Synthesis of 2-acetamido-2-deoxy-3-O-β-d-mannopyranosyl-d-glucose

Condensation of 4,6-di-O-acetyl-2,3-O-carbonyl-α-d-mannopyranosyl bromide with benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-α-d-glucopyranoside (2) gave an α-d-linked disaccharide, further transformed by removal of the carbonyl and benzylidene groups and acetylation into the previously reported benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-3-O-(2,3,4,6-tetra-O-acetyl-α-d-mannopyranosyl)-α-d-glucopyranoside. Condensation of 3,4,6-tri-O-benzyl-1,2-O-(1-ethoxyethylidene)-α-d-glucopyranose or 2-O-acetyl-3,4,6-tri-O-benzyl-α-d-glucopyranosyl bromide with 2 gave benzyl 2-acetamido-3-O-(2-O-acetyl-3,4,6-tri-O-benzyl-β-d-glucopyranosyl)-4,6-O-benzylidene-2-deoxy-α-d-glucopyranoside. Removal of the acetyl group at O-2, followed by oxidation with acetic anhydride-dimethyl sulfoxide, gave the β-d-arabino-hexosid-2-ulose 14. Reduction with sodium borohydride, and removal of the protective groups, gave 2-acetamido-2-deoxy-3-O-β-d-mannopyranosyl-d-glucose, which was characterized as the heptaacetate. The anomeric configuration of the glycosidic linkage was ascertained by comparison with the α-d-linked analog.     

Syntheses of 2-acetamido-2-deoxy-4-O-βD-galacto-pyranosyl-D-mannose and -D-glucose and of 2-acetamido-2-deoxy-4-O-βD-mannopyranosyl-D-mannose and -D-glucose

2-acetamido-2-deoxy-4-O-β-D-galactopyranosyl-D-mannose (6) and -D-glucose (7) were prepared by addition of nitromethane to 3-O-β-D-galactopyranosyl-D-arabinose, followed by acetylation, ammonolysis, and application of the Nef reaction. Similarly, 2-acetamido-2-deoxy-4-O-β-D-mannopyranosyl-D-mannose (14) and -D-glucose (15) were prepared by the same scheme from 3-O-β-D-mannopyranosyl-D-arabinose. In the two series of experiments, 6 and 14 were the respective major products. Epimerization of the 2-acetamido-2-deoxy-D-mannose residue in 6 and 14 yielded 7 and 15, respectively.     

Synthesis of benzyl 2-acetamido-2-deoxy-3-O-β-d-fucopyranosyl-α-d-galactopyranoside and benzyl 2-acetamido-6-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-2-deoxy-3-O-β-d-fucopyranosyl-α-d-galactopyranoside

Condensation of benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-α-d-galactopyranoside with 2,3,4-tri-O-acetyl-α-d-fucopyranosyl bromide in 1:1 nitromethane-benzene, in the presence of powdered mercuric cyanide, afforded benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-3-O-(2,3,4-tri-O-acetyl-β-d-fucopyranosyl)-α-d-galactopyranoside (3). Cleavage of the benzylidene group of 3 with hot, 60% aqueous acetic acid afforded diol 4, which, on deacetylation, furnished the disaccharide 5. Condensation of diol 4 with 2-methyl-(3,4,6-tri-O-acetyl-1,2-di-deoxy-α-d-glucopyrano)-[2,1-d]-2-oxazoline in 1,2-dichloroethane afforded the trisaccharide derivative (7). Deacetylation of 7 with Amberlyst A-26 (OH^?) anion-exchange resin in methanol gave the title trisaccharide (8). The structures of 5 and 8 were confirmed by ¹³C-n.m.r. spectroscopy.     

Synthesis of phenyl 2-acetamido-2-deoxy-3-O-α-l-fucopyranosyl-β-d-glucopyranoside and related compounds

The reaction of phenyl 2-acetamido-2-deoxy-4,6- O-(p-methoxybenzylidene)-β-d-glucopyranoside with 2,3,4-tri-O-benzyl-α-l-fucopyranosyl bromide under halide ion-catalyzed conditions proceeded readily, to give phenyl 2-acetamido-2-deoxy-4,6-O-(p-methoxybenzylidene)-3-O-(2,3,4-tri-O-benzyl-α-l-fucopyranosyl)-β-d-glucopyranoside (8). Mild treatment of 8 with acid, followed by hydrogenolysis, provided the disaccharide phenyl 2-acetamido-2-deoxy-3-O-α-l-fucopyranosyl-β-d-glucopyranoside. Starting from 6-(trifluoroacetamido)hexyl 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranoside, the synthesis of 6-(trifluoroacetamido)hexyl 2-acetamido-2-deoxy-3-O-β-l-fucopyranosyl-β-d-glucopyranoside has been accomplished by a similar reaction-sequence. On acetolysis, methyl 2-acetamido-2-deoxy-3-O-α-l-fucopyranosyl-α-d-glucopyranoside gave 2-methyl-[4,6-di-O-acetyl-1,2-dideoxy-3-O-(2,3,4-tri-O-acetyl-α-l-fucopyranosyl)-α-d-glucopyrano]-[2, 1-d]-2-oxazoline as the major product.     

Synthesis of 2-O-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-D-mannose,and its interaction with D-mannose-specific lectins

Condensation of 3,4:5,6-di-O-isopropylidene-D-mannose dimethyl acetal with 2-methyl-(3,4,6-tri-O-acetyl- 1,2-dideoxy-α-D-glucopyrano)-[2′, 1′:4,5]-2-oxazoline in the presence of a catalytic amount of p-toluenesulfonic acid afforded crystalline 2-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyl)-3,4:5,6-di-O-isopropylidene-D-mannose dimethyl acetal (3) in 25% yield. Catalytic deacetylation of 3 with sodium methoxide, followed by hydrolysis with dilute sulfuric acid, gave 2-O-(2-acetamido-2-deoxy-α-D-glucopyranosyl)-D-mannose (4). Treatment of 3 with boiling 0.5% methanolic hydrogen chloride under reflux gave methyl 2-O-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-α-D-mannopyranoside (5) and methyl 2-O-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-α-D-mannofuranoside (6). The inhibitory activities of 4, 5, and 6 against the hemagglutinating and mitogenic activities of Lens culinaris and Pisum sativum lectins and concanavalin A were assayed. From the results of these hapten inhibition studies, subtle differences of specificity between these D-mannose-specific lectins were confirmed.     

Protective effects of Peroxiredoxin 6 overexpression on amyloid β-induced apoptosis in PC12 cells

Abstract

Oxidative stress triggered by amyloid beta (Aβ) accumulation contributes substantially to the pathogenesis of Alzheimer's disease (AD). In the present study, we examined the involvement of the antioxidant activity of peroxiredoxin 6 (Prdx 6) in protecting against Aβ_25–35-induced neurotoxicity in rat PC12 cells. Treatment of PC12 cells with Aβ_25-35 resulted in a dose- and time-dependent cytotoxicity that was associated with increased accumulation of intracellular reactive oxygen species (ROS) and mitochondria-mediated apoptotic cell death, including activation of Caspase 3 and 9, inactivation of poly ADP-ribosyl polymerse (PARP), and dysregulation of Bcl-2 and Bax. This apoptotic signaling machinery was markedly attenuated in PC12 cells that overexpress wild-type Prdx 6, but not in cells that overexpress the C47S catalytic mutant of Prdx 6. This indicates that the peroxidase activity of Prdx 6 protects PC12 cells from Aβ_25-35-induced neurotoxicity. The neuroprotective role of the antioxidant Prdx 6 suggests its therapeutic and/or prophylactic potential to slow the progression of AD and limit the extent of neuronal cell death caused by AD.     

Synthesis of 3-O-(2-acetamido-2-deoxy-3-O-β-d-galactopyranosyl-β-d-galactopyranosyl)-1,2-di-O-tetradecyl-sn-glycerol

Stereo- and regio-selective synthesis of 3-O-(2-acetamido-2-deoxy-3-O-β-d- galactopyranosyl-β-d-galactopyranosyl)-1,2-di-O-tetradecyl-sn-glycerol by use of 1,2-di-O-tetradecyl-3-O-(3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-d-galactopyranosyl)-sn-glycerol as a key intermediate is described.     

The protective effect of peroxiredoxin II on oxidative stress induced apoptosis in pancreatic β-cells

Cell signaling mediated by morphogens is essential to coordinate growth and patterning, two key processes that govern the formation of a complex multi-cellular organism. During growth and patterning, cells are specified by both quantitative and directional information. While quantitative information regulates cell proliferation and differentiation, directional information is conveyed in the form of cell polarities instructed by local and global cues. Major morphogens like Wnts play critical roles in embryonic development and they are also important in maintaining tissue homeostasis. Abnormal regulation of these signaling events leads to a diverse array of devastating diseases including cancer. Wnts transduce their signals through several distinct pathways and they regulate vertebrate embryonic development by providing both quantitative and directional information. Here, taking the developing skeletal system as an example, we review our work on Wnt signaling pathways in various aspects of development. We focus particularly on our most recent findings that showed that in vertebrates, Wnt5a acts as a global cue to establishing planar cell polarity (PCP). Our work suggests that Wnt morphogens regulate development by integrating quantitative and directional information. Our work also provides important insights in disease like Robinow syndrome, brachydactyly type B1 (BDB1) and spina bifida, which can be caused by human mutations in the Wnt/PCP signaling pathway.     

Synthesis of 2-acetamido-2-deoxy-4-O-β-d-galactopyranosyl-3-O-methyl-d-glucopyranose (N-acetyl-3-O-methyllactosamine) and its benzyl α-glycoside

Benzyl 2-acetamido-2-deoxy-3-O-methyl-α-d-glucopyranoside (3) was obtained by deacetalation of its 4,6-O-benzylidene derivative (2). Compound 2 was prepared by methylation of benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-α-d-glucopyranoside with methyl iodide-silver oxide in N,N-dimethylformamide. Diol 3 was selectively benzoylated and p-toluenesulfonylated, to give the 6-benzoic and 6-p-toluenesulfonic esters (4 and 5, respectively). Displacement of the sulfonyl group of 5 with sodium benzoxide in benzyl alcohol afforded the 6-O-benzyl derivative (6). Glycosylation of 4 with 2,3,4,6-tetra-O-acetyl-α-d-galactopyranosyl bromide (7) in dichloromethane, in the presence of 1,1,3,3-tetramethylurea, furnished the disaccharide derivative 8. Similar glycosylation of compound 6 with bromide 7 gave the disaccharide derivative 10. O-Deacetylation of 8 and 10 afforded disaccharides 9 and 11. The structure of compound 9 was established by ¹³C-n.m.r. spectroscopy. Hydrogenolysis of the benzyl groups of 11 furnished the disaccharide 2-acetamido-2-deoxy-4-O-β-d-galactopyranosyl-3-O-methyl-d-glucopyranose (N-acetyl-3-O-methyllactosamine).     

Use of 3-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-2,4,6-tri-O-acetyl-α-d-galactopyranosyl bromide as a glycosyl donor: Synthesis of p-nitrophenyl 3-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-β-d-galactopyranoside

Acetolysis of methyl 3-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-2,4,6-tri-O-acetyl-α-d-galactopyranoside afforded 3-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-1,2,4,6-tetra-O-acetyl-d-galactopyranose (2). Treatment of 2 in dichloromethane with hydrogen bromide in glacial acetic acid gave 3-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)- 2,4,6-tri-O-acetyl-α-d-galactopyranosyl bromide (3). The α configuration of 3 was indicated by its high, positive, specific rotation, and supported by its ¹H-n.m.r. spectrum. Reaction of 3 with Amberlyst A-26-p-nitrophenoxide resin in 1:4 dichloromethane-2-propanol furnished p-nitrophenyl 3-O-(2-acetamido-3,4,6- tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-2,4,6-tri-O-acetyl-β-d-galactopyranoside (7). Compound 7 was also obtained by the condensation (catalyzed by silver trifluoromethanesulfonate-2,4,6-trimethylpyridine) of 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-d-glucopyranosyl bromide with p-nitrophenyl 2,4,6-tri-O-acetyl-β-d-galactopyranoside, followed by the usual deacylation-peracetylation procedure. O-Deacetylation of 7 in methanolic sodium methoxide furnished the title disaccharide (8). The structure of 8 was established by ¹³C-n.m.r. spectroscopy.     

Comparison of morphological effects of PGE2 and TGFβ on osteoclastogenesis induced by RANKL in mouse bone marrow cell cultures

RANKL, in the presence of M-CSF, induces the development and fusion of TRAP+ osteoclasts in mouse bone marrow cultures at 3–5 days. Early during culture (day 3), most cells are small (up to six nuclei). At lower cell densities, these osteoclasts exhibit a rounded morphology with cytoplasm extending around the cells but, at higher densities, this changes to a stellate morphology with the cytoplasm being retracted around the nuclei with numerous localised cytoplasmic extensions. Under optimal conditions, osteoclast fusion results in conglomerates of many cells, which become large cytoplasmic masses on day 4. PGE2 and TGFβ have both been shown to increase osteoclast development in this model and their effects on the morphology of osteoclasts during fusion and differentiation have been compared under all these conditions. PGE2 or TGFβ increase osteoclast numbers and size and also the number of nuclei, indicating increased osteoclast development and fusion. TGFβ increases the size of rounded osteoclasts (with respect to the number of nuclei) more than PGE2, suggesting that TGFβ increases cytoplasmic extension. TGFβ increases the size and number of nuclei in stellate cells but particularly increases the number and length of the cytoplasmic extensions, in contrast to PGE2. Fusion of these extensions with other osteoclasts results in large networks of interconnected cells. On day 4, spreading cells develop but these are still interconnected by cytoplasmic links, a phenomenon not seen in control wells or after treatment with PGE2. TGFβ is more effective than PGE2 in increasing fusion in the formation of cell conglomerates and cytoplasmic masses. PGE2 decreases overall cell density resulting in additional indirect effects on osteoclast numbers and morphology. However, PGE2 particularly promotes the formation of large mature spreading osteoclasts later during culture.     

2-Deoxy-D-glucose impedes T cell–induced apoptosis of keratinocytes in oral lichen planus

Oral lichen planus (OLP) is a T cell–mediated immunoinflammatory disease. Glycolysis plays an essential role in T-cell immune responses. Blocking glycolytic pathway in activated T cells represents a therapeutic strategy for restraint of immunologic process in autoimmune disorders. 2-Deoxy-D-glucose (2-DG) has been widely used to probe into glycolysis in immune cells. This study was aimed to explore the role of glycolysis inhibition by 2-DG on regulating immune responses of OLP-derived T cells. We observed that lactic dehydrogenase A (LDHA) expression was elevated in OLP lesions and local T cells. 2-DG inhibited the expression of LDHA, p-mTOR, Hif1α and PLD2 in T cells; meanwhile, it decreased proliferation and increased apoptosis of T cells. T cells treated by 2-DG showed lower LDHA expression and elevated apoptosis, resulting in a reduced apoptotic population of keratinocytes that were co-cultured with them, which was related to the decreased levels of IFN-γ in co-culture system. Rapamycin enhanced the effects of 2-DG on immune responses between T cells and keratinocytes. Thus, these findings indicated that OLP-derived T cells might be highly dependent upon high glycolysis for proliferation, and 2-DG treatment combined with rapamycin might be an option to alleviate T-cell responses, contributing to reducing apoptosis of keratinocytes.     

Studies on the koenigs-knorr reaction : Part V. Synthesis of 2-acetamido-2-deoxy-3-O-α-L-fucopyranosyl-α-D-glucose

Optically pure 2-acetamido-2-deoxy-3-O-α-L-fucopyranosyl-α-D-glucose was synthesized by the Koenigs-Knorr reaction of 2-O-benzyl-3,4-di-O-p-nitrobenzoyl-α-L-fucopyranosyl bromide with benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-α-D-glucopyrainoside. Reaction of 2,3,4-tri-O-acetyl-α-L-fucopyranosyl bromide gave the β-L-fucopyranosyl anomer. In contrast to the stereospecificity shown in this reaction by these two bromides, 2,3,4-tri-O-benzyl-α-L-fucopyranosyl bromide afforded a mixture of α-L and β-L anomers in almost equimolar proportions. The disaccharides synthesized were crystallized and characterized, and their optical purity demonstrated by g.l.c. of the per(trimethylsilyl) ethers of the corresponding alditols.     

Synthesis of methyl 2-acetamido-2-deoxy-3-O-(β-d-galactopyranosyl)-α-d-galactopyranoside from a corresponding thioglycoside derivative

The title disaccharide glycoside was synthesized by halide ion-promoted glycosidation, using methanol and the disaccharide bromide derived from methyl 2-azido-3-O-(2,3,4,6-tetra-O-benzoyl--d-galactopyranosyl)-4,6-O-benzylidene-2-deoxy-1-thio--d-galactopyranoside. This derivative in turn was prepared by silver triflate-promoted condensation of monosaccharide derivatives.     

Characterization of thymocyte phenotypic alterations induced by long-lasting β-adrenoceptor blockade in vivo and its effects on thymocyte proliferation and apoptosis

Adult male Wistar rats were subjected to propranolol (P, 0.40 mg/100 g/day) or saline (S) administration (controls) over 14 days. The expression of major differentiation molecules on thymocytes and Thy-1 (CD90) molecules, which are shown to adjust thymocyte sensitivity to TCRαβ signaling, was studied. In addition, the sensitivity of thymocytes to induction of apoptosis and concanavalin A (Con A) signaling was estimated. The thymocytes from P-treated (PT) rats exhibited an increased sensitivity to induction of apoptosis, as well as to Con A stimulation. Furthermore, P treatment produced changes in the distribution of thymocyte subsets suggesting that more cells passed positive selection and further differentiated into mature CD4+ or CD8+ single positive (SP) TCRαβ^high cells. These changes may, at least partly, be related to the markedly increased density of Thy-1 surface expression on TCRαβ^low thymocytes from these rats. The increased frequency of cells expressing the CD4+25+ phenotype, which has been shown to be characteristic for regulatory cells in the thymus, may also indicate alterations in thymocyte selection following P treatment. Inasmuch as positive and negative selections play an important role in continuously reshaping the T-cell repertoire and maintaining tolerance, the hereby presented study suggests that pharmacological manipulations with β-AR signaling, or chemically evoked alterations in catecholamine release, may interfere with the regulation of thymocyte selection, and consequently with the immune response. (Mol Cell Biochem xxx: 1–13, 2005)     

Synthesis of and triplex formation in oligonucleotides containing 2′-deoxy-6-thioxanthosine

This study aimed to synthesize triplex-forming oligonucleotides (TFOs) containing 2′-deoxy-6-thioxanthosine (s⁶X) and 2′-deoxy-6-thioguanosine (s⁶Gs) residues and examined their triplex-forming ability. Consecutive arrangement of s⁶X and s⁶Gs residues increased the triplex-forming ability of the oligonucleotides more than 50 times, compared with the unmodified TFOs. Moreover, the stability of triplex containing a mismatched pair was much lower than that of the full-matched triplex, though s⁶X could form a s⁶X-GC mismatched pair via tautomerization of s⁶X. The present results reveal excellent properties of modified TFOs containing s⁶Xs and s⁶Gs residues, which may be harnessed in gene therapy and DNA nanotechnology.     

Differential protective effects of palmitoleic acid and cAMP on caspase activation and cell viability in pancreatic β-cells exposed to palmitate

Saturated and mono-unsaturated fatty acids exert differential effects on pancreatic β-cell viability during chronic exposure. Long chain saturated molecules (e.g. palmitate) are cytotoxic to β-cells and this is associated with caspase activation and induction of apoptosis. By contrast, mono-unsaturated fatty acids (e.g. palmitoleate) are not toxic and can protect against the detrimental effects of palmitate. In the present study, we show that the protective actions of palmitoleate in BRIN-BD11 β-cells result in attenuated caspase activation following exposure to palmitate and that a similar response occurs in cells having elevated levels of cAMP. However, unlike palmitoleate, elevation of cAMP was unable to prevent the cytotoxic actions of palmitate since it caused a diversion of the pathway of cell death from apoptosis to necrosis. Palmitoleate did not alter cAMP levels in BRIN-BD11 cells and the results suggest that a change in cAMP is not involved in mediating the protective effects of this fatty acid. Moreover, they reveal that attenuated caspase activation does not always correlate with altered cell viability in cultured β-cells and suggest that mono-unsaturated fatty acids control cell viability by regulating a different step in the apoptotic pathway from that influenced by cAMP.     

The biphasic effects of the oxLDL/β2GPI/anti-β2GPI complex on VSMC proliferation and apoptosis

In our previous study, the oxLDL/β₂GPI/anti-β₂GPI complex was demonstrated to further enhance the foam cell formation and migration of VSMC, as well as the expression of inflammatory cytokines, via the TLR4/NF-κB pathway. However, sparse information is available on other pro-atherogenic pathogenic effects of the oxLDL/β₂GPI/anti-β₂GPI complex, such as effects on proliferation and apoptosis. In the present study, we focused on the biphasic effects and underlying mechanisms of the oxLDL/β₂GPI/anti-β₂GPI complex on VSMC survival. The data showed that short exposure to the oxLDL/β₂GPI/anti-β₂GPI complex could activate NF-κB and ERK1/2 pathways and stimulate cell proliferation in VSMC. In contrast, longer exposure increased the level of p38 pathway activation and cell apoptosis. Additionally, the promotion effect of the oxLDL/β₂GPI/anti-β₂GPI complex on both proliferation and apoptosis, as well as signaling pathway activation, was stronger than that of the other control groups. The use of selective blockers showed that TLR4/NF-κB and ERK1/2 partly mediated oxLDL/β₂GPI/anti-β₂GPI complex-induced proliferation and had an inhibitory effect on complex-stimulated apoptosis. Conversely, TLR2/p38 partly mediated oxLDL/β₂GPI/anti-β₂GPI complex-induced apoptosis and had a negative effect on complex-stimulated proliferation. Specific inhibitors of NF-κB and ERK1/2 activation could augment the oxLDL/β₂GPI/anti-β₂GPI complex-induced phosphorylation of p38 and vice versa. Under pretreatment with NADPH oxidase inhibitors, intracellular ROS generation was confirmed to participate in oxLDL/β₂GPI/anti-β₂GPI complex-induced proliferation and apoptosis, as well as the phosphorylation of NF-κB and MAPKs. Taken together, our data clearly revealed that the oxLDL/β₂GPI/anti-β₂GPI complex had biphasic effects on VSMC survival, partly mediated by ROS-induced NF-κB and MAPKs activation. The TLR4/NF-κB and TLR2/p38 pathways played supporting roles in this dual effects-initiated signal network, and there is a trade-off relationship between the phosphorylation of NF-κB, ERK1/2 and p38. The dual effects of the oxLDL/β₂GPI/anti-β₂GPI complex on VSMC survival contribute to the development of the structure typical of atherosclerotic lesions, particularly focal excessive growth alternating with necrosis.     

Melphalan induced germ cell toxicity and dose-dependent effects of β-aminoisobutyric acid in experimental rat model: Role of oxidative stress,inflammation and apoptosis

The success of chemotherapy regimens has led to an increase in cancer survival rate over the last decades. Melphalan has been widely used for the treatment of several types of cancers despite its gonadotoxic effects. Due to its ability to cause mutations in the spermatogonial stem cells and spermatids, melphalan can exert a negative impact on male reproductive health in young cancer survivors. β-aminoisobutyric acid (BAIBA), a myokine released by skeletal muscles, has been reported to have beneficial effects in diabetic nephropathy, cardiomyopathy and hepatic toxicity. However, the exact role of BAIBA in chemotherapy-induced germ cell toxicity is still unexplored. The present study aims to determine the dose-dependent (25, 50, and 100 mg/kg) effects of BAIBA on melphalan-induced (1.5 mg/kg) germ cell toxicity in sprague−dawley (SD) rats. The evaluation parameters included quantification of oxidative stress biomarkers, sperm count, sperm motility and head morphology, sperm and testicular DNA damage, sperm mitochondrial membrane potential, ultrastructural changes in sperms, histological and protein expression studies in testes. Melphalan treatment significantly altered all the above-mentioned parameters and the high dose (100 mg/kg) of BAIBA restored melphalan-induced toxicity in a significant manner by exerting antioxidant, anti-inflammatory and antiapoptotic effects. However, the medium dose (50 mg/kg) of BAIBA decreased the toxicity of melphalan and the low dose (25 mg/kg) of BAIBA failed to counteract the melphalan-induced male germ cell toxicity as well as the peripheral blood micronucleus induction. The antioxidant, anti-inflammatory and antiapoptotic role of BAIBA in melphalan-induced gonadal damage is a novel finding in an experimental rat model.