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Yalka Dayanand,1 Reveshni Pather,1 Nombuso Xulu,1 Irvin Booysen,2 Ntethelelo Sibiya,3 Andile Khathi,1 Phikelelani Ngubane1 1School of Laboratory Medicine and Medical Science, University of Kwazulu-Natal, Durban, South Africa; 2School of Chemistry and Physics, University of Kwazulu-Natal, Pietermaritzburg, South Africa; 3Pharmacology Division, Faculty of Pharmacy, Rhodes University, Grahamstown, South AfricaCorrespondence: Reveshni Pather, Department of Human Physiology School of Laboratory Medicine and Medical Sciences College of Health Sciences, University of KwaZulu-Natal, E-Block, Level 4, University Road, Chiltern Hills, Westville Campus, Private Bag X54001, Westville, Durban, 4000, South Africa, Tel +27826570642, Email reveshnipather1@gmail.comAbstract: The prevalence of diabetes mellitus and diabetes-related complications is rapidly increasing worldwide, placing a substantial financial burden on healthcare systems. Approximately 537 million adults are currently diagnosed with type 1 or type 2 diabetes globally. However, interestingly, the increasing morbidity rate is primarily influenced by the effects of long-term hyperglycemia on vital organs such as the brain, the liver and the heart rather than the ability of the body to use glucose effectively. This can be attributed to the summation of the detrimental effects of excessive glucose on major vascular systems and the harmful side effects attributed to the current treatment associated with managing the disease. These drugs have been implicated in the onset and progression of cardiovascular disease, hepatocyte injury and cognitive dysfunction, thereby warranting extensive research into alternative treatment strategies. Literature has shown significant progress in utilizing metal-based compounds, specifically those containing transition metals such as zinc, magnesium and vanadium, in managing hyperglycaemia. Amongst these metals, research carried out on vanadium reflected the most promising anti-diabetic efficacy in cell culture and animal studies. This was attributed to the ability to improve glucose management in the bloodstream by enhancing its uptake and metabolism in the kidney, brain, skeletal muscle, heart and liver. Despite this, organic vanadium was considered toxic due to its accumulative characteristics. To alleviate vanadium’s toxic nature while subsequently manipulating its therapeutic properties, vanadium complexes were synthesized using either vanadate or vanadyl as a base compound. This review attempts to evaluate organic vanadium salts’ therapeutic and toxic effects, highlight vanadium complexes’ research and provide insight into the novel dioxidovanadium complex synthesized in our laboratory to alleviate hyperglycaemia-associated macrovascular complications in the brain, heart and liver.Keywords: diabetes mellitus, hyperglycaemia, dioxidovanadium, toxicity

Nombuso Xulu,1 Phikelelani Ngubane,1 Andile Khathi,1 Irvin Booysen,2 Ntethelelo Sibiya3 1School of Laboratory Medicine and Medical Sciences, University of KwaZulu Natal, Durban, South Africa; 2School of Chemistry and Physics, College of Agriculture, Engineering and Sciences, University of KwaZulu-Natal, Pietermaritzburg, South Africa; 3Pharmacology Division, Faculty of Pharmacy, Rhodes University, Grahamstown, South AfricaCorrespondence: Phikelelani NgubaneDepartment of Human Physiology University of KwaZulu Natal, E-Block, Level 4, University Road, Chiltern Hills, Westville Campus, 3629 Private Bag X54001, Westville, Durban, 4000, South AfricaEmail ngubanep1@ukzn.ac.zaBackground: Despite the effective maintenance of glucose homeostasis by insulin in type 1 diabetes mellitus, the drug has been implicated as one of the causes of haematological disturbances, which give rise to cardiovascular complications. As a result, research into alternative therapies for diabetes is needed. In our laboratory, an anti-hyperglycaemic novel vanadium complex has been synthesized using organic heterocyclic ligands. The complex has been shown and improve glycaemic control. The effects of this complex on haematological function, however, have not yet been established. Therefore, this study sought to investigate the haematological effects of dioxidovanadium(V) complex in (STZ)-induced diabetic rats.Methods: Diabetic rats received vanadium complex (40 mg kg − 1 p.o), diabetic untreated (H2O) and insulin treated (0.175 mg kg− 1 s.c), groups acted as a negative and positive control, respectively. Vanadium complex was administered twice daily, and blood glucose concentration was monitored weekly for 5 weeks. Thereafter, the animals were sacrificed followed by blood and kidneys collection for haematological (full blood count and Annexin V), hormonal (EPO) and oxidative status (SOD and GPx) analysis.Results: After 5 weeks, untreated diabetic rats presented with hyperglycaemia compared to non-diabetic rats which was attenuated by vanadium complex administration. Furthermore, vanadium treated groups presented with an augmented RBC count, haematocrit, haemoglobin concentration, MCHC, MCV, and (EPO) levels compared to diabetic control. An increase in annexin V expression hence cell survival was observed in vanadium complex treated rats. Lastly, the administration of the complex improved antioxidant status as evidenced by increases in SOD and GPx concentration in plasma and in the kidneys.Conclusion: The administration of the anti-hyperglycaemic dioxidovanadium(V) complex improved haematological parameters, cell survival and the antioxidant status displayed by the diabetic rats. These results give an indication that the complex might be an effective alternative therapeutic drug for the treatment of hyperglycaemia in DM.Keywords: hyperglycaemia, vanadium complex, haematological, cardiovascular

Vanadium has demonstrated antihyperglycemic effects in diabetes mellitus (DM) but is, however, associated with toxicity. Therefore, new vanadium complexes envisaged to possess heightened therapeutic potency while rendering less toxicity are being explored. Accordingly, the aim of the study was to investigate the effects of a dioxidovanadium (V) complex, cis-[VO2 (obz) py], on selected glucose metabolism markers in streptozotocin (STZ)-induced diabetic rats. STZ-induced diabetic rats were treated orally with cis-[VO2 (obz) py] (10, 20, and 40 mg/kg) twice every 3rd day for 5 weeks. Blood glucose concentrations, body weight, and food and water intake were monitored weekly, for 5 weeks. Rats were then euthanized after which blood, liver, and muscle tissues were collected for biochemical analysis. The administration of dioxidovanadium complex significantly decreased blood glucose concentrations throughout the 5-week period in comparison with the diabetic control (DC). The attenuation of hyperglycemia was accompanied by an increased glycogen concentration in both liver and muscle tissues in the treated groups. Furthermore, a significant increase was observed in the expression of glucose transporter type 4 (GLUT4) in the skeletal muscle tissues and glycogen synthase in the liver tissues. These findings indicate that our vanadium complex cis-[VO2 (obz) py] may exert antihyperglycemic effects through increased glucose uptake, glycogen synthesis, and increased GLUT4 and glycogen synthase expression., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Bonisiwe Mbatha et al.)

Despite the success of antidiabetic drugs in alleviation of hyperglycaemia, diabetic complications, including renal dysfunction, continue to be a burden. This raises the need to seek alternative therapies that will alleviate these complications. Accordingly, the aim of this study was to investigate the effects of dioxidovanadium(V) complex cis -[VO 2 (obz)py] on renal function in diabetic rats. Streptozotocin-induced diabetic rats were treated with cis -[VO 2 (obz)py] (40 mg·kg -1 ) twice every third day for five weeks. Diabetic untreated and insulin-treated rats served as the diabetic control and positive control, respectively. Blood glucose concentrations, water intake, urinary output, and mean arterial pressure (MAP) were monitored weekly for five weeks. Rats were then euthanized, and blood and kidney tissues were collected for biochemical analysis. Significant decreases in blood glucose concentrations, MAP, glomerular filtration rate (GFR), and SGLT2 expression, as well as plasma angiotensin and aldosterone concentrations, were observed in the treated groups compared with the diabetic control. The complex also increased urinary glucose concentrations, antioxidant enzymes GPx and SOD concentrations, and decreased MDA concentrations and kidney injury molecule (KIM-1) concentrations. These findings suggest that the anti-hyperglycaemic effects of this vanadium complex may ameliorate kidney dysfunction in diabetes.

Cardiovascular complications are among the leading causes of morbidity and mortality in diabetes mellitus (DM). Despite the anti-hyperglycemic effects of various anti-diabetic therapeutic agents like insulin, some of these drugs are implicated in precipitating cardiovascular dysfunction. There is therefore an imperative need to seek alternative drugs that may ameliorate these complications. Accordingly, the aim of the study was to investigate the effects of a dioxidovanadium (V) complex, cis-[VO 2 (obz)py]) on selected cardiovascular function markers in STZ-induced diabetic rats. The vanadium complex (40 mg kg) was administered orally twice every 3rd day 5 weeks, non-diabetic and diabetic control groups received distilled water whereas the insulin group received subcutaneous insulin injections twice daily for 5 weeks. Blood glucose concentrations, mean arterial pressure (MAP), heart rate, triglycerides (TG) and total cholesterol concentrations were monitored weekly for 5 weeks. Rats were then euthanised and blood and hearts were collected for biochemical analysis. There was a significant decrease in blood glucose, triglycerides, cholesterol concentrations as well as blood pressure of vanadium treated rats compared to the untreated diabetic animals. Vanadium treatment also attenuated cardiac oxidative stress and decreased the expression of transforming growth factor β1 (TGFβ1) and Smad7. Lastly, the administration of the vanadium complex significantly decreased C reactive protein (CRP) and cardiotropin 1(CT-1) concentrations in the plasma and heart tissues. The administration of the dioxidovanadium(V) complex to diabetic rats culminated into cardio-protective effects. Taken together, these observations suggest that this metal complex exhibit a significant potential as an alternative therapeutic drug for DM management.

Diabetics are susceptible to hepatic dysfunction risks due to hyperglycaemia and insulin therapy. Conventional diabetes treatments improve glycaemic control; however, hepatic hazards associated with these agents remains a challenge. Accordingly, this study sought to investigate the effect of a dioxidovanadium complex (V) on the hepatic function in streptozotocin-induced diabetic rats. Sprague-Dawley rats (240-250 g) were divided into 4 groups ( n = 6): nondiabetic control, diabetic control, insulin-treated, and vanadium complex groups. The dioxidovanadium (10, 20, and 40 mg/kg) was administered twice every 2nd day for 5 weeks and blood glucose concentration was monitored weekly. At the end of the experimental period, all the experimental groups were sacrificed, and then the lipid profile, liver superoxide dismutase, glutathione peroxidase and malondialdehyde, plasma alanine aminotransferase and aspartate aminotransferase, and C-reactive protein (CRP) concentration were measured. The administration of dioxidovanadium significantly alleviated hyperglycaemia with concomitant attenuation in oxidative stress as evidenced by reduced malondialdehyde concentrations. Furthermore, vanadium complex abolished diabetes-induced dyslipidaemia. Lastly, vanadium complex administration attenuated the increase in alanine aminotransferase, aspartate aminotransferase, and plasma C-reactive protein. These findings suggest that this metallo-compound (dioxidovanadium) may ameliorate liver dysfunction often observed in diabetes.

Infectious and zoonotic disease outbreaks have been linked to increasing volumes of legal and illegal trade. Spatio-temporal and trade network analyses have been used to evaluate the risks associated with these challenges elsewhere, but few details are available for the pig sector in South Africa. Regarding pig diseases, Limpopo province is important as the greater part of the province falls within the African swine fever control area. Emerging small-scale pig farmers in Limpopo perceived pig production as an important means of improving their livelihood and an alternative investment. They engage in trading and marketing their products with a potential risk to animal health, because the preferred markets often facilitate potential longdistance spread and disease dispersal over broad geographic areas. In this study, we explored the interconnectedness of smallholder pig farmers in Limpopo, determined the weaknesses and critical control points, and projected interventions that policy makers can implement to reduce the risks to pig health. The geo-coordinates of surveyed farms were used to draw maps, links and networks. Predictive risks to pigs were determined through the analyses of trade networks, and the relationship to previous outbreaks of African swine fever was postulated. Auction points were identified as high-risk areas for the spread of animal diseases. Veterinary authorities should prioritise focused surveillance and diagnostic efforts in Limpopo. Early disease detection and prompt eradication should be targeted and messages promoting enhanced biosecurity to smallholder farmers are advocated. The system may also benefit from the restructuring of marketing and auction networks. Since geographic factors and networks can rapidly facilitate pig disease dispersal over large areas, a multi-disciplinary approach to understanding the complexities that exist around the animal disease epidemiology becomes mandatory.

The title compound, C(12)H(14)N(5)O(2) (+)·Cl(-)·H(2)O, is the monohydrate of the hydro-chloride of an oxopurine-derived Schiff base in which protonation took place at the pyridine N atom. The organic cation is essentially planar (r.m.s. of all fitted non-H atoms = 0.0373 Å). In the crystal, N-H⋯O and N-H⋯Cl hydrogen bonds as well as C-H⋯O and C-H⋯Cl contacts connect the different entities into a three-dimensional network. The shortest centroid-centroid distance between two pyrimidine rings is 3.6364 (9) Å.

In the title compound, C(12)H(13)N(5)O(2), a Schiff-base-derived chelate ligand, the non-aromatic heterocycle and its substituents essentially occupy one common plane (r.m.s. of fitted non-H atoms = 0.0503 Å). The N=C bond is E-configured. Intra-cyclic angles in the pyridine moiety cover the range 117.6 (2)-124.1 (2)°. Intra- and inter-molecular N-H⋯N and N-H⋯O hydrogen bonds are observed in the crystal structure, as are intra- and inter-molecular C-H⋯O contacts which, in total, connect the mol-ecules into a three-dimensional network. The shortest ring-centroid-to-ring-centroid distance of 3.5831 (14) Å is between the two different types of six-membered rings.

The title compound, C(12)H(14)N(5)O(2) (+)·Br(-), is the hydro-bromide salt of a Schiff base in which protonation has taken place at the pyridine N atom. This organic cation is essentially planar (r.m.s. of all fitted non-H atoms = 0.0448 Å). In the crystal, N-H⋯Br hydrogen bonds as well as C-H⋯O and C-H⋯Br inter-actions connect the mol-ecules, forming a three-dimensional network.

The title compound, C(13)H(12)N(4)O(3), is an imidazole derivative featuring an annealed purine ring system. The benzimidazole-inspired moiety is essentially planar (r.m.s. of all fitted non-H atoms = 0.0205 Å). An intra-molecular O-H⋯N hydrogen bond occurs. In the crystal, inter-molecular N-H⋯O and C-H⋯O hydrogen bonds are observed, which connect the mol-ecules into chains along [110]. The shortest centroid-centroid distance between two aromatic systems is 3.7771 (11) Å.

A new monoclinic form of the title compound, C(14)H(16)N(4)O(2)S, has been identified unexpectedly during an attempt to synthesize a coordination compound. The heterocyclic ring is essentially planar (r.m.s. deviation = 0.005 Å) and makes a dihedral angle of 8.77 (5)° with the benzene ring. This is in contrast to 12.24 (7)° reported for the first monoclinic polymorph [Booysen et al. (2011 ▶). Acta Cryst. E67, o1592]. An intra-molecular N-H⋯S hydrogen bond is observed. In the crystal, inter-molecular N-H⋯O hydrogen bonds link the mol-ecules into zigzag chains along the b axis. The closest distance between the centroids of symmetry-related heterocyclic rings is 3.5161 (6) Å.

The title compound, C(14)H(16)N(4)O(2)S, is a Schiff base derivative of 2-(methyl-sulfan-yl)benzaldehyde. The configuration about the C=N double bond is E. The heterocyclic ring is essentially planar (τ = 3.1°) and makes a dihedral angle of 12.24 (7)° with the benzene ring. An intra-molecular N-H⋯S hydrogen bond is observed. In the crystal, N-H⋯O and C-H⋯O hydrogen bonds link mol-ecules into layers perpendicular to [101]. The closest distance between the centroids of two heterocyclic rings was found to be 3.5268 (8) Å.

In the title compound, C(20)H(16)N(3)O(+)·Br(-)·C(2)H(6)O, the phenol ring forms dihedral angles of 84.5 (1) and 89.3 (1)° with the benzimidazole system and the quinazoline benzene ring, respectively. The two N-H groups act as donors in hydrogen bonds with the bromide ion as acceptor, leading to infinite eight-membered chains along [100]. According to graph-set theory the descriptor on the binary level is C(2) (1)(8). O-H⋯O and O-H⋯Br hydrogen bonds also occur.

In the structure of the title compound, C(20)H(16)N(4)·CH(4)O, the aniline ring forms dihedral angles of 89.9 (2) and 85.4 (2)° with the benzimidazole and benzene rings, respectively. The orientation of the aniline ring is mainly determined by strong hydrogen bonds between the amino group and the non-fused quinazoline N atom. Inter-molecular hydrogen bonds of the N-H⋯N-H⋯N type along [010] and the N-H⋯O-H⋯N type along [100] are formed, resulting in C(2) (2)(4) and C(2) (2)(10) descriptors, respectively, on a binary level of graph-set analysis. There are C-H⋯π contacts with H⋯π distances of 2.44 Å; however, no π-stacking is observed.

In the structure of the title compound, C(20)H(18)N(4)O(2), the N-H and C=O bonds are trans to each other and the amide O atoms are syn to the ortho amino N atom in the benzoyl rings. The amide groups form dihedral angles of 8.4 (2) and 13.8 (2)° with their respective benzoyl rings, and dihedral angles of 51.85 (16) and 51.19 (17)° with the phenyl-enediamine ring. In the crystal, a centrosymmetric dimer is formed by inter-molecular N-H⋯O hydrogen bonds, resulting in an R(2) (2)(14) descriptor on a unitary level of graph-set analysis, and three intramolecular N-H⋯O bonds also occur.