Volume 24, Issue 4

Heat-related illness (HRI) is a broad term that includes clinical conditions ranging from heat cramps and syncope to heat exhaustion and heatstroke, which may result in death. HRIs are one of the major causes of death worldwide and continue to increase in severity with the rise in global temperature. The identification and estimation of heat-related morbidity and mortality is a major challenge. Heat stress manifests itself into respiratory, cardiovascular, and cerebrovascular disorders, leading to the attribution of the deaths caused by heat stress to these disorders. Although HRIs affect mankind in general, certain occupational workers such as soldiers and athletes are more prone. Various pharmacological and nonpharmacological strategies have been employed to combat HRIs. Despite this, heat exposure results in significant morbidity and mortality. Hence, complete understanding of HRIs at physiological as well as molecular level is required to facilitate design of more efficient preventive and treatment strategies. The impact of heat on mankind is not just restricted to HRIs. Heat treatment, i.e., thermotherapy, has been used extensively since ancient times for relieving pain, making heat a two-edged sword. This review attempts to summarize various HRIs, their physiological and molecular basis, and the state-of-the-art techniques/research initiatives to combat the same. It also illustrates the application of thermotherapy as a means for improving quality of life and morbidity associated with several disease conditions such as fibromyalgia syndrome, heart diseases, cancer, chronic pain, and depression.

Background : India has a heterogeneous geographical location with varying ethnic groups with distinct genetic pools. Polymorphisms R577X and insertion/deletion (I/D), occurring in α-actinin3 ( ACTN3 ) and angiotensin converting enzyme ( ACE ) genes, respectively, are reportedly associated with sprint and endurance performance. The normative genetic background of a population provides the baseline genetic diversity of the population. Methods: We investigated the distribution of R577X and I/D polymorphisms in four Indian ethnic populations employed in the Indian Army that requires high levels of physical fitness. A total of 598 army subjects with four different ethnicities were recruited for the study: Rajputs, South Indians, Gorkhas, and Ladakhis. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism followed by statistical analysis. Results : The present study reports for the first time the genotypic distribution of ACTN3 R577X polymorphism in four ethnic groups of the Indian population with no significant change in distribution of R and X alleles among these groups and their overall percentage bearing similarity with the Caucasian population. ACE I/D polymorphism showed significant differences between Rajputs and Gorkhas, Rajputs and Ladakhis, Gorkhas and South Indians, and South Indians and Ladakhis. Combined genotypic analysis showed the highest frequencies of ID+RX in all ethnic groups. Conclusions: Our study reports the genetic predominance of ACE I allele in Gorkhas and I allele predominance in Ladakhis for the first time, thus suggesting that they could be better endurance performers. Both these ethnic groups evolved from the Mongolian race and hence could have similar genotypic distribution. This study provides a comparative account of the Indian normative genetic data in performance-related genes.

Background: After a publication of a study in the Proceedings of the National Academy of Sciences USA in 2001, we published three studies related to birth month and morbidity of patients that can affect longevity. The aim of this study is to check two groups of cardiac deaths, consisting of more than 50% of cardiovascular mortality in the industrial world, to examine this paradigm. Methods: Patients suffering rapid cardiac death (RCD) (≤24 h) and sudden cardiac death (SCD) (≤1 h) in Lithuanian Medical Science University hospital, a tertiary 3000-bed facility, in 2000–2010 were studied. In total, 1239 RCDs and 324 SCDs were included in this study. Monthly, quarterly, trimester and half-year comparisons of the patients’ birth month population were studied. Results : A difference in birth month distribution of the study patients was observed. For RCDs (≤24 h), the highest numbers were found for January (11.0%) and May (10.3%), whereas for the SCDs (≤1 h), April (13.3%) and January (10.5%) dominated. The least numbers were in November (SCD, 5.6%; RCD, 6.2%) and December (5.2–6.1%). Those born in the first and second quarter and first trimester were significantly more than those born in the fourth quarter (I/IV, p=0.0023; I/III, p=0.0074; II/IV, p=0.047) or trimester [I/II, p=0.09 (trend); I/III p=0.014; II/III, p=0.079 (trend)]. In another study at the same location (number of newborns n=286,963), significant correlation between monthly newborn number and month of the year was not found. Possible environmental effects related to the different monthly birth distributions of the studied group are discussed. Conclusions : Victims of SCD and RCD are unequally distributed according to month of birth. The highest numbers were found for January and March to May. The numbers are higher for the first and second quarter and first trimester in comparison with the months at the end of the year. The lowest numbers of study patients were born in November, December and October. This is in accord with the birth months of American centenarians (100–112 years old) found by colleagues from the University of Chicago. Possible mechanisms for predisposition to SCD and RCD need further elucidation. Our findings support the paradigm linking birth month and longevity.

Background: Chronic periodontitis (CP) and peri-implantitis (PI) are inflammatory diseases that affect supporting tissues of teeth or implants. The involvement of hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) in neuronal excitability, hyperalgesia, allodynia, spontaneous pain, synaptic plasticity, and rebound activity was previously determined. Recently, scientists found that HCN2 plays an important role in chronic inflammatory pain. This study aimed to evaluate the relationship between gene polymorphisms of HCN2 and CP/PI. Methods: A total of 74 patients with CP, 37 patients with PI, and 80 healthy controls presenting to the Periodontology Department of Shahid Beheshti University of Medical Sciences were enrolled. DNA was extracted from fresh blood samples of the arm vein of participants and transferred to KBioscience Institute (UK) for genotyping. χ 2 -test was performed with SPSS software v.19 for statistical analyses. A p value <0.05 was considered significant. Results: Both rs55687900 and rs148730222 had significant differences in genotype frequencies between CP and healthy groups (p=0.005 and 0.006, respectively). The allele frequencies also revealed significant frequencies (p=0.004 and 0.006, respectively). The comparison of genotype and allele frequencies between PI and healthy groups had no significant difference. Conclusions: HCN2 polymorphism may play a role in CP but not in PI. Despite this approval, more studies with larger sample sizes in different populations are necessary.

Background: Arsenic, acting as an endocrine disruptor, causes reproductive malfunctions. Studies have been undertaken to find out whether the co-supplementation of α-tocopherol and ascorbic acid (AT-AA) could reduce the arsenic-induced testicular toxicity caused by oxidative stress and resulting DNA damage. Methods: Adult male Wistar rats (120±10 g) were given arsenic trioxide [3 mg/kg body weight (b.wt.) per day] for 30 consecutive days and the supplement group received α-tocopherol (400 mg/kg b.wt. per day) and ascorbic acid (200 mg/kg b.wt. per day). Reproductive functions were evaluated with respect to the histoarchitecture, gametokinetic activity, androgenic potential, glutathione-dependent antioxidant status and DNA damage of the testis. Results: Arsenic treatment caused marked reduction in the relative weight of the testis (p<0.05) but showed no effect on body weight. The number of germ cells at stage VII of the spermatogenic cycle (p<0.01), the seminiferous tubular diameter (p<0.001) and Leydig cell nuclear area (p<0.01) were significantly reduced. Notable decrease in the activities of testicular Δ 5 , 3β-HSD (p<0.05) and 17β-HSD (p<0.01) with a concomitant fall in serum testosterone level (p<0.01) along with significant diminution in testicular glutathione S -transferase (p<0.05) activity and reduced glutathione level (p<0.01) were observed. Significant DNA damage (p<0.001) in spermatogenic cells was also noted. All these alterations including DNA strand breakage were seen to be protected with the coadministration of AT-AA. Conclusions: The data suggest that the protection of testicular toxicity in arsenic-exposed adult rats is possible with combined coadministration of AT-AA.

Background: Stress disturbs homeostasis and may induce various disorders. Immobilization stress (IS) induced due to reduced area provided for mobility results in the imbalance of oxidant and antioxidant status. Stress leads to male reproductive dysfunction in many species, including rodents and humans. Induction of heme oxygenase-1 (HO-1), the rate limiting enzyme in heme degradation, increases host antioxidant defenses. We elucidated the protective role of induction of HO-1 by hemin on testicular damage induced by acute IS. Methods: Male albino rats were immobilized for a period of 6 h. Hemin was given for 3 consecutive days (40 μmol/kg/day, s.c.), before subjecting the animals to acute IS. Results: Upregulation of HO-1 following hemin administration was evidenced in our study by increasing carboxyhemoglobin (COHb) level. Histopathological evaluation confirmed that acute IS caused significant testicular tissue injury, which improves in groups pretreated with hemin. Acute IS also caused significant increases in serum catecholamines and corticosterone levels; however, it produced a significant decrease in testosterone level with non-significant changes in luteinizing hormone (LH) level. In addition, it was found that IS significantly increased testicular malondialdehyde (MDA) and decreased catalase activities. The HO-1 inducer (i.e., hemin) significantly decreased catecholamines and corticosterone levels, and increased testosterone and LH levels. Hemin also decreased testicular MDA and increased catalase activities significantly. Conclusions: Induction of HO-1 protects the testes through its antioxidant and anti-inflammatory effects. Thus, it represents a potential therapeutic option to protect testicular tissue from detrimental effects of IS.

Background: Aggression is a violent behavior emitted against another organism that may lead to its harm or death and thus is of public health significance, which necessitates the search for agents with anti-aggressive property. This study investigated the effect of Jobelyn ® (JB), a unique African polyherbal formulation, on intruder- and isolation-induced aggressive behaviors in mice. Methods: Male mice that showed aggression after being housed individually with female counterparts for 3 weeks or kept in isolation for 4 weeks were treated orally (p.o.) with JB (5, 10 or 50 mg/kg), haloperidol (HP) (1 mg/kg), fluoxetine (FL) (10 mg/kg), p -chlorophenylalanine (PCPA) (20 mg/kg), mianserin (MS) (50 mg/kg) or distilled water (10 mL/kg) 60 min before being tested for aggression. Interaction studies involving oral administration of PCPA (20 mg/kg), FL (10 mg/kg) or MS (50 mg/kg) to aggressive mice that had received JB (5 or 10 mg/kg, p.o.) 30 min earlier were assessed. The effect of JB (5, 10 or 50 mg/kg, p.o.) on defensive behaviors was also evaluated. Results: JB (5, 10 or 50 mg/kg) decreased aggressive behaviors without impairing the defensive mechanisms of mice. PCPA (20 mg/kg), an inhibitor of 5-hydroxytryptamine (5-HT) biosynthesis, increased aggressive responses and reduced the anti-aggressive effect of JB. FL (10 mg/kg), a 5-HT reuptake inhibitor, significantly suppressed aggression but did not alter the effect of JB on aggression. MS (50 mg/kg), a 5-HT receptor antagonist, reduced aggression and enhanced the effect of JB on aggression. Conclusions: These findings suggest that JB has anti-aggressive activity, which may be related to the enhancement of serotonergic system.

Background: Most cancer cells rely on aerobic glycolysis. Dichloroacetate (DCA) inhibits aerobic glycolysis and is a promising relatively nontoxic anticancer compound. However, rapidly proliferating effector T-cells also rely on aerobic glycolysis, whereas regulatory T-cells (Treg) do not. The effect of DCA on glucose metabolism and Treg differentiation was evaluated in alloreactive lymphocytes. Methods: Peripheral blood mononuclear cells from healthy volunteers were used in a two-way mixed lymphocyte reaction. Lymphocyte proliferation was assessed by cell counting; DCA cytotoxicity, by lactate dehydrogenase release assay; and glucose uptake and aerobic glycolysis, by measuring in the supernatants the correspondent glucose and lactate concentrations. Interleukin-10 (IL-10) was measured in the supernatants, whereas the Treg signature transcription factor forkhead box P3 (FOXP3) was measured in cell lysates by means of enzyme-linked immunosorbent assay. Results: DCA had a minor effect on lymphocyte proliferation and cytotoxicity. However, DCA decreased glucose uptake and inhibited aerobic glycolysis. Finally, DCA markedly increased the production of IL-10 and the expression of FOXP3. Conclusions: DCA inhibits aerobic glycolysis and induces Treg differentiation in human alloreactive lymphocytes. This could result in decreased immunosurveillance in case of its use as an anticancer drug. However, DCA could play a role as an immunosuppressant in the fields of transplantation and autoimmunity.

Background: Strophanthus hispidus DC (Apocynaceae) is a medicinal plant widely used in traditional African medicine in the treatment of rheumatic afflictions, ulcer, conjunctivitis, leprosy and skin diseases. This study sought to investigate the antinociceptive, anti-inflammatory and antiulcer properties of the ethanol root extract of S. hispidus. Methods: Antinociceptive activity was evaluated using acetic acid-induced writhing and formalin tests in mice. The carrageenan- and egg albumin-induced rat paw edema tests were used to investigate the anti-inflammatory actions, whereas the antiulcer activity was investigated using ethanol-, HCl- and pyloric ligation-induced gastric ulcer models in rats. Results: S. hispidus [100–800 mg/kg orally (po)] produced significant (p<0.05) inhibition of writhing reflex with peak effect of 74.13% inhibition observed at 800 mg/kg. Similarly, S. hispidus significantly (p<0.05) attenuated formalin-induced early and late phase of nociception with peak effect of 61.84% and 89.43%, respectively, at 200 mg/kg. S. hispidus (25–800 mg/kg po) caused significant (p<0.05) inhibition of edema development in the carrageenan and egg albumin models with peak effect (93.40% and 90.10% inhibition of edema formation) observed at 50 mg/kg. With respect to antiulcer activity, S. hispidus (100–800 mg/kg) showed potent antiulcer activity with respective peak effects of 96% (ethanol-induced), 99% (HCl-induced) and 70.60% inhibition of ulcer. Conclusions : The findings in this study suggest that the ethanol root extract of S. hispidus possesses antinociceptive, anti-inflammatory and antiulcerogenic activities. This justifies the use of the extract in folklore medicine for the treatment of ulcer and inflammatory disorders.

Background: Modulation of inflammatory signaling has been elucidated in several disease models. Acrolein, an environmental pollutant, has been linked to diseases such as atherosclerosis and to the inflammatory process involving nuclear factor κB (NFκB). Serum response factor (SRF), a transcription factor, regulates cell development, differentiation and proliferation through signaling molecules such as extracellular signal-regulated kinase 1/2 (ERK1/2) and CD36. We hypothesized that acrolein toxicity involves SRF in the process of activating NFκB and may involve CD36/ERK1/2. Methods: Vascular smooth muscle cells (VSMCs) were exposed to acrolein (0.5 μg/mL) in the presence or absence of 10 nM QNZ (NFκB inhibitor), 300 nM CCG1423 (SRF inhibitor) and 50 μM PD98059 (ERK1/2 inhibitor). Protein and RNA were isolated. Changes in expression were determined by Western blot and polymerase chain reaction (PCR) array. Results: Subtoxic doses of acrolein increased ERK1/2, SRF and NFκB protein expression, whereas CD36 expression was unchanged. Increase in NFκB expression was accompanied by an increase in activity. ERK1/2 inhibition only blunted SRF expression. SRF inhibition blunted NFκB expression but not that of ERK1/2. CD36 expression was unchanged in the presence of either inhibitor. PCR array analysis indicated up-regulation of nine genes (>4- to 50-fold) and down-regulation of six genes (>4- to 12-fold) involved in inflammatory signaling. Conclusions: We propose that SRF is required in acrolein activation of NFκB and is ERK1/2 dependent.

Background: Cocculus hirsutus , commonly known as broom creeper, belongs to the family Menispermaceae. It is widely used in folk medicine to treat leprosy, skin diseases, dyspepsia, etc. Hence, an effort has been made to investigate the nephroprotective potential of C. hirsutus . Methods: The nephroprotective activity of ethanolic C. hirsutus leaf extract (ECHE) in the 5/6 nephrectomized rat model was investigated. Different parameters like postoperative survival rate, change in body weight and levels of red blood corpuscles (RBCs), hemoglobin (Hb), triglyceride, cholesterol, creatinine, urea and uric acid were estimated in experimental rats. Results: The findings revealed the postoperative survival rate of rats in the investigated novel method to be 100%. Change in the body weight of ECHE-treated groups I and II was found to be 32 and 30 g, respectively. These values suggested that ECHE treatment normalized the elevated body weight levels in experimental rats. Furthermore, ECHE treatment normalized the decreased RBC levels and the elevated Hb, triglyceride, cholesterol, creatinine, urea and uric acid levels in experimental rats. Conclusions: The results indicate that C. hirsutus has strong nephroprotective activity. However, further scrutiny is essential for isolation and characterization of the active components that can be employed to allay various human maladies.

Background: This study was conducted to investigate toxicological effects associated with prolonged consumption of Moringa oleifera leaves as a beverage. Methods: Thirty rats were used in this study. They were grouped into five groups of six rats. Rats in group I received 2 mL/kg body weight (b.w.) of corn oil (vehicle). Animals in groups II, III, IV and V received 50, 100, 200 and 400 mg/kg b.w. of methanolic extract of M. oleifera (MEMO) for 8 weeks. Serum collected was analyzed for alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin, globulin, blood urea nitrogen (BUN) and creatinine. Results: There was a significant (p<0.05) increase in serum total protein and globulin in a dose-dependent manner. Rats that received MEMO at 200 and 400 mg/kg b.w. showed a significant (p<0.05) increase in serum ALT, AST, BUN and creatinine which pointed to hepatic and kidney damage. All experimental animals that received MEMO had a significant (p<0.05) increase in body weight in a dose-dependent manner. Conclusions: This study therefore confirms for the first time that chronic administration of M. oleifera leaves might predispose to hepatic and kidney damage.

Background: Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor used in the treatment of HIV infections and has been reported to be toxic to the male reproductive system. This study was designed to evaluate the ameliorative effects of kolaviron (KV), a biflavonoid from Garcinia kola , on NVP-induced testicular toxicity. Methods: The adult male Wistar rats were given two and four times therapeutic doses of NVP (NVP-2T and NVP-4T; 18 and 36 mg/kg NVP) alone or in combination with KV (200 mg/kg). NVP was given daily, whereas KV was administered five times in a week by oral gavage. Results: Treatment with NVP did not alter the body weight gain and relative weight of testis of the rats. NVP-4T significantly (p<0.05) decreased the sperm motility, protein content, and live-dead ratio and also increased the percentage sperm abnormalities of the rats. Although NVP-4T significantly increased sperm abnormalities, it has no effect on epididymal sperm count. Also, NVP-4T caused a significant (p<0.05) elevation of serum aminotransferases and γ-glutamyl transferase activities. In addition, NVP-4T significantly (p<0.05) decreased the levels of testicular superoxide dismutase, catalase, glutathione S -transferase, and glutathione with marked elevation of malondialdehyde (index of lipid peroxidation) in the rats. In contrast, NVP-2T did not produce an adverse effect on the biochemical indices studied in testes and sperm of rats. Supplementation with KV significantly ameliorated the biochemical changes caused by NVP-4T. Conclusions: Taken together, KV reversed the adverse effects of NVP-4T on testicular antioxidant enzymes and markers of oxidative stress in the rats.

Background: Chemical contaminants have been found to affect reproductive functions in mammals. This study investigated the effect of Chevron Escravos crude oil and Emulsol L.W. dispersant on the testicular functions of guinea pig. Methods: Eight groups of seven sexually mature male guinea pigs each were given 1250, 2500, or 5000 mg/kg of crude oil and dispersant for 7 days. The fluid and food intake and body weight of the animals were measured daily throughout the study. After the exposure period, sperm quality analysis was carried out, and fructose and lactate dehydrogenase were analyzed in tissue homogenate, while testosterone and estradiol were assayed in blood. The right testis was also processed for histological analysis. Results: The epididymal sperm number and fructose level of treated animals showed a significant dose-dependent decrease (p<0.05) compared with controls. Also, sperm motility and morphology were altered in the treated groups, while testosterone and estradiol levels were increased significantly (p<0.05) in the treated groups. Histological examination showed signs of toxicity in the treated animals. Conclusions: From the findings, it was evident that Chevron Escravos crude oil and Emulsol L.W. oil dispersant are able to cause acute testicular toxicity in guinea pigs. The possible mechanism of toxicity is suggested to be by stimulation of hormone production from the adrenal cortex, causing a negative feedback on gonadotropin-releasing hormone in the pituitary gland to suppress spermatogenesis.

Background: Psychosis is a chronic neurological disorder and it remains a major medical and social problem in most African countries. Individuals with psychotic illness in this region tend to seek help from traditional medical practitioners, who prescribe herbal remedies as alternative forms of treatment for the disease. Jobelyn ® (JB) is a commercial polyherbal formulation that has been acclaimed to show beneficial effects in neurological disorders. However, its usefulness in psychosis has not been scientifically validated. Thus, this study was undertaken to evaluate its effects on animal models predictive of human psychosis. Methods: Antipsychotic activity of JB was assessed based on the inhibition of stereotyped behavior induced by amphetamine or apomorphine in mice. Amphetamine-induced hyperactivity and lethality in aggregated mice were additional tests employed to further evaluate the antipsychotic property of JB. The effect of JB on catalepsy was also assessed, using the inclined plane paradigm. Results: JB (5–50 mg/kg, p.o.) significantly (p<0.05) inhibited stereotypy induced by amphetamine (10.0 mg/kg, i.p.) or apomorphine (1 mg/kg, i.p.), which suggests antipsychotic activity. Furthermore, JB (5–50 mg/kg, p.o.) reduced lethality in aggregated mice and inhibited hyperactivity induced by amphetamine, respectively. However, JB (5–50 mg/kg, p.o.) did not cause cataleptic behavior, as it failed to alter the duration of stay of the animals on the inclined plane. Conclusions: Taken together, these findings suggest that JB exhibits antipsychotic-like activity, devoid of the adverse effect of cataleptic behavior, and may offer some beneficial effects in the symptomatic relief of psychotic ailments.