Table 1: List of potential antidiabetic bioactive molecules having plants

Name of plants	Phytochemicals	Pharmacological properties
Gymnema sylvestre^6-7	flavones, anthraquinones, d-quercitol, gymnemic acid, gymnemosides, gymnemasaponins, lupeol, β-amyrin related glycosides and stigmasterol	antidiabetic, antisweetener, hepatoprotective and anti-inflammatory activities.
Momordiaca charantia ^8-10	triterpenoids, saponins, polypeptides, flavonoids, alkaloids and sterols	antihyperglycemic, antimicrobial activity, antitumor, hepatoprotective immunomodulation, antioxidant, anthelmintic, antimutagenic, antiulcer, antilipolytic, antifertility
Syzygium cumini^11-12	anthocyanins, glucoside, ellagic acid, isoquercetin, kaemferol and myrecetin	Diabetes, throat, bronchitis, asthma, hepatoprotective, biliousness, dysentery and ulcers
Trigonella foenum^13-14	ederagin glycosides. Alkaloids such as trigocoumarin, nicotinic acid, trimethyl cou-marin and trigonelline	antidiabetic, anticarcinogenic, hypocholesterolemic, hepatoprotective, antioxidant, and immunological activ-ities
Psidium guajava^15-16	iso-caryophyllene, veridiflorene, farnesene, dl-limonene, δ-cadinene, α-copaene, α-humulene, τ-cadinol .	Treatment of insomnia, hepatoprotective convulsions, epilepsy, bronchitis, asthma, wound healing, pain relief, obesity and to control of diabetes mellitus.
Tinospora cardifolia 17-18	Alkaloids, Terpenoids, Lignans, Steroids and others	antioxidant activity, hepatoprotective, antimicrobial activity, anti-diabetic activity, antistress activity, hypolipidaemic effect, hepatic disorder, anticancer, wound healing, anticomplementary activity, and immunomodulating activity, systemic infection and Parkinson's disease.
Boerhavia diffusa ^19-20	Alkaloids (punarnavine), rotenoids (boeravinones A to J) and flavones.	anti-inflammatory, antifibrinolytic, antibacterial, anti-hepatotoxic, anthelmintic, febrifuge, anti-leprosy, antiasthmatic, antiurethritis, antilymphoproliferative, antimetastatic, hepatoprotective immunosuppressive, antidiabetic, antioxidant, and antiurolithiatic activities.
Coriandrum sativum ^21-22	Linalool, α-Pinene, β-Pinene, γ-Terpinene, α-Cedrene, α-Farnasene, p-Cymene, Limonene, Citronellal, Camphor Geraniol, Anethole.	antimicrobial, antioxidant, hepatoprotective, hypoglycemic, hypolipidemic, anxiolytic, analgesic, anti-inflammatory, anti-convulsant and anti-cancer activities, among others
Andrographis paniculata ^23-24	Andrographolide, deoxyandrographolide, neoandrographolide, 14-deoxy-11,12-didehydroandrographide and isoandrographolide	Anti-inflammation, Anti-cancer, Immunomodulation, Anti-hepatotoxicity, Anti-atherosclerosis, Anti-hyperglycemic effect and Anti-Oxidation
Mixture of Haritaki, Bibhitaki and Amalaki ^25-26	flavonoids, alkaloids, phenols	cardiovascular disease, blood pressure disease, poor liver function, large intestine inflammation, hepatoprotective and ulcerative colitis
Trikatu (Mixture of black pepper (kali mirch), ginger (adhrakh) and long pepper (pippali) ^27-28	Piperine, gingerols, shogaols, and paradols, oleoresins, and alkaloids.	bioavailability enhancer, fevers, gastric and abdominal disorders, urinary difficulties, hepatoprotective, neuralgia and boils etc.

Table: 2 Name of herbal plants for Polyherbal extraction

Name of plants

Biological name

1. Gudmar leaves

2. Karela seed

3. Jamun seed

4. Methi seed

5. Amruda leaves

6. Giloya

4. Punarnava

8. Coriander leaves

9. Kalmegha leaves

10. Triphala

11. Trikatu

12. Aswagandha churna

Gymnema sylvestre

Momordiaca charantia

Syzygium cumini

Trigonella foenum

Psidium guajava

Tinospora cardifolia

Boerhavia diffusa

Coriandrum sativum

Andrographis paniculata

Mixture of Haritaki, Bibhitaki and Amalaki

Mixture of black pepper, and dry ginger

Withania somnifera

Preliminary Phytochemical Screening:

The herbal plants may be considered as a biosynthetic laboratory for a multitude of compounds like alkaloid, glycoside, volatile oils, tannins, saponins, flavonoids, etc. These compounds are termed secondary metabolites and are responsible for therapeutic effects.To check the presence or absence of primary and secondary metabolites; the extract was subjected to a battery of chemical tests^32-33. Results are shown below in Table 3:-

Table 3: Results of Preliminary Phytochemical Screening

Sr. No	Phyto-Constituent Category	Inference
1	Carbohydrate	Positive
2.	Cardiac glycoside	Negative
3	Flavonoids	Positive
4	Alkaloids	Positive
5.	Tannin and phenolic component	Positive
6.	Protein	Positive
8.	Saponin	Positive

In-vivo Hepatoprotective Activity:

Experimental animals:

Evaluation of the in-vivo hepatoprotective activity of poly-herbal formulation and their extract was performed by using paracetamol induced hepatotoxic Wistar-albino rats model. The animals were handling and in vivo experiments were conducted out under guidelines of the “Committee for control and supervision on experiments on animals (CPCSEA), Ministry of Environment and Forests, Govt. of India”. In-vivo Hepatoprotective experimental protocol was approved by the Institutional Animal Ethics Committee (IAEC) of by the Institutional Animal Ethics Committee of B. R. Nahata College of Pharmacy, Mandsaur (Registration no. 2021/08/CPCSEA). Wister albino mice of either sex (25–35gm) were collected at random from the animal house of B. R. Nahata College of Pharmacy, Mandsaur. All animals were kept in a propylene cage with sterilized husk as bedding material in a group of four animals per cage at 22±2 °C in 12:12 light: dark cycle. Standard feeding pellets (Golden feeds, New Delhi) were used for animal feeding and water was available at libitum^34-36.

Paracetamol induced hepatotoxicity:

Animals were divided into 5 groups (n=6/group).

Group 1- Normal control: The animals received saline for 7 days.

Group 2- Induction of hepatotoxicity by using paracetamol: The animals received distilled water

For days and given paracetamol (Themis Pharma, Mumbai) single dose, 500mg/kg bw Orally on day 8 (2.5g/day).

Group 3- Pre-treatment with standard drug sillymarin (100mg/kg) bw/day for 7 days (p.o) followed by a single dose of paracetamol on day 8 (2.5g/day).

Group 4- Pre-treatment with Ethanol: Distilled water (70:30) extract of poly-herbal formulation (50mg/kg bw/day for 7 days (p.o) followed by a single dose of paracetamol on day 8 (2.5g/day).

Group 5- Pre-treatment with Ethanol: Distilled water (70:30) extract of poly-herbal formulation (100mg/kg) Bw/day for 7 days (p.o) followed by a single dose of paracetamol on day 8 2.5g/day).

Histopathological studies:

Histopathological studies were done after blood collection from animals and were sacrificed by cervical dislocation; In-addition, the liver was dissected out and washed with phosphate buffer (pH 7.4) for complete removal of blood stains and clot. After complete washing, tissue was fixed with 10% formalin and implanted in molten paraffin wax followed by cutting of sections carefully by the help of microtome. Deparaffinized tissue sections were then stained using hematoxylin and eosin then after observed microscopically and noted histopathological changes^37-38.

Biochemical analysis:

The biochemical analysis were done by using collected blood samples and were used for the analysis of different biochemical parameters such as aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), bilirubin, total cholesterol, triglyceride, low‑density lipoprotein (LDL), high density lipoprotein (HDL) and were creatinine by using standard diagnostic kits as per manufacturer’s protocol (Lab kit from Merck Chemicals Private Ltd).

Statistical analysis:

ANOVA Analyses of Variance followed by Student–Newman-Keuls test were done using Instant Graph Pad (version 3.0). P < 0.05 and was considered significant, and the values shown in tables are mean ± standard error of the mean (SEM).

Result of hepatoprotective activity:

In the present study, the IP injection of paracetamol induced significant (P < 0.05) hepatocellular changes as evident from enhanced levels of AST, ALT, ALP, and bilirubin compared to normal values. Pretreatment with poly-herbal hydroalcohalic extract at 500 mg/kg body weight dose exhibited a significant (P < 0.05) protection of liver function tests, similar to the results found during pretreatment with sillymarin Table 1.

Hepatic injury induced by paracetamol at a dose of 500 mg/kg body weight exhibited significant raise in the lipid profile, viz., total cholesterol, LDL, and triglycerides levels, whereas HDL level was low as compared to that of control group (P<0.05). However, pretreatment with poly-herbal hydroalcoholic extract at a dose of 500 mg/kg body weight to paracetamol‑induced group shows a significant low (P<0.05) in serum levels of triglyceride and LDL. The efficacy of the poly-herbal hydroalcoholic extract was not found significant in the case of total cholesterol, but HDL level was better significantly (P<0.05) as compared to paracetamol group. In this experiment the 300 mg/kg body weight dose of poly-herbal hydroalcoholic extract shows significant (P<0.05) result only on bilirubin and HDL but another biochemical parameter does not show signs of any significant effect when compare to paracetamol affected group. Administration of paracetamol at dose 500 mg/kg body weight did not show any significant alteration in normal serum creatinine level Table 4.

Histological interpretation:

Histopathological analysis confirmed a degeneration of common architecture of liver cells, infiltration of the lymphocytes, and loss of cell boundaries and the collapse of epithelial tissues (pointed through arrows) induced by the paracetamol. In the our research experimental study the mice pretreated with Sillymarin and poly-herbal extract at 500 mg/kg body weight dose, offered less damage compared to paracetamol group.

Paracetamol Induced Hepatotoxicity:

Pretreatment with poly-herbal extract at the dose 300 mg/kg body weight did not show any type of protective effect Figure 1. Small pieces of liver tissues of each group of Wistar-albino rats were stored in a solution of saleable formaldehyde containers for histopathological studies. Structural injure with integrity and the presence of any type of necrosis or inflammation of tissues was a prime consideration. The studies of histological figures are shown below.

Figure 1: (A) Group 1 (vehicle control) (B) Group 2 (paracetamol) (C) Group 3 (Silimarin), (D and E) Group 4 and 5 hydro-alcoholic polyherbal extract at 300mg/kg and 500mg/kg body weight

In the vehicle-treated group, histological assessment represented the normal architect of cellular constitution. All essential parts of the hepatocellular arrangement were found to be properly arranged and without any type of damage. Hepatic lobule, synosoids, hepatocytes, portal triad (constituting portal vein, portal artery, and bile duct), the general endothelial lining, central vein, vascular endothelium, prominence of nucleus, kupffer cells were observed. All of them were found to be correctly arranged and without any sign of necrosis or inflammation.

Table No. 4:- Effect of extract of poly-herbal formulation on paracetamol exhibited activity in Wistar-albino rats

Biochemical marker	Group 1 (vehicle control)	Group 2 (paracetamol)	Group 3 (Silimarin+ Paracetamol)	Group 4 (PHE 300 mg/kg + paracetamol)	Group 5 (PHE 500 mg/kg + paracetamol)
AST (IU/L)	26.27±2.10	57.21±3.30**	32.273±1.62**	49.16±2.09	35.34±1.66**
ALT (IU/L)	34.50±1.20	65.55±3.34***	40.67±1.18**	55.09±3.07	42.86±1.93**
ALP (IU/L)	192.73±12.73	301.02±12.18***	232.03±17.97**	275.07±9.82	241.53±3.09**
Bilirubin (mg/dL)	0.42±0.12	2.42±0.16***	1.34±0.12**	1.8±0.75*	1.47±0.10**
Total cholesterol (mg/dL)	158.09±5.47	264.34±7.57***	223.80±6.96*	237.39±8.02	232.07±4.92
LDL (mg/dL)	79.77±3.74	124.51±4.20***	98.93±4.41*	118.88±5.64	103.94±2.03**
HDL (mg/dL)	35.90±1.60	21.65±1.62**	32.07±2.34*	29.36±1.91*	34.66±2.45**
Triglycerides (mg/dL)	76.42±3.82	135.34±6.14***	101.66±3.52*	115.96±3.77	93.09±3.89**
Creatinine (mg/dL)	0.59±0.041	0.72±0.044	0.66±0.053	0.65±0.048	0.68±0.040

*Significant elevated level as compared to vehicle treated group (P<0.05)

**Significant protection as compared to paracetamol treated group (P<0.05)

# Significant difference as compared to lower dose i.e. 50 mg/kg (P<0.05)

The customary architecture of the liver was utterly lost in Wistar-albino rats treated with paracetamol with the manifestation of vacuolated Hepatocytes and degenerated nuclei. Vacuolization, fatty changes, and necrosis of hepatocytes were stern in the centrilobular region. Paracetamol poisoning led to a disproportionate pattern of deposition of connective tissue and development of scars and such liver sections were thus assigned as damaged. Livers of animals treated with paracetamol on gross examination seen with scattered yellow and white areas attributed to fatty and necrotic changes.

In poly-herbal hydoalcohalic extract treated group at 50 mg/kg protection and was present but it was not as much significant. Sign of necrosis and inflammation were present.

In poly-herbal hydroalcohalic extract 100 mg/kg treated group protection was quite significant. The sign of intoxication was almost absent. Although few inflammation signs were present necrosis and damage was absent. Thus it can be concluded that the extract at the selected dose also protects at the cellular level.

RESULTS AND DISCUSSION:

Acute liver failure is one of the most important problems worldwide. Hepatic adverse events caused by well-known drugs are of key concern among physician and health care professionals. Medicinal herbal plants either in their isolated form or in the compound formulation have drawn attention all around the world for the treatment of various liver diseases. In Ayurveda, the compound formulations are generally used to enhance the therapeutic effect of individual plants and reduce the side effect if there are any. Paracetamol, a widely used analgesic, and anti‑pyretic drug, is considered to be safe and nontoxic at prescribed doses. However, at repeated and high doses it becomes a potent hepatotoxic. Paracetamol caused liver toxicity is the leading cause of acute liver failure at higher dose³⁹.

Paracetamol mediated acute liver failure is induced by creation of certain reactive metabolites N‑acetyl‑p‑benzoquinone imine. It is generated by several hepatic ezyme like cytochrome P‑450 isoenzymes⁴⁰. In liver injury, the transport mechanism of hepatocytes gets distressed, consequential in the leakage of the plasma membrane, thereby causing an enhanced enzyme level in the serum⁴¹. Administration of paracetamol (500mg/kg body weight) drastically increased the serum level of ALT and AST in mice which was measured as an indication of liver injury.^42-44 Oral administration of the poly-herbal hydroalcoholic extract at a dose of 500mg/kg body weight seems to defend the possible hepatic tissue damage. It caused by paracetamol as it decrease the serum levels of AST, ALT. An overdose of paracetamol induces reduction of glutathione and excessive metabolite reacts with the liver macromolecules and induces hepatic cell death foremost to an prominent level of hepatic cellular enzyme ALP in serum.⁴⁵ Decreasing of elevated bilirubin and ALP level were observed in the serum of mice pretreated with poly-herbal hydroalcoholic extract 500 mg/kg body weight and Sillymarin with paracetamol. In addition, total cholesterol, LDL, and triglyceride level enhances in serum while HDL level decreased in paracetamol treated animals. Elevated levels of total cholesterol and triglyceride may be due to cholesterolemia and modest triglyceridemia, a condition usually occurs in hepatocellular diseases^46-47. The animals pretreated with poly-herbal hydroalcoholic extract (500mg/kg body weight) prevented the increase of triglycerides in serum. It represented its protective nature against paracetamol toxicity but it has no effect on serum cholesterol. It has been reported by various researchers that, hypolipidemic drugs with antioxidant properties, may avoid LDL peroxidation and slow down their accumulation^48-49. The low levels of serum HDL in the paracetamol treated mice may be due to free radicals created during biotransformation. Mice pretreated with the poly-herbal hydroalcohalic extract exhibited improved levels of HDL, which may be due to the ability of the extract to accelerate the decomposition of free radical species generated during acetaminophen toxicity. Hepatoprotective effect of the poly-herbal hydroalcohalic extract was further established by the histopathological observation study of the liver sections, which supported the results obtained from the serum biochemical assays. The Histopathological observation of the liver tissues indicated fatty changes, swelling with the loss of hepatocytes, centrilobular necrosis with lymphocytes and Kupffer cells infiltration in paracetamol intoxicated mice’s. Animals in the group pretreated with poly-herbal extract (500mg/kg body weight) showed regeneration of hepatocytes, normalization of fatty changes and necrosis. The histopathological observations of the liver tissues of mice pretreated with the poly-herbal hydroalcohalic extract exhibited more or less normal architecture of the liver comparable to the vehicle control group. Furthermore, the obstruction in lymphocytes and Kupffer cell penetration‑induced by paracetamol was drastically decreased by poly-herbal hydroalcohalic extract (500 mg/kg body weight) representing its hepatoprotective action. Additional research related to this poly-herbal hydroalcohalic extract is warranted, to explore the exact mechanism and their bioactive molecules that responsible for the pharmacological activity^48-56.

CONCLUSION:

The potent hepatoprotective activity of poly-herbal formulation was found to decrease the level of Total cholesterol, AST, ALT, ALP, Bilirubin, LDL, HDL, Triglycerides and Creatinine in paracetamol treated animals. Accordingly, the poly-herbal hydroalcohalic extract could be developed as an efficient hepatoprotective agent in the treatment and management of liver ailments, as well as a lipid profile.

ACKNOWLEDGEMENTS:

Author Mr. Rama Shankar Dubey and all research team are thankful to Mandsaur University, Mandsaur Madhya Pradesh India for good guidance to carry out this research work.

CONFLICT OF INTREST:

Nil

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Received on 14.06.2022 Modified on 23.08.2023

Research J. Pharm. and Tech 2024; 17(7):3127-3133.

DOI: 10.52711/0974-360X.2024.00489