Review

The impact of p38 MAPK, 5-HT/DA/E signaling pathways in the development and progression of cardiovascular diseases and heart failure in type 1 diabetes

  • Received: 07 August 2020 Accepted: 20 October 2020 Published: 23 October 2020
  • Serotonin or 5-HT, DA and E, all monoamine neurotransmitters, work also as hormones, plays crucial role in the brain and body. This 5-HT, DA and E increased significantly, and regulated by activated p38 MAPK in type I diabetes mellitus (T1DM), and that has been shown to involve in metabolic disorders as well as cardiovascular diseases, leading to heart failure. Even though these molecules are being considered for clinical trials in the treatments of various cardiovascular diseases, the synergistic-pathophysiological mechanisms of these p38 MAPK and neurotransmitters on target molecules, cells and tissues in heart failure are not completely understood in T1DM. However, T1DM results in metabolic dysregulation, impairment/loss of insulin secretion, hyperglycemia and acidosis. These changes are widely reported to be involved in abnormal functions of receptors, which provide binding site for signaling molecules. We are constantly focusing on the mechanisms of alloxan-induced-diabetes, glucose-induced-hyperglycemia and ammonium chloride-induced-acidosis (non-diabetic hyperglycemia (NDH) and non-diabetic acidosis (NDA), respectively) on the levels and functions of neurotransmitters and p38 MAPK. Here, in this review, we are proposing the mechanisms of insulin and/or some of the pharmacological agents on the level and functions of p38 MAPK and neurotransmitters in various areas of rat brain under diabetic or its associated conditions, which leads to cardiovascular dysfunctions. Targeting these molecules/pathways may be useful in the treatment of cardiovascular diseases and diabetes mediated heart failure.

    Citation: Ramakrishnan Ramugounder. The impact of p38 MAPK, 5-HT/DA/E signaling pathways in the development and progression of cardiovascular diseases and heart failure in type 1 diabetes[J]. AIMS Molecular Science, 2020, 7(4): 349-373. doi: 10.3934/molsci.2020017

    Related Papers:

    [1] Nur Laylah, S. Salengke, Amran Laga, Supratomo Supratomo . Effects of the maturity level and pod conditioning period of cocoa pods on the changes of physicochemical properties of the beans of Sulawesi 2 (S2) cocoa clone. AIMS Agriculture and Food, 2023, 8(2): 615-636. doi: 10.3934/agrfood.2023034
    [2] Panagiota Kazai, Christos Noulas, Ebrahim Khah, Dimitrios Vlachostergios . Yield and seed quality parameters of common bean cultivars grown under water and heat stress field conditions. AIMS Agriculture and Food, 2019, 4(2): 285-302. doi: 10.3934/agrfood.2019.2.285
    [3] Abdul Rahim Thaha, Umrah Umrah, Asrul Asrul, Abdul Rahim, Fajra Fajra, Nurzakia Nurzakia . The role of local isolates of Trichoderma sp. as a decomposer in the substrate of cacao pod rind (Theobroma cacao L.). AIMS Agriculture and Food, 2020, 5(4): 825-834. doi: 10.3934/agrfood.2020.4.825
    [4] Pham Thi Thu Ha, Nguyen Thi Bao Tran, Nguyen Thi Ngoc Tram, Vo Hoang Kha . Total phenolic, total flavonoid contents and antioxidant potential of Common Bean (Phaseolus vulgaris L.) in Vietnam. AIMS Agriculture and Food, 2020, 5(4): 635-648. doi: 10.3934/agrfood.2020.4.635
    [5] Hamid El Bilali, Lawali Dambo, Jacques Nanema, Imaël Henri Nestor Bassole, Generosa Calabrese . Biodiversity-pastoralism nexus in West Africa. AIMS Agriculture and Food, 2022, 7(1): 73-95. doi: 10.3934/agrfood.2022005
    [6] Agatha Ifeoma Atugwu, Uchechukwu Paschal Chukwudi, Emmanuel Ikechukwu Eze, Maureen Ogonna Ugwu, Jacob Ikechukwu Enyi . Growth and yield attributes of cowpea accessions grown under different soil amendments in a derived Savannah zone. AIMS Agriculture and Food, 2023, 8(4): 932-943. doi: 10.3934/agrfood.2023049
    [7] Babatope Samuel Ajayo, Baffour Badu-Apraku, Morakinyo A. B. Fakorede, Richard O. Akinwale . Plant density and nitrogen responses of maize hybrids in diverse agroecologies of west and central Africa. AIMS Agriculture and Food, 2021, 6(1): 381-400. doi: 10.3934/agrfood.2021023
    [8] Fitri Damayanti, Salprima Yudha S, Aswin Falahudin . Oil palm leaf ash's effect on the growth and yield of Chinese cabbage (Brassica rapa L.). AIMS Agriculture and Food, 2023, 8(2): 553-565. doi: 10.3934/agrfood.2023030
    [9] Reni Lestari, Mahat Magandhi, Arief Noor Rachmadiyanto, Kartika Ning Tyas, Enggal Primananda, Iin Pertiwi Amin Husaini, Frisca Damayanti, Rizmoon Nurul Zulkarnaen, Hendra Helmanto, Reza Ramdan Rivai, Hakim Kurniawan, Masaru Kobayashi . Genetic characterization of Indonesian sorghum landraces (Sorghum bicolor (L.) Moench) for yield traits. AIMS Agriculture and Food, 2024, 9(1): 129-147. doi: 10.3934/agrfood.2024008
    [10] Patrick A. Blamo Jr, Hong Ngoc Thuy Pham, The Han Nguyen . Maximising phenolic compounds and antioxidant capacity from Laurencia intermedia using ultrasound-assisted extraction. AIMS Agriculture and Food, 2021, 6(1): 32-48. doi: 10.3934/agrfood.2021003
  • Serotonin or 5-HT, DA and E, all monoamine neurotransmitters, work also as hormones, plays crucial role in the brain and body. This 5-HT, DA and E increased significantly, and regulated by activated p38 MAPK in type I diabetes mellitus (T1DM), and that has been shown to involve in metabolic disorders as well as cardiovascular diseases, leading to heart failure. Even though these molecules are being considered for clinical trials in the treatments of various cardiovascular diseases, the synergistic-pathophysiological mechanisms of these p38 MAPK and neurotransmitters on target molecules, cells and tissues in heart failure are not completely understood in T1DM. However, T1DM results in metabolic dysregulation, impairment/loss of insulin secretion, hyperglycemia and acidosis. These changes are widely reported to be involved in abnormal functions of receptors, which provide binding site for signaling molecules. We are constantly focusing on the mechanisms of alloxan-induced-diabetes, glucose-induced-hyperglycemia and ammonium chloride-induced-acidosis (non-diabetic hyperglycemia (NDH) and non-diabetic acidosis (NDA), respectively) on the levels and functions of neurotransmitters and p38 MAPK. Here, in this review, we are proposing the mechanisms of insulin and/or some of the pharmacological agents on the level and functions of p38 MAPK and neurotransmitters in various areas of rat brain under diabetic or its associated conditions, which leads to cardiovascular dysfunctions. Targeting these molecules/pathways may be useful in the treatment of cardiovascular diseases and diabetes mediated heart failure.


    Groundnut (Arachis hypogaea L.) is a very important grain legume crop cultivated for home consumption and market in the semi-arid tropics of West and Central Africa (WCA). The region accounts for about 65 percent of Africa's groundnut area and more than 70 percent of the continent's groundnut production [1]. Nigeria, Senegal, Mali, Burkina Faso, Ghana, Chad, and Niger are the top producers, with smallholder farmers producing the majority of the crop. It is considered a women's crop in several countries, and women and youth play a key role in groundnut cultivation, processing, and marketing. The grain is used in a variety of ways, including boiled/roasted snacks, paste, sauce, cake and oil, and the haulm is a key source of animal feed. It is high in protein and other essential amino acids, and it is frequently used to prepare nutrient-dense foods like plumpynut to treat malnutrition in children and women [2]. Furthermore, it contributes to the long-term viability of agricultural systems by being utilized in crop rotation and fixing nitrogen that can be benefit to the following crop. Groundnut is also an important cash crop, accounting for over half of cash income in rural households [3].

    Earthing up, a practice of covering the base and lower nodes of the plant with soil, is commonly practiced in groundnut cultivation. The practice is tedious, laborious, and time consuming for smallholder farmers because it is normally done manually or in some cases with an oxen-drawn cultivator. There is no consistent evidence about its benefit [4]. Some authors suggested that earthing up should not be used for groundnut as it reduces pod yield [5,6,7]. According to the authors, earthing up, especially in the early stage, influences plant development resulting in deformed plants with low or no production at the lower nodes, where flowers are unable to develop, and hence no pegs or pods form. Earthing up later in the season normally does not result in deformed plants, but it does result in poorer yields [6,7]. Another issue is that the practice can increase the risk of some diseases, such as white mould (Sclerotium rolfsii), causing a reduction in yield [7]. Earthing up during flowering may also affect peg formation due to damage to delicate flowers (hypanthium).

    On the other hand, earthing up after final weeding and gypsum application to compact soil around the effective root zone could increase yield by allowing all pegs formed (geocarpic movement of pegs) to develop into pods. Thilini et al. [8] found that earthing up 37 days after planting was the best time for increasing yield in Sri Lanka. Earthing up has also been shown to boost yield for cultivars that produce aerial pegs [9,10], where many aerial pegs would otherwise remain unproductive in unearthed up plots because they do not enter the soil to develop into pods. The practice may also help late-formed pegs in entering the soil and forming pods. However, while waiting for the late-forming pods to develop, earlier-set pods of varieties with no seed dormancy may sprout or the peg attachment may weaken, resulting in their loss to the soil during harvest [4]. The developing pegs and pods may become exposed due to topsoil erosion in cases where the rainfall is torrential, making them vulnerable to pests and direct solar damage. Further, ridge planting is used for soil moisture management, and soil erosion may reveal the root system, pegs, and pods of those plants on ridges. Light earthing up may help to cover the exposed pegs and pods in such situations. Rather than earthing up, some farmers flatten the plants by stepping over them to bend the stems and branches and allow aerial and or late formed pegs to enter the soil.

    In the semi-arid tropics of West Africa, there is no compelling evidence that earthing up or flattening helps to increase yield, while indications from elsewhere suggest that it might be beneficial if the timing is right. Furthermore, climate change and unpredictability affect crop selections and management methods in the region, necessitating a regular assessment of existing crop management practices such as earthing up. Therefore, this study was designed to evaluate the effects of earthing up and determine the best time to do so to increase groundnut yield, thus filling a knowledge gap in the Sudan agro-climatic conditions for groundnut cropping systems in the region.

    The experiment was conducted at Samanko station, International Crops Research Institute for the Semi-Arid Tropics in Mali (ICRISAT-Mali) for three years, from 2016 to 2018. Samanko is 26 kilometers southwest of Bamako, 12~5'N, 8~54'W. The rainy season runs from June through October, and the station is located in the Sudan Savanah agroclimatic zone. The annual rainfall ranges from 800 to 1200 mm. The soil type is sandy-clay with a pH of 4.5, low fertility, and low organic matter content. The meteorological data collected during the experiment are shown in Table 1. The rainy seasons in 2016 and 2018 started in late June and lasted until the second week of October, as is typical. In 2017, rain began in late June and ended in early September. September and October are crucial in the groundnut grain filling process. The experiment site was plowed and disc harrowed by a tractor before planting, and Diammonium Phosphate fertilizer was applied at a rate of 100 kg/ha.

    Table 1.  Meteorological data during the experiment period.
    Month Total rainfall (mm) Relative humidity Temperature (⊥)
    Rainy season 2016 2017 2018 2016 2017 2018 2016 2017 2018
    min max min max min max
    July 457.7 398.3 252.3 76.7 77.7 71.7 21.9 31.9 21.7 32.7 22.7 34.8
    August 471.0 402.1 359.6 76.9 76.6 74.8 21.6 31.7 21.9 32.1 22.6 34.6
    September 170.0 217.4 255.3 70.1 74.2 75.5 21.8 33.4 21.5 33.8 22.9 34.9
    October 25.9 0 39.8 71.4 63.1 74.7 21.5 36.6 20.8 36.0 23.0 36.1

     | Show Table
    DownLoad: CSV

    The experiment was set up in split plot design with planting arrangement as main plot and time of earthing as subplot replicated three times. Two planting arrangements, row planting on ridges and row planting on flatbeds, were considered. The earthing up time was divided into ten treatments: control (no earthing up), earthing up at 14 days after planting, 21 days after planting, 28 days after planting, 35 days after planting, 42 days after planting, 49 days after planting, 56 days after planting, 63 days after planting, and 70 days after planting. The experiment utilized, ICGV 86124, which is a Spanish type improved groundnut variety with a bunch (erect) growth habit, early maturity (85–95 days) and drought tolerance. Apron Star 42WS (2.5g per kg) was used for seed treatment to protect seeds and seedlings from early season insect pests and soilborne diseases. The plot size was 4 meters long and 2.4 meters wide with 4 rows per plot in a spacing of 60 cm between rows and 10 cm between plants within a row.

    Data were collected on the number of matured pods per plant (NMP) from an average of five random plants, Dry weight of pods per plot (dry pod yield–DPY, kg/plot), Dry weight of haulms per plot (dry haulm yield–DHY, kg/plot), Shelling percentage (%) from 200 random pods, and Dry weight of 100 seeds (100 seeds weight–100 SW, grams-g). For statistical analysis, the DPY and DHY were transformed to per hectare values by multiplying plot level value (in kg) by 10,000 (m2) and dividing by plot size (m2). The difference between treatments for DPY, DHY, NMP, 100 SW, and Shelling percentage was tested using an analysis of variance (ANOVA) using Genstat v.21. The F-test was employed to compare treatments to the ANOVA null hypothesis of equal means using Fisher's protected least significant difference (LSD) test.

    The ANOVA results for DPY and DHY are presented in Table 2. The results revealed no statistically significant difference (P < 0.05) for DPY and DHY between flatbed and ridge planting in 2016, 2017 and 2018. Similarly, there was no statistically significant difference (P < 0.05) in DPY and DHY for the different times of earthing up except in 2017. In 2017, highly significant differences (P < 0.001) were observed between earthing times for both DPY and DHY. The DPY ranged from 1192 kg per hectare for earthing up at 63 days after planting to 1687 kg per hectare for earthing up at 28 days after planting. For DHY, the mean values ranged from 1256 kg per hectare for earthing up 70 days after planting to 1674 kg per hectare for earthing up 28 days after planting. The maximum DHY, 1674 kg per hectare was not statistically significantly different (P < 0.05) from 1619 kg per hectare for the control treatment. For both DPY and DHY, late earthing up at 63 days and 70 days after planting appeared to be detrimental.

    Table 2.  Mean of DPY and DHY during 2016, 2017 and 2018.
    Factors DPY (kg/ha) DHY (kg/ha)
    2016 2017 2018 2016 2017 2018
    Earthing up
    Control 1430 1355c 2079 1384 1619ab 1338
    14 DAP 1406 1386bc 2296 1323 1416abc 1379
    21 DAP 1375 1432bc 2086 1330 1350bc 1450
    28 DAP 1245 1687a 2209 1466 1674a 1422
    35 DAP 1373 1632a 2309 1274 1524abc 1245
    42 DAP 1546 1472b 2261 1315 1422abc 1237
    49 DAP 1360 1398bc 2311 1609 1343bc 1349
    56 DAP 1610 1370bc 2255 1432 1552abc 1358
    63 DAP 1136 1192d 2335 1425 1328bc 1427
    70 DAP 1489 1334c 2328 1228 1256c 1277
    Mean 1397 1426 2247 1379 1448 1348
    Probability¥¥ 0.165 < 0.001 0.374 0.713 < 0.001 0.853
    LSD 316.9 106 258 381 174.2 301.8
    CV 19.3 6.3 9.7 23.5 10.1 19
    Main Plot
    Flatbed 1382 1428 2381 1370 1498 1248
    Ridge 1412 1424 2112 1387 1399 1449
    Probability 0.708 0.638 0.056 0.319 0.739 0.113
    LSD 2388.5 424.2 307.1 1158 3031.9 488.4
      Note: DAP = days after planting; DPY = dry pod yield; DHY = dry haulm yield; LSD = least significant difference; CV = coefficient of variation; probability values greater than 0.05 indicate that the difference is not statistically significant at 5% probability level; ¥¥values with the same letter are not statistically different.

     | Show Table
    DownLoad: CSV

    Table 3 shows ANOVA results for NMP, 100 SW and shelling percent for each year. There was no statistically significant difference (P < 0.05) between the ridge and flatbed planting as main plots for both NMP, 100 SW and shelling percentage. In the case of the subplots (earthing up times), no statistically significant difference (P < 0.05) was observed for NMP in 2016, 2017 and 2018. For 100 SW, a highly significant difference (P < 0.001) was observed in 2018 but not in 2016 and 2017. In 2018, the 100 SW ranged from 23 g for the control treatment to 28.8 g for earthing up at 42 days after planting. The 28.8 g was not statistically significantly different from values obtained for earthing up at 28, 35, and 49 days after planting. In the case of shelling percentage, the treatments showed a highly significant difference (P < 0.001) in 2017 and 2018 but not in 2016. In 2017, the shelling percentage ranged from 61.3% for earthing up at 63 days after planting to 64.5% for earthing up at 28 days after planting. The maximum value, 64.5% was not statistically significantly different from 64.1% obtained for earthing up at 35 days after planting. In 2018, the shelling percentage ranged from 58% for the control treatment to 71.7% for earthing up at 42 days after planting. The control and late earthing up showed a lower values of shelling percentage both in 2017 and 2018.

    Table 3.  Mean of NMP, 100 SW and Shelling percent during 2016, 2017 and 2018.
    Factors NMP (count) 100 SW (g) Shelling percent
    2016 2017 2018 2016 2017 2018 2016 2017 2018
    Earthing up
    Control 24.0 24.0 32.5 31.2 27.0 23.0c 67.3 61.7c 58.0e
    14 DAP 22.5 22.8 35.1 29.0 27.2 24.1bc 65.1 62.7bc 61.0de
    21 DAP 22.3 24.2 30.0 33.6 26.5 24.4bc 67.7 62.2c 63.3d
    28 DAP 22.5 23.3 34.8 29.9 26.3 25.7abc 64.7 64.5a 67.0c
    35 DAP 23.0 22.7 35.2 29.0 26.2 27.6ab 64.3 64.1ab 68.1bc
    42 DAP 23.7 22.8 34.1 28.8 26.2 28.8a 67.4 62.0c 71.7a
    49 DAP 22.8 24.3 32.9 31.2 26.5 28.6a 64.1 61.8c 71.0ab
    56 DAP 23.3 24.3 34.7 33.6 28.7 24.6bc 66.7 62.3c 61.0de
    63 DAP 22.7 24.0 34.0 27.3 25.8 24.0bc 66.8 61.3c 60.2de
    70 DAP 23.2 24.7 35.5 30.8 27.0 26.0abc 68.6 61.5c 60.7de
    Mean 23.0 23.72 33.9 30.5 26.7 25.7 66.3 62.4 64.2
    Probability¥¥ 0.949 0.226 0.781 0.75 0.906 < 0.001 0.288 < 0.001 < 0.001
    LSD 2.567 1.779 6.229 7.321 3.453 2.26 4.011 1.019 2.025
    CV 9.6 6.4 15.6 20.5 11.1 7.4 5.2 1.4 2.7
    Main Plot
    Flatbed 22.71 23.67 36.43 31.22 27.83 26.19 66.85 62.51 64.07
    Ridge 23.3 23.77 31.34 29.68 25.63 25.17 65.7 62.35 64.32
    Probability 0.543 0.885 0.058 0.193 0.076 0.368 0.38 0.766 0.49
    LSD 3.493 2.629 6.289 8.843 2.769 5.753 4.432 2.04 5.718
    Note: DAP = days after planting; NMP = number of matured pods per plant; 100 SW = hundred seed weight; LSD = least significant difference; CV = coefficient of variation; probability values greater than 0.05 indicate that the difference is not statistically significant at 5% probability level; ¥¥values with the same letter are not statistically different.

     | Show Table
    DownLoad: CSV

    Table 4 shows the results of ANOVA across years for DPY, DHY, NMP, 100 SW and shelling percent. A highly significant difference (P < 0.001) was observed between years for all the five traits considered. But there was no statistically significant difference (P < 0.05) between the main plots for all the five traits, and the subplots showed statistically significant differences (P < 0.001) only for the shelling percentage. The earthing up done at 21, 28, 35, 42 and 49 days appeared to have increased shelling percentage. The control treatment and the earthing up at 63 days and 70 days after planting showed lower values of shelling percentage. Highly significant earthing up x year interaction (P < 0.001) was observed for shelling percentage, but not for the other parameters considered.

    Table 4.  Mean of DPY, DHY, NMP, 100 SW and shelling percent across years.
    Factors DPY (kg/ha) DHY (kg/ha) NMP (count) 100 SW (g) Shelling percent
    Earthing up
    Control 1620 1460 26.1 27.1 63.4bcd
    14 DAP 1692 1367 26.8 26.7 62.9cd
    21 DAP 1619 1331 25.5 28.1 64.4abcd
    28 DAP 1713 1480 26.9 28.1 65.4abcd
    35 DAP 1762 1344 26.9 27.6 65.5abc
    42 DAP 1741 1395 26.9 28.0 67.0a
    49 DAP 1689 1388 26.7 28.8 65.7ab
    56 DAP 1764 1436 27.4 29.4 63.4bcd
    63 DAP 1624 1436 26.9 25.8 62.8d
    70 DAP 1704 1282 27.8 28.0 63.6bcd
    Mean 1693 1392 26.8 27.8 64.4
    Probability¥¥ 0.543 0.774 0.846 0.388 < 0.001
    LSD 168.6 225.2 2.468 2.826 1.557
    CV 13.4 21.3 11.9 15.0 3.1
    Main Plot
    Flatbed 1694 1371 26.95 28.3 64.39
    Ridge 1692 1413 26.64 27.25 64.42
    Probability 0.983 0.567 0.780 0.056 0.953
    LSD 295.3 265.7 4.146 1.119 2.026
    Year
    2016 1412b 1356b 23.01b 30.45a 66.60a
    2017 1421b 1472a 23.72b 26.97b 62.41c
    2018 2246a 1348ab 33.67a 25.90b 64.19b
    Probability < 0.001 0.043 < 0.001 < 0.001 < 0.001
    LSD 82.1 107.5 1.152 1.513 0.719
    Earthing up x year
    Probability 0.067 0.780 0.403 0.451 < 0.001
    LSD 268.2 353.9 3.827 4.779 2.399
    Note: DAP = days after planting; DPY = dry pod yield; DHY = dry haulm yield; NMP = number of matured pods per plant; 100 SW = hundred seed weight; LSD = least significant difference; CV = coefficient of variation; probability values greater than 0.05 indicate that the difference is not statistically significant at 5% probability level; ¥¥values with the same letter are not statistically different.

     | Show Table
    DownLoad: CSV

    The study revealed that planting on ridges was not better than planting on flatbeds for DPY, DHY, NMP, 100 SW and shelling percentage. The findings are consistent with those of Mvumi et al. [11], who found no significant differences between planting on flat ground (FG), earthing up after planting on flat ground (EFG), and planting on ridges (R) in pod yield, plant height and stem width but the number of pods and leaves. The present study revealed that earthing up during a typical rainfall season with appropriate planting time doesn*t increase DPY and DHY, which are the priority traits for groundnut producers. The individual years for 2016 and 2018 with typical rainfall seasons and the combined across years analyses showed no statistically significant differences (P < 0.05) between times of earthing up for DPY and DHY. In both 2016 and 2018, rain continued into the second week of October. The result corroborates with the recommendation that earthing up has no benefit and even may reduce yield [5,6], although no significant pod yield reduction was observed in the present study.

    A highly significant difference was observed for the two traits in 2017. The earthing up at 28 and 35 days after planting gave statistically significantly higher DPY than the control treatment. The result for 2017 was in agreement with Thilini et al. [8] who found earthing up at 37 days after planting as the best time for increasing yield in Sri Lanka. However, the 2017 crop season was unusual in that crops, including groundnut, experienced terminal drought as a result of early rainfall cessation. After mid-September, there was no rain in the study area as a whole, with the experimental plots receiving the last rain on September 5. The statistically significant difference between treatments in 2017 suggests that earthing up at the right time can help maintain and increase DPY and DHY in a moisture stress scenario. This could be attributed to two advantages. One, the covering of the base and lower nodes may have reduced the amount of direct sunlight that the pods and roots were exposed to, as well as moisture loss due to evaporation. Second, earthing up as an inter-cultivation method helps in the removal of weeds and inhibits the late emergence of weeds [12], which might have reduced competition of groundnut and weeds for moisture and nutrients. Although the Sudan Savanah agroecology receives adequate rainfall in terms of quantity for groundnut cultivation, terminal drought remains a problem [13]. Rainfall distribution can be erratic, and given the region's current climate change and variability, this is expected to worsen resulting in some atypical rainfall seasons like the one in 2017. Furthermore, while early groundnut planting is encouraged, many farmers, particularly women, lack the requisite planting equipment, such as a plow, to do so. Planting priority is given to sorghum and pearl millet, which are the main staples. As a result, groundnut planting is often delayed, leaving the crop vulnerable to terminal drought. Drought tolerance and early maturity, in addition to pod yield, are among the most desired traits in groundnut varieties by farmers in the Sudan Savanah agroecology [13]. Accurate rainfall forecasts and making them available to groundnut farmers through climate services and national meteorological services would assist decision-making and management of cultural operations, such as whether or not to earth up. On the other hand, groundnut production in the Sahelian agroecology is seriously affected by terminal drought like many other crops [14,15].

    For other traits, the NMP indicated no statistically significant differences (P < 0.05) for analyses at both the individual year and combined across years levels, unlike Ahmad et al. [9], who observed an increase in the number of pods per plant in Pakistan when earthing up was used. In the present study, although significant differences were observed between treatments for 1oo SW and shelling percentage in 2018, these variations did not transfer into an impact on DPY. Ahmad et al. [9] reported an increased 100 SW when earthing up was used.

    In the Sudan Savanah agro-climatic conditions of the semi-arid tropics of West Africa, earthing up is not economically beneficial during a typical rainfall season with appropriate planting time. Instead, it will increase the cost of production, lowering income. Hence, it shouldn*t be done. On the other hand, the findings from the present study, albeit only for one year, revealed that earthing up may be beneficial under a moisture stress scenario to increase yield by retaining soil moisture for extended periods. More research in representative sites for the Sahel agro-climatic zone, where moisture stress is one of the main groundnut production constraints, would be helpful to validate the benefits.

    The research was funded by the Institutional Core Fund from ICRISAT. The authors are thankful to the team of the Groundnut Improvement Program, ICRISAT-Mali. The project "Climate Smart Agricultural Technologies for improving rural livelihoods and food security in Mali (CSAT-Mali)" is acknowledged for covering the article publishing charges (APC).

    The authors have declared no conflict of interest.


    Abbreviation 5-HT: 5-hydroxytryptamine; CaMKII: Ca-calmodulin dependent protein kinase II; CNS: central nervous system; CPST: Ca-dependent-phorbol esters sensitive,-and a family of serine/threonine protein kinases; CVDs: cardiovascular diseases; DA: dopamine; DMHF: diabetes-mediated heart failure; E: epinephrine; GLUT-4: glucose transporter type-4; HF: heart failure; IL1-β: interleukin 1 beta; IRS-1: Insulin receptor substrate-1; LV: left ventricle; MD: metabolic disorders; NDA: non-diabetic acidosis; NDH: non-diabetic hyperglycemia; NHCl: ammonium chloride; p38 MAPK: p38-mitogen activated protein kinase; PDB: phorbol 12, 13-dibutyrate; PKC-α: protein kinase C-alpha; T1DM: type I diabetes mellitus; TGF-β: transforming growth factor beta; TNF-α: tumor necrosis factor alpha;
    Acknowledgments



    The author(s) are thankful to University of Madras for their financial support in part, during this study.

    Conflict of interest



    There is no potential conflict of interest relevant to this article.

    [1] Ramakrishnan R, Namasivayam A (1995) Norepinephrine and epinephrine levels in the brain of alloxan diabetic rats. Neurosci Lett 186: 200-202. doi: 10.1016/0304-3940(95)11315-N
    [2] Ramakrishnan R, Suthanthirarajan N, Namasivayam A (1996) Brain dopamine in experimental diabetes. Indian J Physiol Pharmacol 40: 193-195.
    [3] Ramakrishnan R, Nazer MY, Suthanthirarajan N, et al. (2003) An experimental analysis of the catecholamine's in hyperglycemia and acidosis induced rat brain. Int J Immunopathol Pharmacol 16: 233-239. doi: 10.1177/039463200301600308
    [4] Ramakrishnan R, Kempuraj D, Prabhakaran K, et al. (2005) A short-term diabetes induced changes of catecholamine's and p38 MAPK in discrete areas of rat brain. Life Sci 77: 1825-1835. doi: 10.1016/j.lfs.2004.12.038
    [5] Ramakrishnan R (2014)  Brain Biogenic Amines in Diabetes LAP Lambert Academic Publishing, 1-148.
    [6] Ramakrishnan R (2019) Brain signaling systems: A target for treating type 1 diabetes mellitus. Brain Res Bull 152: 191-201. doi: 10.1016/j.brainresbull.2019.07.017
    [7] Shpakov AO, Derkach KV, Berstein LM (2015) Brain signaling systems in the Type 2 diabetes and metabolic syndrome: promising target to treat and prevent these diseases. Future Sci OA 1: FSO25. doi: 10.4155/fso.15.23
    [8] Watson AMD, Gould EAM, Penfold SA, et al. (2019) Diabetes and Hypertension Differentially Affect Renal Catecholamines and Renal Reactive Oxygen Species. Front Physiol 10: 309. doi: 10.3389/fphys.2019.00309
    [9] Akalu Y, Birhan A (2020) Peripheral arterial disease and its associated factors among type 2 diabetes mellitus patients at Debre Tabor general hospital, Northwest Ethiopia. J Diabetes Res 9419413.
    [10] Ramakrishnan R, Sheeladevi R, Suthanthirarajan N (2004) PKC-alpha mediated alterations of indoleamine contents in diabetic rat brain. Brain Res Bull 64: 189-194. doi: 10.1016/j.brainresbull.2004.07.002
    [11] Ramakrishnan R, Prabhakaran K, Jayakumar AR, et al. (2005) Involvement of Ca(2+)/calmodulin-dependent protein kinase II in the modulation of indolamines in diabetic and hyperglycemic rats. J Neurosci Res 80: 518-528. doi: 10.1002/jnr.20499
    [12] Ramakrishnan R, Sheeladevi R, Suthanthirarajan N, et al. (2005) An acute hyperglycemia or acidosis-induced changes of indolamines level correlates with PKC-alpha expression in rat brain. Brain Res Bull 67: 46-52. doi: 10.1016/j.brainresbull.2005.06.001
    [13] Ramakrishnan R, Sheeladevi R, Namasivayam A (2009) Regulation of protein kinases and co-regulatory interplay of S-100β between PKAII and PKC-α on serotonin level in diabetic rat brain. J Neurosci Res 87: 246-259. doi: 10.1002/jnr.21833
    [14] Moran C, Phan TG, Chen J, et al. (2013) Brain Atrophy in Type 2 Diabetes: Regional distribution and influence on cognition. Diabetes Care 36: 4036-4042. doi: 10.2337/dc13-0143
    [15] Moran C, Beare R, Wang W, et al. (2019) Type 2 diabetes mellitus, brain atropy, and cognitive decline. Neurology 92. doi: 10.1212/WNL.0000000000006955
    [16] Chen K (2004) Organization of MAO A and MAO B promoters and regulation of gene expression. Neurotoxicology 25: 31-36. doi: 10.1016/S0161-813X(03)00113-X
    [17] Fang C, Wu B, Le NTT, et al. (2018) Prions activate a p38 MAPK synaptotoxic signaling pathway. PLoS Pathog 14: e1007283. doi: 10.1371/journal.ppat.1007283
    [18] Dewi DAMS, Wiryana M (2019) The interaction of neuroimmunology, neuromodulator, and neurotransmitter with nociceptor and MAPK signaling. J Immunol Res Ther 4: 9.
    [19] Yang X, Guo Z, Lu J, et al. (2017) The Role of MAPK and Dopaminergic Synapse Signaling Pathways in Antidepressant Effect of Electroacupuncture Pretreatment in Chronic Restraint Stress Rats. Evid Based Complement Alternat Med 2357653.
    [20] Elliott G, Juan BG, Jacqueline HF, et al. (2017) Serotonin and catecholamine's in the development and progression of heart valve diseases. Cardiovasc Res 113: 849-857. doi: 10.1093/cvr/cvx092
    [21] Rosano GMC, Vitale C, Seferovic P (2017) Heart Failure in Patients with Diabetes Mellitus. Card Fail Rev 3: 52-55. doi: 10.15420/cfr.2016:20:2
    [22] Packer M (2018) Heart Failure: The Most Important, Preventable, and Treatable Cardiovascular Complication of Type 2 Diabetes. Diabetes Care 41: 11-13. doi: 10.2337/dci17-0052
    [23] Kenny HC, Abel ED (2019) Heart Failure in Type 2 Diabetes Mellitus: Impact of Glucose-Lowering Agents, Heart Failure Therapies, and Novel Therapeutic Strategies. Circ Res 124: 121-141. doi: 10.1161/CIRCRESAHA.118.311371
    [24] De Vecchis R, Cantatrione C, Mazzei D, et al. (2016) Non-Ergot-Dopamine Agonists don't Increase the Risk of Heart Failure in Parkinson's disease Patients: A Meta-Analysis of Randomized Controlled Trials. J Clin Med Res 8: 449-460. doi: 10.14740/jocmr2541e
    [25] Evangelista I, Nuti R, Picchioni T, et al. (2019) Molecular Dysfunction and Phenotypic Derangement in Diabetic Cardiomyopathy. Int J Mol Sci 20: 3264. doi: 10.3390/ijms20133264
    [26] Tank AW, Lee WD (2015) Peripheral and central effects of circulating catecholamine's. Compr Physiol 5: 1-15.
    [27] Duarte AI, Moreira PI, Oliveira CR (2012) Insulin in central nervous system: more than just a peripheral hormone. J Aging Res 384: 1414-1431.
    [28] Zheng J, Wang Y, Han S, et al. (2018) Identification of Protein Kinase C Isoforms Involved in Type 1 Diabetic Encephalopathy in Mice. J Diabetes Res 8431249.
    [29] Das SK, Yuan YF, Li MQ (2018) Specific PKC βII inhibitor: one stone two birds in the treatment of diabetic foot ulcers. Biosci Rep 38: BSR20171459. doi: 10.1042/BSR20171459
    [30] Nokkaew N, Mongkolpathumrat P, Junsiri R, et al. (2019) p38 MAPK Inhibitor (SB203580) and Metformin Reduces Aortic Protein Carbonyl and Inflammation in Non-obese Type 2 Diabetic Rats. Ind J Clin Biochem 1–7.
    [31] Nokkaew N, Sanit J, Mongkolpathumrat P, et al. (2019) Anti-diabetic drug, metformin, and the p38 inhibitor (SB203580) reduces internal organs oxidative stress in non-obese type 2 diabetic rats. J Appl Pharm Sci 9: 12-20.
    [32] Cramer SC, Sur M, Dobkin BH, et al. (2011) Harnessing neuroplasticity for clinical applications. Brain 134: 1591-1609. doi: 10.1093/brain/awr039
    [33] Hui C, Jingli L, Jiao D, et al. (2015) TAK1 inhibition prevents the development of autoimmune diabetes in NOD mice. Sci Rep 5: 14593. doi: 10.1038/srep14593
    [34] Luchsinger JA, Reitz C, Patel B, et al. (2007) Mayeux, Relation of diabetes to mild cognitive impairment. Arch Neurol 64: 570-575. doi: 10.1001/archneur.64.4.570
    [35] Carvalho C, Cardoso S, Correia SC, et al. (2012) Metabolic alterations induced by sucrose intake and Alzheimer's disease promote similar brain mitochondrial abnormalities. Diabetes 61: 1234-1242. doi: 10.2337/db11-1186
    [36] Bell DS (2003) Diabetic cardiomyopathy. Diabetes Care 26: 2949-2951. doi: 10.2337/diacare.26.10.2949
    [37] Tschope C, Walther T, Koniger J, et al. (2004) Prevention of cardiac fibrosis and left ventricular dysfunction in diabetic cardiomyopathy in rats by transgenic expression of the human tissue kallikrein gene. Faseb J 18: 828-835. doi: 10.1096/fj.03-0736com
    [38] Fischer TA, Ludwig S, Flory E, et al. (2001) Activation of cardiac c-Jun NH(2)-terminal kinases and p38-mitogen-activated protein kinases with abrupt changes in hemodynamic load. Hypertension 37: 1222-1228. doi: 10.1161/01.HYP.37.5.1222
    [39] Zhang GX, Kimura S, Nishiyama A, et al. (2004) ROS during the acute phase of Ang-II hypertension participates in cardiovascular MAPK activation but not vasoconstriction. Hypertension 43: 117-124. doi: 10.1161/01.HYP.0000105110.12667.F8
    [40] Steendijk P, Staal E, Jukema JW, et al. (2001) Hypertonic saline method accurately determines parallel conductance for dual-field conductance catheter. Am J Physiol Heart Circ Physiol 281: H755-H763. doi: 10.1152/ajpheart.2001.281.2.H755
    [41] Steenbergen C (2002) The role of p38 mitogen-activated protein kinase in myocardial ischemia/reperfusion injury; relationship to ischemic preconditioning. Basic Res Cardiol 97: 276-285. doi: 10.1007/s00395-002-0364-9
    [42] Gorog DA, Tanno M, Cao X, et al. (2004) Inhibition of p38 MAPK activity fails to attenuate contractile dysfunction in a mouse model of low-flow ischemia. Cardiovasc Res 61: 123-131. doi: 10.1016/j.cardiores.2003.09.034
    [43] Westermann D, Rutschow S, Van Linthout S, et al. (2006) Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus. Diabetologia 49: 2507-2513. doi: 10.1007/s00125-006-0385-2
    [44] Pereira S, Yu WQ, Moore J, et al. (2016) Effect of a p38 MAPK inhibitor on FFA-induced hepatic insulin resistance in-vivo. Nutr Diabetes 6: e210. doi: 10.1038/nutd.2016.11
    [45] Xu J, Li J, Hou R, et al. (2019) JPQ downregulates the P38 MAPK signal pathway in skeletal muscle of diabetic rats and increases the insulin sensitivity of Skeletal Muscle. Int J Clin Exp Med 12: 5130-5137.
    [46] Erik V, Marjut L, Hanna F, et al. (2010) Sirtuin1-p53, forkhead box O3a, p38 and post-infarct cardiac remodeling in the spontaneously diabetic Goto-Kakizaki rat. Cardiovasc Diabetol 9: 1-13. doi: 10.1186/1475-2840-9-1
    [47] Wang S, Ding L, Ji H, et al. (2016) The Role of p38 MAPK in the Development of Diabetic Cardiomyopathy. Int J Mol Sci 17: 1037. doi: 10.3390/ijms17071037
    [48] Jantira S, Eakkapote P, Punyanuch A, et al. (2019) Combination of metformin and p38 MAPK inhibitor, SB203580, reduced myocardial ischemia/reperfusion injury in non-obese type 2 diabetic Goto-Kakizaki rats. Exp Ther Med 18: 1701-1714.
    [49] Xie D, Zhao J, Guo R (2020) Sevoflurane pre-conditioning ameliorates diabetic myocardial ischemia/reperfusion injury via differential regulation of p38 and ERK. Sci Rep 10: 23. doi: 10.1038/s41598-019-56897-8
    [50] Gao F, Yue TL, Shi DW, et al. (2002) p38 MAPK inhibition reduces myocardial reperfusion injury via inhibition of endothelial adhesion molecule expression and blockade of PMN accumulation. Cardiovasc Res 53: 414-422. doi: 10.1016/S0008-6363(01)00488-6
    [51] Dubash AD, Kam CY, Aguado BA, et al. (2016) Plakophilin-2 loss promotes TGF-β1/p38 MAPK-dependent fibrotic gene expression in cardiomyocytes. J Cell Biol 212: 425. doi: 10.1083/jcb.201507018
    [52] Umbarkar P, Singh AP, Gupte M, et al. (2019) Cardiomyocyte SMAD4-Dependent TGF-β Signaling is Essential to Maintain Adult Heart Homeostasis. JACC Basic Transl Sci 4: 41-53. doi: 10.1016/j.jacbts.2018.10.003
    [53] Palojoki E, Saraste A, Eriksson A, et al. (2001) Cardiomyocyte apoptosis and ventricular remodeling after myocardial infarction in rats. Am J Physiol Heart Circ Physiol 280: H2726-H2731. doi: 10.1152/ajpheart.2001.280.6.H2726
    [54] Dong H, Cui B, Hao X (2019) MicroRNA-22 alleviates inflammation in ischemic stroke via p38 MAPK pathways. Mol Med Rep 20: 735-744.
    [55] Yu L, Li Z, Dong X, et al. (2018) Polydatin Protects Diabetic Heart against Ischemia-Reperfusion Injury via Notch1/Hes1-Mediated Activation of Pten/Akt Signaling. Oxid Med Cell Longev 2018: 2750695.
    [56] Stockand JD, Meszaros JG (2003) Aldosterone stimulates proliferation of cardiac fibroblasts by activating Ki-Ras A and MAPK1/2 signaling. Am J Physiol Heart Circ Physiol 284: H176-H184. doi: 10.1152/ajpheart.00421.2002
    [57] Koga Y, Tsurumaki H, Aoki-Saito H, et al. (2019) Roles of Cyclic AMP Response Element Binding Activation in the ERK1/2 and p38 MAPK Signaling Pathway in Central Nervous System, Cardiovascular System, Osteoclast Differentiation and Mucin and Cytokine Production. Int J Mol Sci 20: 1346. doi: 10.3390/ijms20061346
    [58] Turner NA, Blythe NM (2019) Cardiac Fibroblast p38 MAPK: A Critical Regulator of Myocardial Remodeling. J Cardiovasc Dev Dis 6: 27. doi: 10.3390/jcdd6030027
    [59] Thum T, Gross C, Fiedler J, et al. (2008) Micro RNA-21 contributes to myocardial disease by stimulating MAP kinase signaling in fibroblasts. Nature 456: 980-984. doi: 10.1038/nature07511
    [60] Liang Q, Molkentin JD (2003) Redefining the roles of p38 and JNK signaling in cardiac hypertrophy: dichotomy between cultured myocytes and animal models. J Mol Cell Cardiol 35: 1385-1394. doi: 10.1016/j.yjmcc.2003.10.001
    [61] Xu Z, Sun J, Tong Q, et al. (2016) The Role of ERK1/2 in the Development of Diabetic Cardiomyopathy. Int J Mol Sci 17: 2001. doi: 10.3390/ijms17122001
    [62] Ruiz M, Coderre L, Allen BG, et al. (2018) Protecting the heart through MK2 modulation, toward a role in diabetic cardiomyopathy and lipid metabolism. Biochim Biophys Acta Mol Basis Dis 1864: 1914-1922. doi: 10.1016/j.bbadis.2017.07.015
    [63] Liao P, Georgakopoulos D, Kovacs A, et al. (2001) The in-vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy. Proc Natl Acad Sci U S A 98: 12283-12288. doi: 10.1073/pnas.211086598
    [64] Jia G, Hill MA, Sowers JR (2018) Diabetic Cardiomyopathy An Update of Mechanisms Contributing to This Clinical Entity. Circ Res 122: 624-638. doi: 10.1161/CIRCRESAHA.117.311586
    [65] Streicher JM, Ren S, Herschman H, et al. (2010) MAPK-activated protein kinase-2 in cardiac hypertrophy and cyclooxygenase-2 regulation in heart. Circ Res 106: 1434-1443. doi: 10.1161/CIRCRESAHA.109.213199
    [66] Hill JA, Olson EN (2008) Cardiac plasticity. N Engl J Med 358: 1370-1380. doi: 10.1056/NEJMra072139
    [67] Vikas K, Kumar A, Rahul S, et al. (2019) Chronic Pressure Overload Results in Deficiency of Mitochondrial Membrane Transporter ABCB7 Which Contributes to Iron Overload, Mitochondrial Dysfunction, Metabolic Shift and Worsens Cardiac Function. Sci Rep 9: 13170. doi: 10.1038/s41598-019-49666-0
    [68] Takeda N, Manabe I, Uchino Y, et al. (2010) Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload. J Clin Invest 120: 254-265. doi: 10.1172/JCI40295
    [69] Small EM (2012) The actin-MRTF-SRF gene regulatory axis and myofibroblast differentiation. J Cardiovasc Transl Res 5: 794-804. doi: 10.1007/s12265-012-9397-0
    [70] Zent J, Guo LW (2018) Signaling Mechanisms of Myofibroblastic Activation: Outside-in and Inside-Out. Cell Physiol Biochem 49: 848-868. doi: 10.1159/000493217
    [71] Bujak M, Frangogiannis NG (2007) The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res 74: 184-195. doi: 10.1016/j.cardiores.2006.10.002
    [72] Ieda M, Tsuchihashi T, Ivey KN, et al. (2009) Cardiac fibroblasts regulate myocardial proliferation through beta1 integrin signaling. Dev Cell 16: 233-244. doi: 10.1016/j.devcel.2008.12.007
    [73] Souders CA, Bowers SL, Baudino TA (2009) Cardiac fibroblast: the renaissance cell. Circ Res 105: 1164-1176. doi: 10.1161/CIRCRESAHA.109.209809
    [74] Kakkar R, Lee RT (2010) Intramyocardial fibroblast myocyte communication. Circ Res 106: 47-57. doi: 10.1161/CIRCRESAHA.109.207456
    [75] Martin ML, Blaxall BC (2012) Cardiac intercellular communication: are myocytes and fibroblasts fair-weather friends? J Cardiovasc Transl Res 5: 768-782. doi: 10.1007/s12265-012-9404-5
    [76] Furtado MB, Costa MW, Pranoto EA, et al. (2014) Cardiogenic genes expressed in cardiac fibroblasts contribute to heart development and repair. Circ Res 114: 1422-1434. doi: 10.1161/CIRCRESAHA.114.302530
    [77] Miyazaki T, Haraguchi S, Kim-Kaneyama JR, et al. (2019) Endothelial calpain systems orchestrate myofibroblast differentiation during wound healing. FASEB J 33: fj.201800588RR. doi: 10.1096/fj.201800588RR
    [78] Zhang ZY, Wang N, Qian LL, et al. (2020) Glucose fluctuations promote aortic fibrosis through the ROS/p38 MAPK/Runx2 signaling pathway. J Vasc Res 57: 24-33. doi: 10.1159/000503608
    [79] Nian M, Lee P, Khaper N, et al. (2004) Inflammatory cytokines and postmyocardial infarction remodeling. Circ Res 94: 1543-1553. doi: 10.1161/01.RES.0000130526.20854.fa
    [80] Lee MMY, McMurray JJV, Lorenzo-Almorós A, et al. (2016) Diabetic cardiomyopathy. Heart 105.
    [81] Kocabaş U, Yılmaz Ö, Kurtoğlu V (2019) Diabetic cardiomyopathy: acute and reversible left ventricular systolic dysfunction due to cardiotoxicity of hyperglycaemic hyperosmolar state—a case report. Eur Heart J Case Rep 3: ytz049. doi: 10.1093/ehjcr/ytz049
    [82] Gao M, Wang X, Zhang X, et al. (2015) Attenuation of Cardiac Dysfunction in Polymicrobial Sepsis by MicroRNA-146a Is Mediated via Targeting of IRAK1 and TRAF6 Expression. J Immunol 195: 672-682. doi: 10.4049/jimmunol.1403155
    [83] Mann DL (2003) Stress-activated cytokines and the heart: from adaptation to maladaptation. Annu Rev Physiol 65: 81-101. doi: 10.1146/annurev.physiol.65.092101.142249
    [84] Fiordelisi A, Iaccarino G, Morisco C, et al. (2019) NFkappaB is a Key Player in the Crosstalk between Inflammation and Cardiovascular Diseases. Int J Mol Sci 20: 1599. doi: 10.3390/ijms20071599
    [85] Frati G, Schirone L, Chimenti I, et al. (2017) An overview of the inflammatory signaling mechanisms in the myocardium underlying the development of diabetic cardiomyopathy. Cardiovasc Res 113: 378-388. doi: 10.1093/cvr/cvx011
    [86] Sharov VG, Todor A, Suzuki G, et al. (2003) Hypoxia, angiotensin-II, and norepinephrine mediated apoptosis is stimulus specific in canine failed cardiomyocytes: a role for p38 MAPK, Fas-L and cyclin D1. Eur J Heart Fail 5: 121-129. doi: 10.1016/S1388-9842(02)00254-4
    [87] Kaiser RA, Bueno OF, Lips DJ, et al. (2004) Targeted inhibition of p38 mitogen-activated protein kinase antagonizes cardiac injury and cell death following ischemia-reperfusion in-vivo. J Biol Chem 279: 15524-15530. doi: 10.1074/jbc.M313717200
    [88] Wakeman D, Guo J, Santos JA, et al. (2012) p38 MAPK regulates Bax activity and apoptosis in enterocytes at baseline and after intestinal resection. Am J Physiol Gastrointest Liver Physiol 302: G997-1005. doi: 10.1152/ajpgi.00485.2011
    [89] Xu Q, Fang H, Zhao L, et al. (2019) Mechano growth factor attenuates mechanical overload-induced nucleus pulposus cell apoptosis through inhibiting the p38 MAPK pathway. Biosci Rep 39: BSR20182462. doi: 10.1042/BSR20182462
    [90] Aggeli IK, Beis I, Gaitanaki C (2008) Oxidative stress and calpain inhibition induces alpha B-crystallin phosphorylation via p38 MAPK and calcium signaling pathways in H9c2 cells. Cell Signal 20: 1292-1302. doi: 10.1016/j.cellsig.2008.02.019
    [91] Mitra A, Ray A, Datta R, et al. (2014) Cardioprotective role of P38 MAPK during myocardial infarction via parallel activation of alpha-crystallin B and Nrf2. J Cell Physiol 229: 1272-1282. doi: 10.1002/jcp.24565
    [92] Kim JK, Pedram A, Razandi M, et al. (2006) Estrogen prevents cardiomyocyte apoptosis through inhibition of reactive oxygen species and differential regulation of p38 kinase isoforms. J Biol Chem 281: 6760-6767. doi: 10.1074/jbc.M511024200
    [93] Liu H, Pedram A, Kim JK (2011) Oestrogen prevents cardiomyocyte apoptosis by suppressing p38alpha-mediated activation of p53 and by down-regulating p53 inhibition on p38beta. Cardiovasc Res 89: 119-128. doi: 10.1093/cvr/cvq265
    [94] Wu H, Wang G, Li S, et al. (2015) TNF-α- Mediated-p38-Dependent Signaling Pathway Contributes to Myocyte Apoptosis in Rats Subjected to Surgical Trauma. Cell Physiol Biochem 35: 1454-1466. doi: 10.1159/000373965
    [95] Zuo G, Ren X, Qian X, et al. (2019) Inhibition of JNK and p38 MAPK-mediated inflammation and apoptosis by ivabradine improves cardiac function in streptozotocin-induced diabetic cardiomyopathy. J Cell Physiol 234: 1925-1936. doi: 10.1002/jcp.27070
    [96] Li Z, Ma JY, Kerr I, et al. (2006) Selective inhibition of p38alpha MAPK improves cardiac function and reduces myocardial apoptosis in rat model of myocardial injury. Am J Physiol Heart Circ Physiol 291: H1972-H1977. doi: 10.1152/ajpheart.00043.2006
    [97] Adhikary L, Chow F, Nikolic-Paterson DJ, et al. (2004) Abnormal p38 mitogen-activated protein kinase signaling in human and experimental diabetic nephropathy. Diabetologia 47: 1210-1222. doi: 10.1007/s00125-004-1437-0
    [98] Kojonazarov B, Novoyatleva T, Boehm M, et al. (2017) p38 MAPK Inhibition Improves Heart Function in Pressure-Loaded Right Ventricular Hypertrophy. Am J Respir Cell Mol Biol 57: 603-614. doi: 10.1165/rcmb.2016-0374OC
    [99] Seeger FH, Sedding D, Langheinrich AC, et al. (2010) Inhibition of the p38 MAP kinase in-vivo improves number and functional activity of vasculogenic cells and reduces atherosclerotic disease progression. Basic Res Cardiol 105: 389-397. doi: 10.1007/s00395-009-0072-9
    [100] Nediani C, Borchi E, Giordano C, et al. (2007) NADPH oxidase-dependent redox signaling in human heart failure: relationship between the left and right ventricle. J Mol Cell Cardiol 42: 826-834. doi: 10.1016/j.yjmcc.2007.01.009
    [101] Newby LK, Marber MS, Melloni C, et al. (2014) SOLSTICE Investigators. Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial. Lancet 384: 1187-1195. doi: 10.1016/S0140-6736(14)60417-7
    [102] Halpern CH, Tekriwal A, Santollo J, et al. (2013) Amelioration of binge eating by nucleus accumbens shell deep brain stimulation in mice involves D2 receptor modulation. J Neurosci 33: 7122-7129. doi: 10.1523/JNEUROSCI.3237-12.2013
    [103] Ter Horst KW, Lammers NM, Trinko R, et al. (2018) Striatal dopamine regulates systemic glucose metabolism in humans and mice. Sci Transl Med 10: eaar3752. doi: 10.1126/scitranslmed.aar3752
    [104] Figee M, De Koning P, Klaassen S, et al. (2014) Deep brain stimulation induces striatal dopamine release in obsessive-compulsive disorder. Biol Psychiatry 75: 647-652. doi: 10.1016/j.biopsych.2013.06.021
    [105] Boot E, Booij J, Hasler G, et al. (2008) AMPT-induced monoamine depletion in humans: Evaluation of two alternative (123I) IBZM SPECT procedures. Eur J Nucl Med Mol Imaging 35: 1350-1356. doi: 10.1007/s00259-008-0739-8
    [106] Zeng C, Zhang M, Asico LD, et al. (2007) The dopaminergic system in hypertension. Clin Sci 112: 583-597. doi: 10.1042/CS20070018
    [107] Channabasappa S, Sanjay K (2011) Bromocriptine in type 2 diabetes mellitus. Indian J Endocrinol Metab 15: S17-S24. doi: 10.4103/2230-8210.83058
    [108] Reda E, Hassaneen S, El-Abhar HS (2018) Novel Trajectories of Bromocriptine Antidiabetic Action: Leptin-IL-6/ JAK2/p-STAT3/SOCS3, p-IR/p-AKT/GLUT4, PPAR-γ/Adiponectin, Nrf2/PARP-1, and GLP-1. Front Pharmacol 9: 771. doi: 10.3389/fphar.2018.00771
    [109] Leicht M, Briest W, Zimmer HG (2003) Regulation of norepinephrine-induced proliferation in cardiac fibroblasts by interleukin-6 and p42/p44 mitogen activated protein kinase. Mol Cell Biochem 243: 65-72. doi: 10.1023/A:1021655023870
    [110] Lubahn CL, Lorton D, Schaller JA, et al. (2014) Targeting a-and b-adrenergic receptors differentially shift Th1, Th2, and inflammatory cytokine profiles in immune organs to attenuate adjuvant arthritis. Front Immunol 5: 346. doi: 10.3389/fimmu.2014.00346
    [111] Moliner P, Enjuanes C, Tajes M, et al. (2019) Association Between Norepinephrine Levels and Abnormal Iron Status in Patients With Chronic Heart Failure: Is Iron Deficiency More Than a Comorbidity? J Am Heart Assoc 8: e010887. doi: 10.1161/JAHA.118.010887
    [112] Zhang P, Li Y, Nie K, et al. (2018) Hypotension and bradycardia, a serious adverse effect of piribedil, a case report and literature review. BMC Neurol 18: 221. doi: 10.1186/s12883-018-1230-1
    [113] Michael E, Shuqin L, Nicholas C, et al. (2019) 1793-P: Dopamine D1 plus D2 Receptor Coactivation Ameliorates Metabolic Syndrome (MS) and Nonalcoholic Fatty Liver Disease (NAFLD) in Mice. Diabetes 68.
    [114] Monti JM, Monti D (2007) The involvement of dopamine in the modulation of sleep and waking. Sleep Med Rev 11: 113-133. doi: 10.1016/j.smrv.2006.08.003
    [115] Wang X, Wang ZB, Luo C, et al. (2019) The Prospective Value of Dopamine Receptors on Bio-Behavior of Tumor. J Cancer 10: 1622-1632. doi: 10.7150/jca.27780
    [116] Chávez-Castillo M, Ortega Á, Nava M, et al. (2018) Metabolic risk in depression and treatment with selective serotonin reuptake inhibitors: are the metabolic syndrome and an increase in cardiovascular risk unavoidable? Vessel Plus 2: 6. doi: 10.20517/2574-1209.2018.02
    [117] Fortier JH, Pizzarotti B, Shaw RE, et al. (2019) Drug-associated valvular heart diseases and serotonin-related pathways: a meta-analysis. Heart 105: 1140-1148.
    [118] Mawe GM, Hoffman JM (2013) Serotonin signaling in the gastrointestinal tract. Nat Rev Gastroenterol Hepatol 10: 473-486. doi: 10.1038/nrgastro.2013.105
    [119] Selim AM, Sarswat N, Kelesidis I, et al. (2017) Plasma Serotonin in Heart Failure: Possible Marker and Potential Treatment Target. Heart Lung Circ 26: 442-449. doi: 10.1016/j.hlc.2016.08.003
    [120] Guo S, Chen L, Cheng S, et al. (2019) Comparative cardiovascular safety of selective serotonin reuptake inhibitors (SSRIs) among Chinese senile depression patients: A network meta-analysis of randomized controlled trials. Medicine 98: e15786. doi: 10.1097/MD.0000000000015786
    [121] Lancellotti P, Nchimi A, Hego A, et al. (2015) High-dose oral intake of serotonin induces valvular heart disease in rabbits. Int J Cardiol 197: 72-75. doi: 10.1016/j.ijcard.2015.06.035
    [122] Seferovic PM, Ponikowski P, Anker SD, et al. (2019) Clinical practice update on heart failure 2019: pharmacotherapy, procedures, devices and patient management. An expert consensus meeting report of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 21: 1169-1186. doi: 10.1002/ejhf.1531
    [123] Shimizu Y, Minatoguchi S, Hashimoto K, et al. (2002) The role of serotonin in ischemic cellular damage and the infarct size-reducing effect of sarpogrelate, a 5-hydroxytryptamine-2 receptor blocker, in rabbit hearts. J Am Coll Cardiol 40: 1347-1355. doi: 10.1016/S0735-1097(02)02158-7
    [124] Chen YG, Mathews CE, Driver JP (2018) The Role of NOD Mice in Type 1 Diabetes Research: Lessons from the Past and Recommendations for the Future. Front Endocrinol 9: 51. doi: 10.3389/fendo.2018.00051
    [125] Pei Y, Cui F, Du X, et al. (2019) Antioxidative nanofullerol inhibits macrophage activation and development of osteoarthritis in rats. Int J Nanomedicine 14: 4145-4155. doi: 10.2147/IJN.S202466
    [126] Kullmann S, Heni M, Hallschmid M, et al. (2016) Brain Insulin Resistance at the Crossroads of Metabolic and Cognitive Disorders in Humans. Physiol Rev 96: 169-209. doi: 10.1152/physrev.00032.2015
    [127] Grillo CA, Woodruff JL, Macht VA, et al. (2019) Insulin resistance and hippocampal dysfunction: Disentangling peripheral and brain causes from consequences. Exp Neurol 318: 71-77. doi: 10.1016/j.expneurol.2019.04.012
    [128] Nakabeppu Y (2019) Origins of brain insulin and its function. In: Diabetes Mellitus. Advances in Experimental Medicine and Biology. Adv Exp Med Biol 1128: 1-11. doi: 10.1007/978-981-13-3540-2_1
    [129] Bode BW, Garg SK (2016) The Emerging Role of Adjunctive Noninsulin Anti-hyperglycemic Therapy in the Management of Type 1 Diabetes. Endocr Pract 22: 220-230. doi: 10.4158/EP15869.RA
    [130] Otto-Buczkowska E, Nowowiejska B, Jarosz-Chobot P, et al. (2009) Could oral antidiabetic agents be useful in the management of different types of diabetes and syndromes of insulin resistance in children and adolescents? Przegl Lek 66: 388-393.
    [131] Otto-Buczkowska E, Natalia J (2018) Pharmacological Treatment in Diabetes Mellitus Type 1 – Insulin and What Else? Int J Endocrinol Metab 16: e13008.
    [132] Grizzanti J, Corrigan R, Casadesusa G (2018) Neuroprotective Effects of Amylin Analogues on Alzheimer's Disease Pathogenesis and Cognition. J Alzheimers Dis 66: 11-23. doi: 10.3233/JAD-180433
    [133] Alicic RZ, Neumiller JJ, Johnson EJ, et al. (2019) Sodium-Glucose Cotransporter 2 Inhibition and Diabetic Kidney Disease. Diabetes 68: 248-257. doi: 10.2337/dbi18-0007
    [134] Mullane K, Williams M (2019) Preclinical Models of Alzheimer's Disease: Relevance and Translational Validity. Curr Protoc Pharmacol 84: e57. doi: 10.1002/cpph.57
    [135] Antal Z, Baker JC, Smith C, et al. (2012) Beyond HLA-A*0201: new HLA-transgenic non-obese diabetic mouse models of type 1 diabetes identify the insulin C-peptide as a rich source of CD8+T cell epitopes. J Immunol 188: 5766-5775. doi: 10.4049/jimmunol.1102930
    [136] Serr P, Santamaria P (2019) Antigen-specific therapeutic approaches for autoimmunity. Nature Biotechnol 37: 238-251. doi: 10.1038/s41587-019-0015-4
    [137] Singer-Englar T, Barlow G, Mathur R (2018) Obesity, diabetes, and the gut microbiome: an updated review. Expert Rev Gastroenterol Hepatol 13: 3-15. doi: 10.1080/17474124.2019.1543023
    [138] Siljandera H, Honkanenb J, Knipa M (2019) Microbiome and type 1 diabetes. Ebiomedicine 46: 512-521. doi: 10.1016/j.ebiom.2019.06.031
    [139] Escós A, Risco A, Alsina-Beauchamp D, et al. (2016) p38γ and p38δ Mitogen Activated Protein Kinases (MAPKs), New Stars in the MAPK Galaxy. Front Cell Dev Biol 4: 31. doi: 10.3389/fcell.2016.00031
    [140] Cuenda A, Rousseau S (2007) p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta 1773: 1358-1375. doi: 10.1016/j.bbamcr.2007.03.010
    [141] Beardmore VA, Hinton HJ, Eftychi C, et al. (2005) Generation and characterization of p38beta (MAPK11) gene-targeted mice. Mol Cell Biol 25: 10454-10464. doi: 10.1128/MCB.25.23.10454-10464.2005
    [142] Remy G, Risco AM, Iñesta-Vaquera FA, et al. (2010) Differential activation of p38 MAPK isoforms by MKK6 and MKK3. Cell Signal 22: 660-667. doi: 10.1016/j.cellsig.2009.11.020
    [143] Jiang Y, Gram H, Zhao M, et al. (1997) Characterization of the structure and function of the fourth member of p38 group mitogen activated protein kinases, p38δJ Biol Chem 272: 30122-30128. doi: 10.1074/jbc.272.48.30122
    [144] Sumara G, Formentini I, Collinsetal S (2009) Regulation of PKD by the MAPK p38 delta in insulin secretion and glucose homeostasis. Cell 136: 235-248. doi: 10.1016/j.cell.2008.11.018
    [145] Lee JC, Laydon JT, McDonnelletal PC (1994) A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372: 739-746. doi: 10.1038/372739a0
    [146] Jiang Y, Chen C, Li Z, et al. (1996) Characterization of the structure and function of a new mitogen activated protein kinase (p38β). J Biol Chem 271: 17920-17926. doi: 10.1074/jbc.271.30.17920
    [147] Cuenda A, Rouse J, Dozaetal YN (1995) SB203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Letters 364: 229-233. doi: 10.1016/0014-5793(95)00357-F
    [148] Ramachandra CJ, Mehta A, Wong P, et al. (2016) ErbB4 Activated p38gamma MAPK isoform mediates early cardiogenesis through NKx2.5 in human pluripotent stem cells. Stem Cells 34: 288-298. doi: 10.1002/stem.2223
    [149] González-Terán B, López JA, Rodríguez E, et al. (2016) p38gamma and delta promote heart hypertrophy by targeting the mTOR-inhibitory protein DEPTOR for degradation. Nat Commun 7: 10477. doi: 10.1038/ncomms10477
    [150] Cuevas BD, Abell AN, Johnson GL (2007) Role of mitogen-activated protein kinase kinase kinases in signal integration. Oncogene 26: 3159-3171. doi: 10.1038/sj.onc.1210409
    [151] Cuenda A, Rousseau S (2007) p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta 1773: 1358-1375. doi: 10.1016/j.bbamcr.2007.03.010
    [152] Chang CI, Xu BE, Akella R, et al. (2002) Crystal structures of MAP kinase p38 complexed to the docking sites on its nuclear substrate MEF2A and activator MKK3b. Mol Cell 9: 1241-1249. doi: 10.1016/S1097-2765(02)00525-7
    [153] Biondi RM, Nebreda AR (2003) Signaling specificity of Ser/Thr protein kinases through docking-site-mediated interactions. Biochem J 372: 1-13. doi: 10.1042/bj20021641
    [154] Enslen H, Brancho DM, Davis RJ (2000) Molecular determinants that mediate selective activation of p38 MAP kinase isoforms. EMBO J 19: 1301-1311. doi: 10.1093/emboj/19.6.1301
    [155] Tomlinson DR (1999) Mitogen-activated protein kinases as glucose transducers for diabetic complications. Diabetologia 42: 1271-1281. doi: 10.1007/s001250051439
    [156] Begum N, Ragolia L (2000) High glucose and insulin inhibit VSMC MKP-1 expression by blocking iNOS via p38 MAPK activation. Am J Physiol Cell Physiol 278: C81-C91. doi: 10.1152/ajpcell.2000.278.1.C81
    [157] Chen S, Qiong Y, Gardner DG (2006) Aroleforp38mitogen-activatedproteinkinase and c-Myc inendothelin-dependent rat aortic smooth muscle cell proliferation. Hypertension 47: 252-258. doi: 10.1161/01.HYP.0000198424.93598.6b
    [158] Natarajan R, Scott S, Bai W, et al. (1999) Angiotensin II signaling in vascular smoothmuscle cells under high glucose conditions. Hypertension 33: 378-384. doi: 10.1161/01.HYP.33.1.378
    [159] Igarashi M, Wakasaki H, Takahara N, et al. (1999) Glucose or diabetes activates p38 mitogen-activated protein kinase via different pathways. J Clin Invest 103: 185-195. doi: 10.1172/JCI3326
    [160] Dorenkamp M, Riad AS, Stiehl S, et al. (2005) Protection against oxidative stress indiabetic rats: role of angiotensinAT1 receptor and beta 1-adrenoceptor antagonism. Eur J Pharmacol 520: 179-187. doi: 10.1016/j.ejphar.2005.07.020
    [161] Begum N, Ragolia L (2000) High glucose and insulin inhibit VSMC MKP-1 expression by blocking iNOS via p38 MAPK activation. Am J Physiol Cell Physiol 278: C81-C91. doi: 10.1152/ajpcell.2000.278.1.C81
    [162] Chen S, Qiong Y, Gardner DG (2006) A role for p38 mitogen-activated protein kinase and c-Myc in endothelin-dependent rat aortic smooth muscle cell proliferation. Hypertension 47: 252-258. doi: 10.1161/01.HYP.0000198424.93598.6b
    [163] Cain BS, Meldrum DR, Meng X, et al. (1999) p38 MAPK inhibition decreases TNF-α production and enhances post ischemic human myocardial function. J Surg Res 83: 7-12. doi: 10.1006/jsre.1998.5548
    [164] Communal C, Colucci WS, Singh K (2000) p38 mitogen-activated protein kinase pathway protects adult rat ventricular myocytes againstβ-adrenergic receptor-stimulated apoptosis. Evidence for Gi-dependent activation. J Biol Chem 275: 19395-19400. doi: 10.1074/jbc.M910471199
    [165] Liang Q, Molkentin JD (2003) Redefining the roles of p38 and JNK signaling in cardiac hypertrophy: dichotomy between cultured myocytes and animal models. J Mol Cell Cardiol 35: 1385-1394. doi: 10.1016/j.yjmcc.2003.10.001
    [166] Li M, Georgakopoulos D, Luetal G (2005) p38MAPkinase mediates inflammatory cytokine induction in cardiomyocytes and extracellular matrix remodeling in heart. Circulation 111: 2494-2502. doi: 10.1161/01.CIR.0000165117.71483.0C
    [167] Hu SS, Kong LZ, Gaoetal RL (2010) Outline of the report on cardiovascular disease in China. Biomed Environ Sci 25: 251-256.
    [168] Yang HS, Zheng QY, Duetal YY (2016) Influence of different acupoint combinations on immediate effect of surface electromyography of patients with cervical spondylosis. World J Acupunct Moxibustion 26: 7-13. doi: 10.1016/S1003-5257(17)30056-9
    [169] Pan YX, Chen KF, Lin YX, et al. (2013) Intracisternal administration of SB203580, a p38 mitogen-activated protein kinase tumor necrosis factor-alpha. J Clin Neurosci 20: 726-730. doi: 10.1016/j.jocn.2012.09.012
    [170] Wu S, Li J, Hong YQ, et al. (2012) Efects of electroacupuncture at Neiguan (PC 6) on p38 MAPK signaling pathway in rats with cardiac hypertrophy. Chin Acupunct Moxibustion 32: 145-148.
    [171] Du Y, Tang J, Li G, et al. (2010) Effects of p38 MAPK Inhibition on Early Stages of Diabetic Retinopathy and Sensory Nerve Function. Invest Ophthalmol Vis Sci 51: 2158-2164. doi: 10.1167/iovs.09-3674
    [172] Wang S, Ding L, Zheng Y, et al. (2016) The role of p38 MAPK in the development of diabetic cardiomyopathy. Int J Mol Sci 17: 1037. doi: 10.3390/ijms17071037
    [173] Muslin AJ (2008) MAPK signaling in cardiovascular health and disease: Molecular mechanisms and therapeutic targets. Clin Sci (Lond) 115: 203-218. doi: 10.1042/CS20070430
    [174] Radi ZA, Marusak RA, Morris DL (2009) Species comparison of the role of p38 MAPK in the female reproductive system. J Toxicol Pathol 22: 109-124. doi: 10.1293/tox.22.109
  • This article has been cited by:

    1. Milica Dima, Mirela Paraschivu, Elena Partal, Aurelia Diaconu, Reta Drăghici, Irina Titirica, The Impact of the Sowing Time on Peanuts Yield`s Components in Marginal Sandy Soils in Southern Oltenia, Romania, 2023, 40, 12224227, 307, 10.59665/rar4029
  • Reader Comments
  • © 2020 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

Metrics

Article views(6287) PDF downloads(100) Cited by(3)

Figures and Tables

Figures(3)  /  Tables(1)

Other Articles By Authors

/

DownLoad:  Full-Size Img  PowerPoint
Return
Return

Catalog