeated several times until a small yellow colour crystal of Andrographolide is obtained ³⁷.

Microwave-Assisted Extraction: The novel method for the isolation of Andrographolide is the Microwave-Assisted extraction process. In this process, the sample is powdered and mixed with the solvents such as methanol for polar compounds and hexane for non-polar compounds. The extraction was usually carried out in the Pyrex beaker, and they are placed inside the microwave oven and exposed to microwave radiation for 5 min under the power level of 20%. After the irradiation process, the samples were cooled, and they were centrifuged and made concentrated ^38-39.

The extraction intensity, amount of solvent and the time required should be optimized prior to process ⁴⁰. Two parameters such as microwave power – 75 to 175 W and ethanol concentration – 20 to 85% are generally important in this process. Higher yield is obtained by initial screening on the mesh size and solid-solvent ratio.

The optimum condition was found at a microwave power of 140 W with 85% ethanol concentration, which generally gave the highest yield of Andrographolide. Hence, the microwave-assisted extraction process gave more yield of Andro-grapholide than the conventional methods ⁴¹.

Isolation of Hesperidin: Hesperidin can be isolated by the following methods from orange peels. They include the conventional method (maceration) and modern method (Soxhlet extraction process).

Conventional Methods (Maceration): The dried orange peels or powder (250 g) was macerated with 800 ml of aqueous alkaline solution (10% KOH) and kept overnight. The pH of KOH should be 8-9. After maceration the obtained mixture is filtered by Buchner funnel and the filtrate was evaporated to obtain the syrupy mass which is further treated with 6% acetic acid. They are refrigerated overnight to obtain solid crystalline substance and taken out and again filtered to obtain the crude hesperidin ^42-43.

Modern Method (Soxhlet Extraction Process): Petroleum Ether of 150 ml (40 – 60°) is filled in a 250 ml round bottom flask with a magnetic stir bar, 50g of dried and powdered orange peel are placed in the extraction sleeve of a Soxhlet extractor and covered with a little glass wool. A reflux condenser is put on the Soxhlet extraction unit, and then the reaction mixture is stirred and heated for 4hours under strong reflux. The petroleum ether extract is discarded. In order to remove the adherent petroleum ether, the content of the extraction sleeve is laid out in an extensive crystallization dish. Afterward the substance is placed again in an extraction sleeve like before, but with 150 ml methanol, extracted till the solvent leaving the extraction sleeve is colourless (1 to 2 h).

The extract is evaporated at the rotary evaporator until a syrupy consistency is reached. The residue is mixed with 50 ml of 6% acetic acid; the precipitated solid is the crude Hesperidin.  It is sucked off with a Buchner funnel, washed with 6% acetic acid, and dried at 60° until it is constant in weight. For recrystallization, 5% solution of the crude product in Dimethyl Sulfoxide is added, stirred, and heated to 60–80°. Afterward the same amount of water is added slowly while stirring. When cooling to room temperature, the Hesperidin precipitates. It is sucked off, first washed with little warm water and then with Isopropanol, and dried in the desiccators until it is constant in weight ^44-45.

Rapid Extraction of Hesperidin: A new and novel method was identified in which the sample is extracted with methanol and crystallization is done by using water with the addition of dichloro-methane, which resulted in rapid extraction of the flavonoid compound Hesperidin. In this process, the volume of solvent used and the extraction time is shorter compared to various other methods and hence resulted in the production of a higher amount of Hesperidin ⁴⁶.

Purification of Hesperidin: Hesperidin can be purified by two ways, they are

Procedure 1:  The crude Hesperidin is added to dimethylformamide and warmed to about 60°, and little acetic acid is added. The solution was then filtered through a Buchner Funnel, diluted with an equal volume of water, and was allowed to stand for 4 h in order to crystallize. After crystallization, the crystal of Hesperidin is filtered.

Procedure 2: The crude Hesperidin obtained is added to chloroform. The white crystalline Hesperidin is obtained, and they are filtered through a Buchner Funnel ⁴⁷.

TABLE 2: PHYSICAL PROPERTIES OF ANDROGRAPHOLIDE AND HESPERIDIN ^48-51

Identification and Characterization:

Andrographolide: The Identification and Characterization can be done by a variety of methods. The most commonly employed laboratory method generally include the following

Chromatographic Techniques: TLC Method (Thin Layer Chromatography)

Spectral Analyses: UV (Ultra Violet Spectro-scopy)

Chemical Identification

Chromatographic Methods:

Thin Layer Chromatography: In this method precoated plates of Silica Gel 60F254 were used. Different Mobile phase used for the process are

Chloroform: Methanol: Ethylacetate (7:2:1)

Chloroform: Methanol (9:1)

Chloroform: Ethylacetate (6:4)

Chloroform: Acetone: Formic acid (7.5:1.65:0.85)

Spraying agent: 3, 5 -Dinitrobenzoic acid (2% w/v)

Visualizing agent: KOH in Ethanol (6% w/v).

The spotting was done by CAMAG LINOMAT IV Automatic TLC Spotter. The Purity was identified by using CAMAG TLC Scanner. The Mobile Phase Chloroform: Methanol: Ethylacetate (7:2:1) was effective for both the Extract used and Standard Andrographolide used ^52-54.

Spectral Analysis:

Ultraviolet Spectroscopy: The UV Absorption was recorded in UV/VIS Spectrophotometer (JASCO Model 7850). The best solvent for the UV Spectroscopy experiment of Andrographolide is Methanol: Water (50:50 v/v).

In determining the UV Spectrum of the Andro-grapholide, they were scanned in UV Spectro-photometer between the ranges of 400 – 200 nm. They showed Maximum Absorbance at a wavelength at 312 nm ⁵⁵.

In Nano Emulsion preparations, Detection and Quantification were done by UV/VIS Spectro-photometry and read at maximum with Picric Acid reagent and NaOH (8:2) in Methanol solvents. They are read at a maximum wavelength of 479 nm with 22 min of Incubation time ⁵⁶.

Validation of UV spectroscopy: They are validated for Selectivity, Specificity, Linearity, Range, Limit of Quantification, Limit of Detection, Precision, Robustness, Ruggedness, and Solution Stability ⁵⁷.

Chemical Identification: The small amount of the sample was dissolved in 5ml of Methanol and treated with 1 ml of 2,4 – Dinitrophenyl hydrazine, and 100 ml of 2M HCl was added. Yellow Orange colour is obtained, which indicates the presence of Andrographolide ⁵⁸.

Alcoholic Potassium hydroxide, 8 drops were added to the sample powder, and Red colour is obtained which is kept for 14 min. The Red colour changed to Yellow, which indicates the presence of Andrographolide ⁵⁹.

Hesperidin: The Identification and Charac-terization can be done by a variety of methods. The most commonly employed Laboratory method generally includes,

Chromatographic Techniques: TLC Method (Thin Layer Chromatography)

Spectral Analyses: UV (Ultra Violet Spectro-scopy)

Chemical Identification:

Chromatographic Techniques:

Thin Layer Chromatography: The Thin Layer Chromatography can be carried out by using the solvent nButanol: Acetic acid: Water in (3:1:1) Ratio.

Two spots were obtained for the Hesperidin determination one at R_f 0.62 and Rf 0.20. Orange colour spots were obtained ⁶⁰.

Spectroscopy Analysis:

Ultraviolet Spectroscopy: In this process UV/Visible Double Beam Spectrophotometer was used. The Hesperidin showed good absorbance when dissolved in 0.2N NaOH. The Maximum Wavelength of Hesperidin was 285 nm and they showed good absorbance at this Nanometer ⁶¹.

Validation of UV spectroscopy: They are validated for Selectivity, Specificity, Linearity, Range, Limit of Quantification, Limit of Detection, Precision, Robustness, Ruggedness and Solution Stability ⁶².

Chemical Identification: The Powder sample was treated with Ferric Chloride solution. A bright Red colour is obtained which indicates the presence of Hesperidin Shinoda Test: A bright pinkish violet colour is obtained which indicates the presence of Hesperidin ⁶³.

Pharmacological Actions:

Andrographolide:

Anticancer Properties: The cytotoxic potential of Andrographolide on HT- 29 cell was determined by MTT Assay, Tryphan Blue Exclusion Assay, Colon Formation Assay, Morphological Analysis Apoptotic Property by DAPI, Hoechst Staining, FITC Annexin Assay, DNA Fragmentation Assay and Caspase-3-Activity.

Therefore from the above study, it was identified that Andrographolide exhibited antiproliferative and apoptotic properties against Colon cancer HT-29 cells ⁶⁴.

Recent work demonstrates that Tumour Necrosis Factor – α (TNF – α) related Apoptosis inducing ligand (TRAIL – An important member of extrinsic apoptosis pathway) was significantly enhanced in various Human cancer ⁶⁵.

Andrographolide is also effective in combination therapy. They increased the Apoptosis rate in Multidrug-Resistant cancer cells when used in combination treatment with other anticancer agents like 5-Fluorouracil, Adriamycin, and Cisplatin ⁶⁶.

The in-vivo antitumor efficacy of Andrographolide was examined in Xenografts nude mice, and the results indicated that Andrographolide could significantly inhibit the proliferation of Human Breast Cancers and inhibit COX-2 Mediated Angiogenesis in human Endothelial Cells ⁶⁷. Andrographolide inhibited the growth of Huh-7 cells independent of Apoptosis ⁶⁸.

Antivenom Properties: Anti-Snake venom is the specific antidote to Snake venom actions. Experiments were carried out to investigate the Anti-Cobra Venom effect of alcoholic extract of Andrographis paniculata. Male Swiss Albino Mice was used for the experiment.  The ethanolic extract of the plant increased the mean survival time and the protection fold but could not protect animals from death. So, therefore, Anti-Snake Venom was found more effective than the plant extract, but when given along with plant extract, it potentiates its effects ⁶⁹.

Anti-malarial Properties: Malaria is a very serious hazard which causes major Mortality and Morbidity in the Endemic countries. The most affected region is Asia, Central and Latin America and Sub-Saharan Africa ⁷⁰.

Andrographolide was found to have potent antiplasmodial activity when tested in isolation and in combination with Curcumin and Artesunate against the Erythrocytic stages of Plasmodium falciparum in-vitro and Plasmodium berghei in-vivo. Andrographolide activity exhibited better Antimalarial activity, not only by reducing Parasitemia but also by extending the life span by 2-3 folds ⁷¹.

Andrographolide could protect liver and renal injuries induced by Plasmodium berghei infection in mice. Blood glucose level control was also observed in the mice ⁷².

Respiratory Properties: Cigarette smoke is the major cause for Chronic Obstructive Pulmonary Disease (COPD). Andrographolide possesses Antioxidative properties against cigarette smoke-induced lung injury by augmentation of Nrf2 activity and has potential to treat COPD ⁷³.

Andrographolide is used for Prophylaxis and treatment of Upper Respiratory infections, such as the Common Cold, Uncomplicated Sinusitis, Bronchitities and Pharayngotonsillitis and also used for Urinary tract infection and acute diarrhea ⁷⁴.

Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) were the diseases caused by severe Bacterial Pneumonia, Burns and Trauma. So hence study was conducted on mice and its result indicate that Andrographolide dose-dependently suppressed the severity of LPS-induced acute lung injury by NF-KB inhibition. So hence Andrographolide is considered as effective and safe drug ⁷⁵.

Antifertility Activity: The Antifertility activity of Andrographis paniculata were conducted on stored grain pest Tribolium confusum in 5^th instar and 6^th instar Larvae and Pupae with Andrographolide. Andrographolide caused interruption of insect reproduction and prevented normal growth and development of the ovaries of Tribolium confusum. So hence they caused sterility in Tribolium confusum. Therefore Andrographolide can be used for the development of safe and specific antifertility agent ⁷⁶. In another study, Andro-grapholide was injected intramuscularly into Male Albino rats to test the anti-fertility activity. They cause a decrease in the protein content with a significant increase in Cholesterol, Acid Phosphatase, and Alkaline Phosphatase levels with the appearance of Fructose in the reproductive system of rats. Hence all the above reason suggests the general inhibitory effects of Andrographolide in the Testis and Epidymis ⁷⁷.

Hesperidin:

Neuroprotective Properties: Neurodegenerative diseases are known as a group of chronic disorders characterized by loss of brain and spinal cord cells ⁷⁸. These diseases include Alzheimer’s disease, Parkinsonism, and Huntington disease ⁷⁹.

A human study was conducted by Placebo-Controlled, Randomized and Double-Blinded clinical study by chronic administration of orange juice on 37 healthy adults (60-81 years) was examined. The study concluded that Hesperidin possesses an Inhibitory effect against the development of Neurodegenerative diseases. Neuroprotective effect is highly dependent on antioxidant and anti-inflammatory activities. Hesperidin also showed Antidepressant activity ⁸.

Antiobesity Properties: Obesity is a pathological state which causes excessive body fat and makes the bodyweight more than 20% of the standard bodyweight. Fat accumulation causes Cardio-vascular Hypertension, Hyperlipidaemia, Insulin Resistance, and Inflammation ⁸⁰.

Hesperidin improves Hypercholesterolemia and Fatty Liver by inhibiting Cholesterol synthesis and absorption. Hesperidin has a therapeutic effect on Obesity by mediating AMPK and PPAR pathways to regulate inflammatory signalling pathways. So Hesperidin can help expand the range of weight loss and reduce the rate of obesity in the body ⁸¹.

Anticancer Properties: Liver cancer is caused by various factors such as Alcoholic Cirrhosis, Hepatitis B and C infections. In the given study, HepG2 cells were used and treated with crude Ethanolic extract from citrus seeds, and they cause Human Hepatocellular Carcinoma Apoptosis ⁸².

Breast cancer is the first-ranked case of cancer in women worldwide. The study was conducted to determine the effect of Hesperidin performed on MCF-7 and MCF-7/Dox cells. The results obtained were that Hesperidin has cytotoxic effect on MCF-7/Dox cells. The application of doxorubicin and hesperidin on MCF-7/Dox cells showed a synergism effect through inhibition of cancer cells ⁸³. Hesperidin can also induce both Apoptotic and Autophagic cell death in colon carcinogenesis ⁸⁴.

Antidiabetic Properties: The study was designed to investigate the effect of Hesperidin on Serum Glucose, Blood Glycosylated Haemoglobin and Serum Insulin levels in high fat fed or Streptozotocin (STZ)-Induced type 2 diabetic rats. They cause elevated levels of Glucose, Glycosylated Haemoglobin, AST, LDH and CK-MB and Lowered Serum Insulin levels. So hence from the above result it is found that Hesperidin shows Antihyperglycemic and Antidyslipidemic efficacy as well as improve cardiac function in HFD/STZ – induced type 2 diabetic rats ⁸⁵. Another study was conducted on STZ-Induced marginal Type I diabetic rats. The Hesperidin normalizes blood glucose by altering the activity of glucose regulating enzymes and lower serum and liver lipid levels. So hence Hesperidin showed both Hypoglycaemic and Hypolipidemic effects but did not affect bone marginal type I diabetic rat ⁸⁶.

Varicose Vein Treatment: Hesperidin is the most effective medication against Varicose Vein as it acts also as an Anti-inflammatory. They have greater activity when they are combined with Disomin along with other natural medication against varicose vein. Hesperidin also used for swelling sensations, Haemorrhoids, Cramps, Pain and Capillary Bruising. Disomin: Hesperidin (9:1) combination is used for Haemorrhoids and Varicose Vein ⁸⁷.

CONCLUSION: This review summarizes the extraction, isolation and various pharmacological activities or properties of the chemical constituents Andrographolide and Hesperidin. They can be used to cure various ailments. In recent times the constituents Andrographolide has been proven effective against COVID-19 which acts as a immunostimulant. Further studies can be done by isolating the constituents and can be formulated into any form of novel drug delivery system which has nowadays created a huge impact in modern medicine. So, in conclusion, Andrographolide and Hesperidin have a huge impact on the well-being of individuals.

ACKNOWLEDGEMENT: Authors are grateful to the Friends and Families for helping through this process. Special Thanks to College of Pharmacy, Madras Medical College, Chennai, and Tamil Nadu Dr. M. G. R Medical University for providing the necessary facilities.

CONFLICTS OF INTEREST: Authors have no conflict of interest.

REFERENCES:

1. Chevallier A: The Encyclopedia of Medicinal Plants. DK Publishing Book, United States, First Edition1996: 8
2. Linn XY, Chan JSW, Tan TYC, Teh BP, Mohamed S and Mohamed AFS: Andrographis paniculata (Burm.F.) Wall.ex Nees, andrographolide and andrographolide analogues as SARS-CoV-2 antivirals? A rapid review. Natural Product Communication 2021; 16(5): 1-25.
3. Hossain MS, Urbi Z, Sule A and Rahman KMH: Andrographis paniculata (Burm.f.) Wall.ex Nees: A Review of Ethnobotany Phytochemistry and Pharmacology. The Scienti World Journal 2014; 28: 1-28.
4. Burgos RA, Alarcon B, Quiroga J, Manosalva C and Hancke J: Andrographolide, an anti-inflammatory multitarget drug: All roads leads to cellular metabolism. Molecules 2021; 26(1): 5
5. Nayak AG, Ahammad J, Kumar N, Shenoy S and Roche M: Can methanolic extract of Andrographis paniculata be used as a supplement to anti-snake venom to normalize hemostatic parameters: A thromboelastographic study. Journal of Ethonopharmacology 2020; 252: 112480.
6. Dai Y, Chen SQ, Chai L, Zhao J, Wang Y and Wang YL: Overview of Pharmacological activities of Andrographis paniculata and its major compound andrographolide. Critical Reviews in Food Science and Nutrition 2019; 59(1): S17-S29.
7. Etebu E and Nwauzoma AB: A Review on Sweet Orange (Citrus sinensis L Osbeck): Health, Diseases and Mangement. American Journal of Research Communication 2014; 2(2): 33-70.
8. Hajialyani M, Farzari MH, Echeverria J, Nabavi SM, Uriate E and Sobarzo-Sanchez E: Hesperidin as a Neuroprotective agent: A Review of Animal and Clinical Evidence. Molecules 2019; 24(3): 648.
9. Xiong H, Wang J, Ran Q, Lou G, Peng C and Gan Q: Hesperidin: A therapeutic agent for obesity. Drug Design Development and Therapy 2019; 2019: 3855-66.
10. Zanwar AA, Badole SL, Shende PS, Hegde MV and Bodhankar SL: Cardiovascular effects of Hesperidin: A Flavanone Glycoside. Polyphenols in human health and diseases. Academic Press – Elseiver Inc, San Diego 2014; 989-92.
11. Khare CP: Indian Medicinal Plants: An Illustrated Dictionary. Springer; First Edition 2004.
12. Kumar S, Singh B and Bajpai V: Andrographis paniculata (Burm.f.) Nees: Traditional uses, Phytochemistry, Pharmacological properties and Quality control/Quality assurance. Journal of Ethnopharmacology 2021; 275: 114054.
13. Fardiyah Q, Ersam T, Suyanta, Slamet A, Suprapto and Kurniawan F: New potential and characterization of Andrographis paniculata Nees plant extracts as photo protective agent. Arab J of Chem 2020; 13(12): 8888-97.
14. Samson JA: Citrus sinensis (L.) Osbeck. In: Plant Resources of South-East Asia No.2: Edible fruits and nuts. PROSEA Foundation 1991.
15. Shah BN and Seth AK: Textbook of Pharmacognosy and Phytochemistry. Elsevier, First Edition 2010.
16. Nonthaburi: Manual for Cultivation, production and utilization of herbal medicines in primary healthcare, Department of Medical sciences. Ministry of public health 1990.
17. Firdous J, Latif NA, Mona R, Mansor R and Muhamed N: Andrographis paniculata and its endophytes: A review on their pharmacological activities. Research Journal of Pharmacy and Technology 2020; 13(4): 2027-30.
18. Kokate CK, Puroht AP and Gokhale SB: Pharmacognosy. Nirali Publications, Pune, Edition 34, 2006: 251-52.
19. Favela-Hernandez JMJ, Gonzalez-Santiago O, Ramirez-Cabrera MA, Esquivel-Ferrino PC and Camacho-Corona MDR: Chemistry and Pharmacology of Citrus sinensis. Molecules 2016; 21(2): 247.
20. Miri YB, Arino A and Djenane D: Study of antifungal, anti-aflatoxigenic, antioxidant activity and phytotoxicity of Algerian Citrus limon eureka and Citrus sinensis Var. Valencia essential oils. Journal of Essential Oil Bearing Plants 2018; 21(2): 345-61.
21. Mannucci C, Calapai F, Cardia L, Inferrera G, Pietro MD and Navarra M: Clinical pharmacology of Citrus aurantium and Citrus sinensis for treatment of anxiety. Evidence Based Complementary and Alternative Medicine 2018; 2018: 1-18.
22. Jiang M, Sheng C, Zhang Z, Ma X, Gao T and Fu C: Andrographis paniculata (Burm.f.) Nees and its major constituent Andrographolide as potential antiviral agents. Journal of Ethnopharmacology 2021; 272: 113954.
23. Tan MES, Oyong GG, Shen CC and Ragasa CY: Chemical constituents of Andrographis paniculata (Burm.f.) Nees. International Journal of Pharmacognosy and Phytochemical Research 2016; 8(8): 1398-02.
24. Rajagopal K, Varakumar P, Baliwada A and Byran G: Activity of phytochemical constituents of Curcuma longa (Turmeric) and Andrographis paniculata against Coronavirus (COVID-19): an in-silico Future Journal of Pharmaceutical Sciences 2020; 6(1): 104.
25. Butu M and Rodino S. Fruit and Vegetable-Based Beverages – Nutritional properties and Health benefits. Natural Beverages 2019; 13: 303-38.
26. Seidavi A, Esteghamati HZ and Salem AZM: A review on practical applications of Citrus sinensis by-products and waste in poultry feeding. Agroforestry system 2020; 94: 1581-89.
27. Karmakar S and de S: Pectin Removal and Clarification of Juices.Separation of Functional Molecules in Food by Membrane Technology. Academic Press, London 2019; 155-94.
28. Guo Q, Liu K, Deng W, Zhong B, Yang W and Chun J: Chemical composition and antimicrobial activity of gannan navel orange (Citrus sinensis Osbeck cv. Newhall) Peel essential Oils. Food Science and Nutrition 2018; 6(6): 1431-37.
29. Kushram A, Masih SK and Mir SA: Variation of Andrographolide content in Andrographis paniculata from different sites of Balaghat region of Jabalpur (M.P). International Journal of Current Research and Reviews 2020; 9(22): 1-4.
30. Man MQ, Yang B and Elias PM: Benefits of Hesperidin for Cutaneous Functions. Evidence Based Complementary and Alternative Medicine 2019; 2019:1-19.
31. Kumar S, Dhanani T and Shah S: Extraction of three Bioactive Diterpenoids from Andrographis paniculata: Effect of the extraction techniques on extract composition and Quantification of three Andrographolide using High-performance Liquid Chromatography. Journal of Chromatographic Science 2014; 52(9):1043-50.
32. Ramasamy J, Kandasamy R, Palanisamy S and Nadesan S: Optimization of Ultrasonic-assisted extraction of Flavanoids and anti-oxidant capacity from the whole plant of Andrographis echioides (L.) Nees by response surface methodology and chemical composition analysis. Pharmacognosy Magazine 2019; 15(65): 547-56.
33. Anticona M, Blesa J, Frigola A and Esteve MJ: High biological value compounds extraction from citrus waste with Non-conventional methods. Foods 2020; 9(6): 1-24.
34. Bruno MR, Russo D, Cetera P, Faraone I, Giudice VL and Todaro L: Chemical analysis and antioxidant properties of orange-tree (Citrus sinensis) biomass extracts obtained via different extraction techniques. Biofuels, Bioproducts and Biorefining 2020; 14(3): 509-20.
35. Rajani M, Shrivastava N and Ravishankara MN: A Rapid Method for isolation of Andrographolide from Andrographis paniculata Nees (Kalmegh). Pharmaceutical Biology 2000; 38(3): 204-09.
36. Rafi M, Devi AF, Syafitri UD, Heryanto R, Suparto IH and Amran MB: Classification of Andrographis paniculata extracts by solvent extraction using HPLC fingerprint and chemometric analysis. BMC Research Notes 2020; 13: 1-6.
37. Pundarikakshudu K, Shah PA, Panchal SR and Joshi HR: A simple and facile method for the isolation of andrographolide from Andrographis paniculata American Journal of Pharmtech Research 2016; 6(6): 266-75.
38. Ganzler K, Salgo A and Valko K: Microwave extraction: A Novel sample preparation method for chromatography. Journal of Chromatography A 1986; 371: 299-06.
39. Niphadkar S and Rathod V: Optimization of Microwave-assisted extraction of acetyl 11 keto boswellic acid (AKBA) from Boswellia serrata by using orthogonal array design (OAD). Journal of Biologically active products from nature 2018; 8(2): 90-03.
40. Rao PR and Rathod VK: Microwave Assisted three phase extraction of Andrographolide from Andrographis paniculata. Journal of Biologically active products from Nature 2019; 9(3): 215-26.
41. Vien V, Pang SF, Abdullah S, Yusoff M and Gimbun J: Microwave assisted extraction of Andrographolide, 14-Deoxy-11, 12-didehydroandrographolide and Neoandrographolide from Andrographis paniculata: An Optimisation Study. Current Nutrition and Food Science 2020; 16: 1-8.
42. Jarald EE and Jarald SE: Textbook of Pharmacognosy and Phytochemistry.CBS Publishers and Distributors, First Edition 2010.
43. Fekadu T, Seifu T and Abera A: Extraction of essential oil from orange peel using different methods and effects of solvents, time, temperature to maximize the yield. International Journal of Engineering Science and Computing 2019; 9(12): 24300-08.
44. Sharma P, Pandey P, Gupta R, Roshan S, Garg A and Shulka A: Isolation and Characterization of Hesperidin from orange peel. Indo American Journal of Pharmaceutical Research 2013; 3(4): 3892-97.
45. Chaudhri VK, Hussain Z, Pandey A, Khan A and Srivastava AK: Isolation and characterization of hesperidin from dried orange peel. International Journal of Research in Pharmacy and Science 2016; 6(2): 15-18.
46. Victor MM, David JM, Cortex M, Leite JL and Silva GBSD: A high-yield process for extraction of hesperidin from orange (Citrus sinensisosbeck) peels waste, and its transformation to Diosmetin, A valuable and Bioactive Flavanoid. Waste Biomass Valorization 2020; 12(1): 1-8.
47. Lahmer N, Belboukhari N, Cheriti A and Sekkoum K: Hesperidin and Hesperetin preparation and purification from Citrus sinensis Der Pharma Chemica 2015; 7(2): 1-4.
48. ncbi.nlm.nih.gov. United States: Andrographolide – PubChem – NIH; c2005 [updated 2020 August 08]. Available from:https://pubchem.ncbi.nlm.nih. gov/compound/Andrographolide
49. com. China: Compound encyclopedia > 5508-58-7, Andrographolide; c2017. [updated 2017 August 12] Available from:https://www.molbase.com/en/cas-5508-58-7.html
50. com.Cambridge, United Kingdom: Andrographolide, Antiinflammatory agent (ab120636); c2014 [updated 2019 March 19]. Available from: https://www.abcam.com/andrographolide-inflammatory-agent-ab120636.html
51. chemical book.com. United States: Chemical Book > CAS Database List > Hesperidin; c2015 [updated 2020 February 15]. Available from: https://m.chemicalbook. com/product Index_EN.aspx
52. Percheron EV, Ferreira V, Campos JF, Destandau E, Pichon C and Raboin SB: Quantitative determination of andrographolide and related compounds in Andrographis paniculata extracts and biological evaluation of their anti-inflammatory activity. Foods 2019; 8(12): 1-11.
53. Hafid AF, Rifai B, Tumewu L and Widiastuti E: Andrographolide determination of Andrographis paniculata extracts, Ethylacetate fractions and tablets by Thin Layer Chromatography. Journal of Chemical and Pharmaceutical Research 2015; 7(12): 557-61.
54. Fujita T, Fujitani R, Takeda Y, Takaishi Y, Yamada T and Kido M: On the diterpenoids of Andrographis paniculata: X-Ray crystallographic analysis of Andrographolide and structure determination of new minor diterpenoids. Chem and Pharma Bul 1984; 32(6): 2117-25.
55. Pancham Y, Patil N, Girish B and Mannur V: Development and Validation of analytical method for determination of Andrographolide in Bulk Powder. Int J of Pharma Res and Health Sciences 2019; 7(1): 2899-03.
56. Hairunisa I, Dai M, Wikantyasning ER, Mahaputra ARG and Normaidah N: Validated UV- Vis Spectrophotometric Determination of Andrographolide in Herbal Nano- Preparation. Asian J of Chemistry 2019; 31(9):1985-88.
57. ICH guidance. Validation of analytical method: Definition and Terminology. International Conference on Harmonization. Q2A: Geneva.
58. Mukherjee PK: Quality Control of herbal drugs: An approach to evaluation of botanicals. Business Horizons Pharmaceutical Publisher, New Delhi, 2002.
59. Medicinal Plant Research Institute, Department of Medical Science, Ministry of Public Health. Standards of Thai Herbal Medicine: Andrographis paniculata The War Veterans Organization Press, Bangkok, 1999: 66-67.
60. Markham KR: Techniques of Flavonoid Identification. Academic Press, London 1982.
61. Srilatha D, Nasara M, Nagasandhya B, Prasad V and Diwan P: Development and Validation of UV Spectro-photometric Method for Simultaneous estimation of Hesperidin and Diosmin in the Pharmaceutical Dosage Form. ISRN Spectroscopy 2013: 1-4.
62. Kuntic V, Pejic N and Micic S: Direct Spectrophotometric Determination of Hesperidin in Pharmaceutical Preparations. Acta Chimica Slovenica 2012; 59: 436-41.
63. Geissman A: The Chemistry of Flavanoid Compounds. The Macmillan Company, New York, 1962.
64. Khan I, Khan F, Farooqui A and Ansari IA: Andro-grapholide exhibits Anticancer potential against Human Colon cancer cells by inducing cell cycle arrest and programmed cell death via Augmentation of Intracellular reactive oxygen species level. Nutrition and Cancer 2018; 70(5): 787-03.
65. Farooqi AA, Attar R, Taliyevich UYS, Alaaeddine N, Xu B and Cho WC: The prowess of andrographolide as a natural weapon in war against cancer. Cancers 2020; 12(8): 1-15.
66. Malik Z, Parveen R, Parveen B, Zahiruddin S, Khan MA and Khan A: Anticancer potential of andrographolide from Andrographis paniculata (Burm.f) Nees and its mechanisms of action. Journal of Ethnopharmacology 2021; 272: 113936.
67. Peng Y, Wang Y, Tang N, Sun D, Lan Y and Yu Z: Andrographolide inhibits breast cancer through suppressing COX-2 expression and angiogenesis via inactivation of p300 signalling and VEGF pathway. Journal of Experi Clinical Cancer Research 2018; 37: 248.
68. Wang S, Li H, Chen S, Wang Z, Yao Y and Chen T: Andrographolide induces apoptosis in human osteosarcoma cells via the ROS/JNK pathway. International Journal of Oncology 2020; 56(6): 1417-1428.
69. Nayak AG, Kumar N, Shenoy S and Roche M: Anti-snake venom and methanolic extract of Andrographis paniculata: A multiprolonged strategy to neutralize Naja Naja venom acetylcholinesterase and hyaluronidase. 3 Biotech 2020; 10(11): 1-12.
70. Burman SN: Malaria-An overview. J Indian Med Assoc 2000; 98(10): 634-37.
71. Prakoso NI, Zakiyah ZN, Liyanita A, Rubiyanto D, Fitriastuti D, Ramadani AP and et al: Antimalarial activity of Andrographis paniculata Ness ‘S N-hexane extract and its major compounds. Open Chemi 2019; 17(1): 788-97.
72. Somsak V: Antimalarial Drug Discovery: Andrographis paniculata leaf extract. Malaria Chemotherapy, Control and Elimination 2016; 5(3): 1-2
73. Zhang XF, Ding MJ, Sheng C, Zhang Y, Xiang SY and Lu J: Andrographolide attenuates oxidative stress injury in cigrattee smoke extract exposed macrophages through inhibiting SIRT1/ERK signalling. International Immuno-pharmacology 2020; 81: 106230.
74. Panossian AG and Georg W: Efficacy of Andrographis paniculata in upper respiratory tract infectious diseases and the mechanism of action. Evidence and rational based research on Chinese drug 2013; 137-79.
75. Zhu T, Wang DX, Zhang W, Liao XQ, Guan X and Bo H: Andrographolide protects against LPS-induced acute lung injury by inactivation of NF-KB. PLoS One 2013; 8(2):1-12.
76. Lingampally V, Solanki VR and Raja SS: Andro-grapholide: An effective anti-fertility agent for the control of Tribolium confusum. Asian Journal of Plant Science and Research 2012; 2(3): 313-17.
77. Muslichah S and Wiratmo: Antifertility effect of n-hexane, chloroform and methanol fractions of seed on male wistar rats. Jurnal Farmasi Sains Dan Terapan 2015; 2: 10-14.
78. Gitler AD, Dhillon P and Shorter J: Neurodegenerative disease: Models, mechanisms and a new hope. Disease Models and Mechanisms 2017; 10(5): 499-502.
79. Kovaes GG: Molecular pathological classification of neurodegenerative disease turning towards precision medicine. Int J of Molecular Sciences 2016; 17(2): 1-33.
80. Akter N, Qureshi NK and Ferdous HS: Obesity: A review of pathogenesis and management strategies in adult. Delta Medical College Journal 2017; 5(1): 35-48.
81. Xiong H, Wang J, Ran Q,Lou G, Peng C and Gan Q: Hesperidin: A Therapeutic agent for Obesity. Drug Design, Development and Therapy 2019; 13: 3855-66.
82. Banjerdpongchai R, Wudtiwai B, Khaw-on P, Rachakhom W, Duangil N and Kongtawelert P: Hesperidin from citrus seeds induces human hepatocellular carcinoma HepG2 cell apoptosis via both mitochondrial and death receptor pathways. Tumour Biology 2015; 37(1): 227-37.
83. Febriansah R, Putri DDP, Sarmoko, Nurulita NA, Meiyanto E and Nugroho AE: Hesperidin as a preventive resistance agent in MCF-7 breast cancer cells line resistance to doxorubicin. Asian Pacific Journal of Tropical Medicine 2014; 4(3): 228-33.
84. Saiprasad G, Chitra P, Manikandan R and Sudhandiran G: Hesperidin induces apoptosis and triggers autophagic markers through inhibition of Aurora-A mediated Phosphoinositiside-3-kinase/Akt/Mammalian target of Rapamycin and Glycogen synthase kinase-3 beta signalling cascades in experimental Colon Carcinogenesis. European Journal of Cancer 2014; 50(14): 2489-07.
85. Mahmoud AM and Hussein OE: Hesperidin as promising anti-diabetic flavanoid: the underlying molecular mechanism. International Journal of Food and Nutritional Science 2016; 3(2): 313-14.
86. Ashafaq M, Varshney L, Khan MHA, Salman M, Naseem M and Wajid S: Neuromodulatory effects of hesperidin in mitigating oxidative stress in Streptozotocin induced diabetics. BioMed Res International 2014; 2014: 249031.
87. Soncul H, Iriz E, Ereren E, Poyraz A, Erer D and Oktar L: Effects of Calcium dobesilate and Disomin-hesperidin on apoptosis of venous wall in primary varicose veins. Journal for Vascular Diseases 2008; 37(3): 233-40.
    

    ---

    How to cite this article:

    Navenaa S, Vadivu R and Radha R: Andrographolide and hesperidin - a brief overview. Int J Pharm Sci & Res 2021; 12(8): 4132-42. doi: 10.13040/IJPSR.0975-8232.12(8).4132-42.

    ---

    All © 2013 are reserved by the International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.

    ---