Review of pharmacological properties of Channa striatus (Ha-ruan) in diabetes and cardiovascular complications

Simple Summary: This review was carried out following previous reports on the hypoglycemia, hypolipidemia, antioxidant, and anti-inflammatory activities of Channa striatus . The fact that there are relationships between diabetes, oxidative stress, and inflammation processes has also triggered the authors to determine the potential of C. striatus against diabetes and cardiovascular disease. For information, C. striatus is a traditional medicine that widely used in Malaysia to treat ailments related to wound, pain, and also ulcers. This present review aims to assess the potential of C. striatus to use in the prevention and/or treatment of diabetes and cardiovascular complications. Abstract: Diabetes mellitus remains a major risk factor for developing cardiovascular diseases, resulting in increased morbidity and mortality associated with cardiovascular complications. Given the burden of diabetes-related cardiovascular complications, there is a need to identify strategies, safe and effective therapeutic agents that could effectively prevent and control diabetes. Presently, many patients living with diabetes depends on traditional medicines as an alternative cure. Channa striatus (Haruan) is a freshwater fish traditionally used to treat wounds, inflammations, and pains. Several pharmacological investigations have supported the folkloric claims of C. striatus extracts , including hypoglycemic, hypolipidemic, antioxidant, anti-inflammatory, and pro-platelet aggregation activities. The therapeutic potentials of C. striatus were demonstrated to be associated with the presence of high content essential amino acids and good fatty acids known to improve cell growth and facilitate wound healing. Therefore, C. striatus bioactive compounds have great potentials to serve as lead candidates in developing novel therapeutic agents for the management of diabetes and related cardiovascular diseases. This review aims to provide a comprehensive overview of the pharmacological properties and therapeutic potentials of C. striatus for the management of diabetes and associated cardiovascular complications.


Introduction
Diabetes mellitus has emerged as one of the rapidly increasing chronic noncommunicable diseases with a substantial public health burden globally [1]. The World Health Organization (WHO) have estimated that over 450 million adults lived with diabetes globally in 2017, and it is projected to increase to over 690 million by 2045 in the absence of effective prevention and control strategies [1][2][3][4]. Diabetes is a metabolic disorder of several etiologies characterized by chronic hyperglycemia resulting from absolute or relative lack of insulin. Cardiovascular diseases (CVD) remain the leading cause of morbidity and mortality among people living with diabetes [5]. Diabetes increases the risk of developing coronary heart disease, ischemic stroke, and death by many folds [6]. A substantial burden of diabetes is related to vascular complications, including coronary heart disease, peripheral artery disease, stroke, neuropathy, nephropathy, and retinopathy [5]. Given the progressive burden of diabetes-related cardiovascular disorders, it is imperative to identify and institute new strategies to prevent and control diabetes.
Despite the advancements in technologies and health, many patients still live in traditional ways that influence their health-seeking behaviors. To date, in many parts of the world, the majority of the population continues to rely on traditional medicine as the primary source of care [7]. Worldwide, plant-based traditional medicines received more attention in the medical literature compared to animal-based natural medicines. Several medicines are driven from animal sources, including those used in diabetes, many of which have been documented with their pharmacological properties. Animal-based natural products have become an essential source of new bioactive compounds that can potentially lead to drug development [8]. Specific animal-based natural products like Channa striatus (Haruan) have been demonstrated to have therapeutic effects against several diseases, particularly diabetes, with fewer side effects, lower cost, and are more accessible locally.

Methods
A non-systematic search of academic databases (PubMed and Google Scholar) and grey literature (Google) was performed to extract and synthesize relevant studies that describe the potential roles of C. striatus in the management of diabetes and related cardiovascular complications. The search terms used include C. striatus, Haruan, diabetes, and cardiovascular diseases.

Animal description
C. striatus (Haruan), known as snakehead murrel, is an obligate air-breathing freshwater fish found mostly in tropical and subtropical Asian countries. C. striatus is consumed all over the Asia Pacific region and is considered a valuable source of protein with several therapeutic benefits [31]. C. striatus has high protein content, mainly albumin and essential amino acids, good fatty acids, minerals, and vitamins [13,14]. The fish is known to have nutritional benefits over other types of fish responsible for its therapeutic benefit.

Animal morphology
C. striatus has a large and slightly flattened scaled head like a snake with a big mouth and sharp teeth, a round body shape, and an extended dorsal fin and a rounded tail fin ( Figure 1a). The upper side of the body is dark, brownish, or greenish; the underside of the body is white, while the sides part of the body have thick lines [32] (Figure 1b). The fish grows up to one meter in length, although bigger sizes are rarely found in the wild because of continuous fishing.

Chemical composition
The common bioactive compounds attributed to C. striatus therapeutic effects are amino acids and fatty acids. The high protein and fat content of the fish make it an important dietary source of essential amino acids like lysine and methionine, as well as a good source of omega-3 fatty acids, particularly docosahexanoic acid (DHA) and eicosapentanoic acid (EPA) [33]. These compounds have been shown to have a beneficial effect in preventing diabetes and cardiovascular complications [33]. In addition, the fish is also known to contain polyunsaturated fatty acids that regulate prostaglandins synthesis and hence wound healing [34,35]. Amino acids and fatty acids are also major biochemical components of the healing process, and deficiency could delay full recovery [13].
A study by Mat Jais et al. reported several fatty acids and amino acids in C. striatus fillet [13]. In the study, the mid-line fillet of C. striatus (Figure 1b Another study by Gam et al. has shown that C. striatus fillet comprises certain amino acids as the major chemical component, including glutamic acid, aspartic acid, lysine, arginine, leucine, alanine, valine, threonine, and glycine [36]. The study also demonstrated that C. striatus contain higher quantities of amino acids in C. stratus than Keli (a freshwater catfish), Rainbow trout, and the salmon fish [36].
Studies have demonstrated the antioxidant effect of amino acids extracted from C.

Pharmacological properties of C. striatus
Cardiovascular complications are the primary cause of morbidity and mortality in patients with diabetes. Hyperglycemia leads to increased glucose autoxidation, lipid peroxidation, and non-enzymatic protein glycosylation, leading to an increase in reactive Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 9 August 2021 doi:10.20944/preprints202108.0200.v1 oxygen species (ROS), advanced glycation end products (AGEs), and endothelial dysfunction [47]. The details of studies demonstrating the pharmacological properties of C. striatus via hypoglycemic, hypolipidemic, antioxidant, and anti-inflammatory are highlighted in the following sections.

Hypoglycemic and hypolipidemic properties
Only a single study was identified to demonstrate the hypoglycemic effect of C.
striatus. The in-vivo study showed the antidiabetic activity of C. striatus in an alloxaninduced diabetic mice model. Administration of the ethanol extract of C. striatus powder at a dose of 300 mg/kg reduced blood glucose concentration after 12 days of treatment [15].
The hypoglycemic effect of the crude extract of C. striatus was linked to certain amino acids and fatty acids in C. striatus, such as palmitic acid, oleic acid, and arginine.
An in-vivo study by Lee et al. reported the hypoglycemic property of palmitic acid in type 2 diabetic db/db mice [48]. In this study, administration of palmitic acid-modified This finding showed that palmitic acid-modified exendin-4 should be viewed as a longacting candidate for treating type-2 diabetes [48]. atherogenic index, and increased high-density lipoprotein cholesterol (HDL-C) [45].
Supplementation also produced marked increases in serum NO levels [46]. Shimura et al. demonstrated that administration of DHA in a diabetic mice model reduced triglycerides and free fatty acids levels compared to control rats [43].
The hypoglycemic and hypolipidemic effects of C. striatus extract, with its amino acid and fatty acid composition, could prevent glucose autoxidation, reducing ROS production, particularly superoxide anion, thereby improving NO bioavailability and attenuate endothelial dysfunction in diabetes. The attenuation of endothelial dysfunction in diabetes may prevent the development of atherosclerosis as wells as other cardiovascular complications.

Antioxidant property
The presence of excess free radicals around the cells can be harmful [16]. Cell damage caused by ROS appears to be a major contributor to vascular complications in diabetes [50].
Chronic hyperglycemia in diabetes induces mitochondrial overproduction of ROS, particularly in the endothelium of both large and small vessels [51].  [30]. The antioxidant effect of crude extract of C.
striatus might be associated with the presence of certain amino acids and fatty acids. Amino acids such as aspartic acid, glutamic acid, and leucine possess antioxidant effects [38][39][40].
Previous studies have also reported the antioxidant effect of fatty acids such as DHA [41,42].

Anti-inflammatory property
Inflammation is a normal response to tissue injury or pathogen exposure and a critical factor in the body's ability to heal itself or fight off infection. The inflammatory response involves the activation of leukocytes and is mediated, in part, by a family of cytokines and chemokines. Although inflammation is beneficial, it can have a detrimental effect [52].
Diabetes has been considered a state of chronic and low-level inflammation. Some evidence has suggested that this immune activation may precede insulin resistance in diabetic and pre-diabetic conditions. These effects may be the factor that initially increases cardiovascular risk in this disease process [52][53][54].
Previous studies have shown reduced NO bioavailability (a potent vasodilator) and increased vasoconstrictor and growth factor endothelin-1 in subjects with metabolic syndrome. These abnormalities not only increase vasoconstriction but are associated with the release of pro-inflammatory cytokines [52,55]. The increase in pro-inflammatory cytokines is directly proportional to the cells' oxidative status or tissues in question.
These imply that there will be an increase in oxidative status due to the rise in the production of ROS by the endoplasmic reticulum (ER) stress, mitochondria, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and other sources of ROS. ER stress can also activate inflammatory cytokines such as tumor necrosis factor-alpaha (TNF-), interleukins-4 (IL-4), and IL-6.
Pro-inflammatory cytokine induces or exacerbates injury by various mechanisms, including enhanced vascular permeability, programmed cell death (apoptosis), recruitment of invasive leukocytes, and the promotion of ROS production [52,56]. In the diabetic condition, augmented pro-inflammatory cytokines contribute to endothelial dysfunction and atherogenesis. Studies have shown increased pro-inflammatory cytokines, particularly TNF- in aortas and cardiac tissue of diabetic rat models [57,58]. TNF- regulates vascular permeability to control inflammation, since increased permeability of micro-and macro vessels allow blood molecules and inflammatory cells to enter the injured vascular tissue. The increased micro and macrovascular permeability contribute to the formation of atherosclerotic plaques initiated by sub-endothelial accumulation of blood lipids and inflammatory cells [59]. In a diabetic state, increased TNF- activates NADPH oxidase that increases the generation of free radicals, particularly superoxide anion. The overproduction of superoxide anion scavenges NO to form peroxynitrite, disrupting eNOS activity, thus reducing NO bioavailability [60]. Therefore, studies on the effects of C. This study showed that NSAIDs decreased granuloma (cotton pellet) size by inhibiting granulocyte inflammation, preventing the generation of collagen fibers, and suppressing mucopolysaccharides [11,61]. Monocyte infiltration, fibroblast proliferation, and exudation take place in chronic inflammation. This proliferation may spread to small vessels or granuloma [11,62]. Therefore, the aqueous extract of C. striatus could inhibit monocyte infiltration and fibroblast proliferation; these may potentially prevent atherosclerosis development.
An in-vivo study by Abedi et al. reported on the anti-inflammatory property of C.
striatus based cream on acute inflammation in the croton oil-induced mice's ear-edema model [17]. Based on the studies highlighted, it could be deduced that the anti-inflammatory effects of C. striatus is attributed to the inhibition of the pro-inflammatory cytokine, TNF- production. Thus, a reduction of TNF- may impair ROS production as well as oxidative stress. Therefore C. striatus have the potential to prevent vascular endothelial dysfunction and atherosclerosis development in diabetes.

Conclusion
Studies have established the ethnopharmacological uses and therapeutic potentials of C. striatus against diabetes and cardiovascular complications. Limited studies have shown C. striatus to have hypoglycemic, hypolipidemic, antioxidant, anti-inflammatory potentials in diabetes models. The therapeutic potentials of C. striatus were demonstrated to be associated with the presence of bioactive compounds, particularly high content essential amino acids and good fatty acids known to improve cell growth and wound healing.
Therefore, the biochemical composition and pharmacological effects of C. striatus suggested its therapeutic potential in managing diabetes and cardiovascular complications.
Further studies would be required to fully elucidate the molecular mechanisms in which C. striatus exerts its pharmacological effects. Therefore, there is also a need for further bioassay-guided fractionation, isolation, and characterization of the extracts and fractions of C. striatus are necessary to understand the bioactive compounds responsible for the pharmacological activities fully and to enable the discovery of novel antidiabetic agents.
Since the fish is generally consumed, further clinical trials should also be performed to